WO1998015643A1 - Fragments de plasminogene efficaces pour inhiber la croissance de tumeurs et dissemination metastasique et procede de preparation desdits fragments - Google Patents

Fragments de plasminogene efficaces pour inhiber la croissance de tumeurs et dissemination metastasique et procede de preparation desdits fragments Download PDF

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WO1998015643A1
WO1998015643A1 PCT/JP1997/003635 JP9703635W WO9815643A1 WO 1998015643 A1 WO1998015643 A1 WO 1998015643A1 JP 9703635 W JP9703635 W JP 9703635W WO 9815643 A1 WO9815643 A1 WO 9815643A1
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plasminogen
heparin
lys
lbs
binding
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PCT/JP1997/003635
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English (en)
Japanese (ja)
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Wataru Morikawa
Seiji Miyamoto
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Juridical Foundation The Chemo-Sero-Therapeutic Research Institute
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Priority to AU45714/97A priority Critical patent/AU4571497A/en
Publication of WO1998015643A1 publication Critical patent/WO1998015643A1/fr
Priority to US11/378,647 priority patent/US20060147441A1/en

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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
    • C12N9/14—Hydrolases (3)
    • C12N9/48—Hydrolases (3) acting on peptide bonds (3.4)
    • C12N9/50—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25)
    • C12N9/64—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25) derived from animal tissue
    • C12N9/6421—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25) derived from animal tissue from mammals
    • C12N9/6424—Serine endopeptidases (3.4.21)
    • C12N9/6435—Plasmin (3.4.21.7), i.e. fibrinolysin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/01—Hydrolysed proteins; Derivatives thereof
    • A61K38/012—Hydrolysed proteins; Derivatives thereof from animals
    • A61K38/017—Hydrolysed proteins; Derivatives thereof from animals from blood
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Y—ENZYMES
    • C12Y304/00—Hydrolases acting on peptide bonds, i.e. peptidases (3.4)
    • C12Y304/21—Serine endopeptidases (3.4.21)
    • C12Y304/21007—Plasmin (3.4.21.7), i.e. fibrinolysin

Definitions

  • the present invention relates to a novel biologically active plasma protein fragment and a method for preparing the protein fragment. More specifically, the present invention relates to an elastomer of rice plasminogen (Lys-Plasminogen; hereinafter, sometimes referred to as "Lys-P1g.”), which is a kind of N-terminal modified plasminogen.
  • a plasminogen fragment having an inhibitory effect on tumor metastasis and proliferation which is preferably a fragment having a high heparin binding property, which is a digestion product, and a tumor metastasis and growth inhibitor comprising the plasminogen fragment as a main component
  • a method for preparing the plasminogen fragment is preferably a fragment having a high heparin binding property, which is a digestion product, and a tumor metastasis and growth inhibitor comprising the plasminogen fragment as a main component.
  • the elastase degradation product of Lys-P 1 g., Particularly the Lys-P 1 g. Fragment exhibiting high heparin binding, according to the present invention is represented in the fields of biochemistry and medicine, such as lung cancer and colon cancer. It is useful in the field of clinical treatment of solid cancer and the like.
  • Plasminogen is a plasma protein with a molecular weight of 800,000, and is a precursor to the enzyme plasmin involved in the blood coagulation and fibrinolysis systems. Plasminogen is a glycoprotein, and it is known that there are about 10 components having different isoelectric points due to differences in the sugar chain structure. Plasminogen itself has no enzymatic activity, but undergoes limited degradation by plasmin, perokinase, or plasminogen activator to be converted to the active form of plasmin, which breaks down fibrin clots It becomes more active. Plasminogen contains five kringle moieties (kringle 1 to kringle 5) and a serine protease domain with an active center (see FIGS. 1 and 2). Plasminogen also Since it can bind to lysine depending on the properties of the kringle portion, it can be specifically prepared using a lysine-binding carrier.
  • plasminogen is restricted by elastase to three sites in the serine protease domain, including the amino acid sequence 79Tyr to Kringle 3, the Kringle 4 site, and the Kringle 5 site. Generate Each of these three sites is a lysine binding site I
  • LBS-I Lysine Binding Site I
  • LBS-I lysine binding site ⁇
  • miniplasminogen mini—
  • Plasminogen (hereinafter sometimes referred to as “mini P 1 g.”) (Davidson JF et al., “Primary structure of human plasminogen: limited by elastase-catalyzed specific proteolysis. Isolation of lysine-binding fragment and "mini-one" plasminogen (Mw 38,000) (The primary structure of human plasminogen:
  • Plasminogen includes glulusminogen having a glutamic acid residue at the N-terminus (Glu-Plasminogen; hereinafter sometimes referred to as “G1u-P1g.”) And rice plasminogen having a lysine residue ( Lys—
  • Plasminogen; Lys-P 1 g.) Is known.
  • the former is an intact type of plasminogen, while the latter, as shown in Fig. 2, shows that Lys in the N-terminal region of G1 uP 1 g. s 76-Ly s 77 You.
  • Lys-P1g. In addition to those in which Lys is an N-terminal amino acid, those in which Va1 and Met are N-terminal amino acids are also detected. When these Lys-Plg and Glu-Pig. Are compared, Lys-P1g. Has a much higher activation rate by perokinase than G1u-P1g. Lys-P1 g.
  • Angiostatin a navel angiogenesis inhibitor that mediates the suppression of metastases by a lewis lung carcinoma) ⁇ Cell 79: 315-328, 1994).
  • the present inventors have proposed a plasminogen lysine binding site I (hereinafter referred to as rice-type lysine binding site I (Lys-LBS-I) obtained by treating G 1 u-P 1 g. To distinguish them, they may be referred to as “G1u-LBS-I”), and reproduction experiments were performed in accordance with their experiments. Some difference, but significant difference compared to control group I didn't do it.
  • plasminogen is treated with a certain substance (enzyme) before it is directly treated with elastase to obtain G1u-LBS-I
  • plasmin is digested with plasmin before elastase degradation to prepare a molecule whose N-terminal starts with a lysine residue, that is, Lys-P 1 g.
  • the rice-type lysine-binding site I (Lys-LBS-I) having a different N-terminal amino acid residue from the lysine-binding site I (G1u—LBS—I) of Oleilly et al.
  • Lys—P 1 g a degradation product of plasminogen degraded with plasmin, as a starting material. It was found that Lys-LBS-I obtained as described above had a strong tumor metastasis growth inhibitory effect. Furthermore, as a result of examining the substance of the substance exhibiting the tumor metastasis growth inhibitory effect, it was found that Lys-LBS-I was bound to the heparin carrier at a low ion intensity which is not observed in G1u-LBS-I. After G1u-P1g.
  • Lys-LBS-I which is produced by elastase degradation, has the effect of inhibiting the growth of tumor metastasis for the first time. Furthermore, they have found that a fragment having an angiogenesis inhibitory effect can be efficiently prepared using a carrier to which heparin is bound by utilizing the property of binding to heparin, and have completed the present invention.
  • the present invention relates to an elastase degradation product of Lys-P 1 g. It is intended to provide a plasminogen fragment having a tumor metastasis growth inhibitory effect, in which a fragment exhibiting particularly high heparin binding properties is a preferred embodiment.
  • the present invention also provides a method for preparing a plasminogen fragment having the tumor metastasis growth inhibitory effect.
  • the preparation method according to the present invention comprises the following steps: 1) Plasmin or the like is allowed to act on plasminogen to produce Lys-P 1 g .; 2) Lys-P 1 g. To obtain a fraction of kringle 3-containing fragment (Lys-LBS-I) from kringle 1; 3 of the obtained fractions, select a portion having strong binding to heparin, and obtain a desired tumor. A plasminogen fragment having a metastatic growth inhibitory effect is obtained.
  • the present invention further provides a tumor metastasis growth inhibitor comprising, as an active ingredient, a plasminogen fragment having the tumor metastasis growth inhibitory effect.
  • FIG. 1 is a schematic diagram showing a product obtained by elastase digestion of plasminogen.
  • FIG. 2 is a schematic diagram showing degradation products when plasminogen is subjected to elastase treatment after limited degradation with plasmin.
  • FIG. 3 is a graph showing the elution pattern of Lys-LBS-I by immunoaffinity mouth chromatography using heparin as a ligand.
  • FIG. 4 is a graph showing an elution pattern of G1u-LBS-I by immunoaffinity chromatography using heparin as a ligand.
  • FIG. 5 is a diagram showing the results of analysis of the heparin high-binding fraction of Lys-LBS-I by SDS-PAGE (gel electrophoresis).
  • FIG. 6 is a graph showing the heparin binding of Lys-LBS-I at various ⁇ .
  • Figure 7 shows suppression of lung metastasis growth of Lewis lung cancer using C57BL6ZJ mice 4 is a graph showing the effect of Lys-LBS-I in a test in comparison with G1u-LBS-I.
  • FIG. 8 is a graph showing the effect of Lys-LBS-I as compared to G1u-LBS-I in a test for inhibiting the growth of lung metastasis of Lewis lung cancer using skid (SCID) mice.
  • FIG. 9 is a graph showing the effect of Lys-LBS-I on inhibiting the tumor metastasis and growth of the fraction showing high heparin binding, as compared to the fraction not binding to heparin.
  • FIG. 1 shows a degradation product obtained by elastase digestion of plasminogen
  • FIG. 2 shows a degradation product obtained by digesting plasminogen according to the present invention with plasmin and then with elastase.
  • the plasminogen fragment having a tumor metastasis growth inhibitory effect of the present invention is Ly s-LBS-I obtained by elastase decomposition of Lys-P 1 g. Among them, a particularly strong tumor metastasis growth inhibitory effect is exhibited. Indicates high heparin binding.
  • Lys-LBS-I is a protein that is composed of kringles 1 to 3 whose N-terminal amino acid starts with 77 Lys and has a sugar chain-free molecular weight of 38 Kda on SDS polyacrylamide gel electrophoresis (PAGE). This shows stronger heparin binding as compared to other sugar chain-containing isoforms.
  • the fragment cannot bind to heparin at physiological ion concentrations (physiological conditions) in the neutral region, but has the characteristic that it can bind to heparin at physiological ion concentrations when the environment is acidic.
  • Heparin has an action of suppressing blood coagulation by binding to antithrombin m which is a plasma component. Heparin or heparin-like substances are widely distributed on vascular endothelial cells occupying the vascular lumen, and suppress extra coagulation in the blood vessel.
  • the heparin-binding property of the plasminogen fragment of the present invention is determined by the binding mode exemplified by the binding with lysine, which is required when plasminogen (plasmin) binds to fibrin or the like, which has been conventionally considered. In addition, it has the potential to directly bind to the vascular endothelial cells and exert some effect.
  • the heparin-binding property of the plasminogen fragment of the present invention must satisfy the necessary conditions for exerting an inhibitory effect on the function of vascular endothelial cells. I can say.
  • the plasminogen fragment of the present invention cannot bind to heparin or a heparin-like substance under physiological conditions (isotonic state), but has non-physiological conditions in which the environmental pH is reduced. Underneath, it has the property of acquiring heparin binding. Therefore, as reported by Jane et al., In an acidic environment such as in a tumor, the plasminogen fragment of the present invention binds to heparin or heparin-like substance in the tumor, and as a result, It seems to act specifically on the ulcer.
  • the mechanism by which the plasminogen fragment of the present invention suppresses the growth of tumor cells is unknown, but considering its structure, it may be due to competitive inhibition of plasmin action.
  • plasminogen fragments directly inhibit the proliferation of vascular endothelial cells. They found that tumor-bearing animals transplanted with Lewis lung cancer produced potent angiogenesis inhibitors in their blood and urine, purified this substance and named it angiostatin. did.
  • the angiostatin showed extremely high homology with the internal fragment of plasminogen, and it was reported that purified human LBS-I (G1u-LBS-I) showed similar activity.
  • the human LBS-I is a substance having three isoforms having a molecular weight of 38 Kda to 42.5 Kda, and is noted for showing high homology with the plasminogen fragment of the present invention.
  • the plasminogen fragment of the present invention does not contain a sugar chain, and significantly inhibits the growth of distant metastatic tumor cells as compared with other isoforms containing a sugar chain.
  • the plasminogen fragment of the present invention has a clear difference in physical properties and biological activity such as not exhibiting the effect of suppressing the growth of vascular endothelial cells as much as angiostin.
  • the method for producing the plasminogen fragment of the present invention is not particularly limited, and includes, for example, a method comprising the following steps: (1) Lys-P 1 g.
  • the solution containing 1 g of Lys-P is treated with elastase to obtain a fraction of a fragment containing kringle 3 from kringle 1 (Lys-LBS-I); 3 of the obtained fractions, A portion having a strong binding property to heparin is selected to obtain a plasminogen fragment having a desired tumor metastasis growth inhibitory effect.
  • plasminogen is separated from a blood sample, and Lys-Pig. Is prepared from the obtained plasmaminogen.
  • Blood-derived plasmino The following method is mentioned as a method for producing one gene.
  • a method of Deutsch (DG) purifying by affinity chromatography using a lysine carrier (Deutsch, DG, Science 170: 1095, 1970) and a modified method thereof (Blockway ( Brockway.W.J.) Et al., Arch. Biochem. Biophys. 151: 194, 1972).
  • aprotinin (2 OUZm 1) and EDTA (2.5 mM) are added to fresh plasma and mixed, then bound to a lysine carrier, and a buffer solution containing 0.1 M Na C 1 /2.5 mM EDTAZ20U aprotinin / m 1, Further, after washing with the same buffer solution containing a surfactant, elution with 6-aminohexanoic acid makes it possible to prepare high-purity plasminogen. Finally, purification and concentration are performed using an ultrafiltration membrane (for example, YM10: manufactured by Amicon).
  • an ultrafiltration membrane for example, YM10: manufactured by Amicon
  • plasminogen in its full molecular form is present in the blood, and there is little Lys-P1 g. Whose N-terminal residue is lysine. Therefore, for the purpose of the present invention, a step of converting the complete molecular form of plasminogen to Lys-P 1 g. Is required. As a method for this conversion, a method of directly acting plasminogen on plasminogen is used. (Ruzy Jungberg
  • a preferable method is to incubate plasminogen in the presence of tranexamic acid, autolyze it, and prepare Lys-P The method of preparing 1 g. Is recommended.
  • Lys-P obtained is digested with elastase, and a molecule (Lys-LBS-I) containing 1 to 3 kringles of Lys-P is recovered from the resulting fragment.
  • a molecule Lys-LBS-I
  • good preparation of Lys-LBS-I is achieved, for example, by a gel filtration method using Sephadex G-75 and a subsequent lysine-affinity chromatography.
  • the obtained Lys-LBS-I is contacted with a resin using heparin as a ligand to obtain a bound fraction, whereby a fraction that strongly binds to heparin can be specifically prepared.
  • the plasminogen fragment of the present invention can also be produced directly based on gene recombination techniques. That is, Lys-plasminogen-producing cells are constructed by gene recombination technology, and Lys-plasminogen thus prepared is fragmented with elastase, or the plasminogen fragment (Ly- s-LBS-I) is directly introduced into a suitable host cell such as a eukaryotic cell, a mammalian cell or an insect cell using a suitable vector or the like to constantly produce a desired plasminogen fragment. As a result, Lys-LBSI-I can be prepared.
  • the plasminogen fragment of the present invention prepared by the above-mentioned method should be used fresh to maintain the activity to the maximum, or within 5 words after storage when stored at 4 ° C. It is preferred to use
  • the plasminogen fragment of the present invention can also be stored in lyophilized or liquid form with suitable stabilizers such as human albumin, gelatin, salts, sugars or amino acids, and furthermore, plasminogen. It is also possible to freeze and store the gene fragment solution.
  • Heat treatment of lyophilized or liquid state under specified conditions for example, lyophilized state at 65 ° C for 96 hours, and liquid state at 60 ° C for 10 hours, is required from the viewpoint of drug safety. This is a very preferred embodiment.
  • the plasminogen fragment of the present invention can be used as a tumor metastasis growth inhibitor by using the fragment as an active ingredient and combining it with a known suitable excipient.
  • the effective dose of the tumor metastasis / proliferation inhibitor comprising the plasminogen fragment of the present invention as an active ingredient varies depending on various factors, for example, the age, symptoms, and severity of the administration subject. Depending on the judgment, it may be generally in the range of 50 to 50 mg / day for an adult, preferably 100 to 300 mg / day in 1 to 2 divided doses.
  • the best mode of administration is a single large dose (bolus) or intravenous drip. It is also possible to use the antitumor agent in combination with the antitumor agent provided by the present invention, which is a preferred embodiment.
  • the solution was passed through a lysine-sepharose 4B column (inner diameter 5.0 ⁇ 30 cm; manufactured by Pharmacia) at a flow rate of 1.0 m1 equilibrated with (pH 7.5), and further washed with 5 volumes of the same buffer. Thereafter, the buffer was replaced with the same buffer containing 1 OmM aminohexanoic acid to perform elution. The eluate was dialyzed overnight at 4 ° C against 0.1 M ammonium carbonate buffer.
  • Example 3 After the eluate obtained by the chromatographic operation of Example 1 was concentrated, it was dialyzed overnight against 5 OmM Tris / ⁇ 2 OmM citrate buffer (pH 6.5), and ImM tranexamic acid was added to the concentrate. Incubated overnight at 30 ° C.
  • Example 3
  • reaction was carried out while stirring at 5 ° C overnight. After completion of the reaction, the reaction solution was filtered with a glass filter, and the filtrate was passed through resin-sepharose (Pharmacia) equilibrated with 0.1 M, and then washed with the same buffer. The lysine-cepharose-bound fraction was eluted with the same buffer containing 2 OmM aminohexanoic acid. The eluate was concentrated on an ultrafiltration membrane (YM-10; Amicon) and equilibrated with 0.1 M ammonium carbonate buffer (Sephadex G-75 column (5.0 x 40 cm id; Pharmacia)) And G 1 u—resin binding site I
  • Glu-LBS-I Lys-lysine binding site I
  • Lys-LBS-I Lys-LBS-I
  • the G 1 u-LB S-I and Lys-LB S-I obtained by the method described in Example 4 were used for immunoaffinity chromatography using heparin as a ligand (high trap heparin (Hi trap trap Heparin) (trade name; manufactured by Pharmacia), and the protein in the heparin-bound fraction obtained by performing a concentration gradient elution based on the salt concentration is monitored by absorbance, and the heparin affinity and amount are measured. The ratios were compared.
  • FIGS. 3 and 4 The results of heparin affinity are shown in FIGS. 3 and 4.
  • Lys-LBS-I is divided into a non-heparin-binding fraction, a medium-binding fraction, and a high-binding fraction, while G1u-LBS-I is a high-binding fraction. No part corresponding to was found (Fig. 4).
  • SDS-PAGE of 12.5% of the high binding fraction of heparin showed that its molecular weight was around 38 kda, which was consistent with the molecular weight of LBS-I containing no sugar chain (FIG. 5).
  • the plasminogen used as the raw material did not dissolve in the equilibration buffer composition, and the same operation could not be performed.
  • Lys-LBS-I obtained by the method shown in Example 4 was subjected to immunoaffinity chromatography using heparin as a ligand at a physiological salt concentration in the range of pH 5.0 to 7.2 (high trap heparin). Pharmacia) to determine the binding to heparin.
  • Lys-LBS-I (lmg / ml) dissolved in the chromatresin lm1 equilibrated with a citrate buffer (pH 5.0 to 7.2) containing 15 OmM NaC1 with the same buffer was washed with 1 Oml of the same buffer under the conditions of a flow rate of 0.5 m1Z, and eluted with 10 ml of 1 M NaC1 / citrate buffer (pH 5.0 to 7.2).
  • FIG. 6 shows the relationship between the heparin binding property of Lys-LBS-I and pH. As shown in the figure, Lys-LBS-I cannot bind to heparin near neutral under isotonic conditions, but as pH decreases, heparin's binding property increases. All the fractions bound to heparin under the condition of pH 5.0.
  • Example 4 G1u-LBS-I and Lys-LBS-I obtained in Example 4 were dialyzed overnight against Tris buffer (pH 7.2) containing 50 mM NaCl, and then the heparin affinity gel of Example 5 was used. A chromatographic operation was performed to prepare a heparin-binding fraction at a concentration of 1 Omg / ml.
  • Cancer cells are from Lewis Lung Cancer LL 2 (Bertram, JS) and others. Establishment of a cloned line of Lewis Lung uarcinoma cells adapted to cell culture: Cancer Lett. Vol.11, 63-73, 1980) was purchased from Dainippon Pharmaceutical Co., Ltd. and used after continuous cultivation and passage in high-concentration glucose-DMEM medium Zl 0% FCS.
  • mice 6 weeks old male mice C57BL 6ZJ
  • 100 1 Lewis lung carcinoma 107 cells Zm 1 were implanted subcutaneously on the back, were housed 15 to 18 days. Thereafter, the formed primary lesion was removed by a surgical operation, and the skin was sutured.
  • Mice are divided into three groups and bred for 14 days, taking into account body weight and primary tumor weight After that, in each group, Lys-LBS-I 0.5 mg / kg prepared in Example 4 and G1 ⁇ -LBS-I 0.5 mg / kg, and saline 1001 as a control group daily for 10 days It was administered intraperitoneally. After the administration, the lungs of the mice were excised and their weights were compared. The statistical processing used nonparametric analysis.
  • the lung weight of the control group (physiological saline) -administered group was 0.705 ⁇ 0.411 g, whereas the weight of the Lys-LBS-I-administered group was 0.247 ⁇ 0.05 g, and Lys- LBS-I Significantly inhibited metastatic growth of cancer.
  • the G 1 u—LB S—I administration group weighed 0.406 ⁇ 0.186 g, and no significant difference was observed.
  • mice were replaced with immunodeficient animal skid (SCID) mice, and lung metastatic growth was similarly evaluated.
  • SCID immunodeficient animal skid
  • FIG. 8 shows the results of the model of the present example in which the effect of immunity due to continuous administration of a heterologous protein was considered.
  • Lung weights of the control group, saline administration group, Lys-LBS-I administration group and G1u-LBS-I administration group were 0.522 ⁇ 0.232g, 0.217 ⁇ 0.019g and 0.324 ⁇ 0.152g, respectively. And the same results as in Example 8 were obtained.
  • FIG. 9 shows the results of evaluating the tumor metastasis growth inhibitory effect of the heparin-binding fraction and the heparin non-binding fraction prepared by the method of Example 7 in the same manner as in Example 8.
  • the lung weight of the control group (physiological saline) administration group was 0.689 ⁇ 0.250 g, while the weight of the heparin-binding fraction administration group was 0.248 ⁇ 0.05 g.
  • the heparin-bound fraction significantly suppressed metastatic growth of cancer.
  • the value was 0.515 ⁇ 0.208 g, and no significant difference was observed.

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Abstract

Fragments d'un plasminogène efficaces pour inhiber la croissance tumorale et la dissémination métastasique, procédé de préparation desdits fragments et inhibiteur de la croissance tumorale et de la dissémination métastasique contenant ces fragments en tant que principe actif. Lesdits fragments sont obtenus à partir du produit d'hydrolyse, induit par l'élastase, de plasminogène Lys, lui-même obtenu par traitement d'un plasminogène à l'aide d'une plasmine, et ils ont de préférence une activité puissante de liaison de l'héparine. Ledit inhibiteur est utile pour la thérapie clinique de cancers solides, tels que les cancers du poumon et du colon.
PCT/JP1997/003635 1996-10-09 1997-10-09 Fragments de plasminogene efficaces pour inhiber la croissance de tumeurs et dissemination metastasique et procede de preparation desdits fragments WO1998015643A1 (fr)

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US11/378,647 US20060147441A1 (en) 1996-10-09 2006-03-20 Plasminogen fragment having activity to inhibit tumor metastasis and growth and process for preparing same technical field

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JP28765196A JP3806471B2 (ja) 1996-10-09 1996-10-09 腫瘍転移増殖抑制効果を有するプラスミノーゲン断片および該断片の調製方法
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EP4190911A4 (fr) * 2020-08-20 2024-03-13 Talengen Int Ltd Procédé et médicament pour le traitement des tumeurs

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EP4190911A4 (fr) * 2020-08-20 2024-03-13 Talengen Int Ltd Procédé et médicament pour le traitement des tumeurs

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