WO2022037687A1 - 一种治疗肿瘤的方法和药物 - Google Patents
一种治疗肿瘤的方法和药物 Download PDFInfo
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- WO2022037687A1 WO2022037687A1 PCT/CN2021/113850 CN2021113850W WO2022037687A1 WO 2022037687 A1 WO2022037687 A1 WO 2022037687A1 CN 2021113850 W CN2021113850 W CN 2021113850W WO 2022037687 A1 WO2022037687 A1 WO 2022037687A1
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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
- A61K38/43—Enzymes; Proenzymes; Derivatives thereof
- A61K38/46—Hydrolases (3)
- A61K38/48—Hydrolases (3) acting on peptide bonds (3.4)
- A61K38/482—Serine endopeptidases (3.4.21)
- A61K38/484—Plasmin (3.4.21.7)
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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
- A61K38/43—Enzymes; Proenzymes; Derivatives thereof
- A61K38/46—Hydrolases (3)
- A61K38/48—Hydrolases (3) acting on peptide bonds (3.4)
- A61K38/49—Urokinase; Tissue plasminogen activator
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- 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 the role of components of plasminogen activation pathway, such as plasminogen, in preventing and treating tumors, thereby providing a new therapeutic strategy for preventing and/or treating tumors.
- Malignant tumor is a disease that seriously threatens human health.
- cancer is the leading cause of death in developed countries, accounting for 21.6% of all deaths.
- WHO statistics in the past few years, the number of patients who died of cancer in the world has reached more than 7 million every year, which is very close to the number of cardiovascular diseases, and is expected to surpass the number of cardiovascular diseases and become the world's largest cause of death.
- the incidence of tumors remains high and is on the rise, which has seriously threatened life and health.
- the pathogenesis of tumors is complex, the effect of tumor treatment is poor, the recurrence and metastasis rate is high, and the side effects of tumor treatment are large. Therefore, its prevention and treatment It is also difficult to study.
- the present invention finds that the components of the plasminogen activation pathway, such as plasminogen, have obvious inhibitory effect on the growth of tumors, and may become a new approach for the prevention and treatment of tumors.
- the present application relates to a method of treating tumors, comprising administering to a subject an effective amount of one or more compounds selected from the group consisting of components of the plasminogen activation pathway, capable of directly activating fibrinolysis Zymogens or compounds that activate plasminogen indirectly by activating upstream components of the plasminogen activation pathway, compounds that mimic the activity of plasminogen or plasmin, are capable of upregulating plasminogen or Antagonists of plasminogen activator-expressed compounds, plasminogen analogs, plasmin analogs, tPA or uPA analogs, and fibrinolysis inhibitors.
- one or more compounds selected from the group consisting of components of the plasminogen activation pathway capable of directly activating fibrinolysis Zymogens or compounds that activate plasminogen indirectly by activating upstream components of the plasminogen activation pathway, compounds that mimic the activity of plasminogen or plasmin, are capable of upregulating plasminogen or Antagonists of plasminogen activ
- the present application also relates to the use of one or more compounds selected from the group consisting of components of the plasminogen activation pathway, capable of directly activating plasminogen or by activating fibers in the preparation of a medicament for the treatment of tumors.
- Compounds that indirectly activate plasminogen by activating upstream components of the protein lysinogen pathway compounds that mimic the activity of plasminogen or plasmin, and are capable of upregulating plasminogen or plasminogen activation
- the present application also relates to the use of one or more compounds selected from the group consisting of or a pharmaceutical composition comprising one or more compounds selected from the group consisting of: a component of the plasminogen activation pathway , Compounds capable of directly activating plasminogen or indirectly activating plasminogen by activating upstream components of the plasminogen activation pathway, compounds that mimic the activity of plasminogen or plasmin, Compounds that up-regulate plasminogen or plasminogen activator expression, plasminogen analogs, plasmin analogs, tPA or uPA analogs, and antagonists of fibrinolysis inhibitors.
- a component of the plasminogen activation pathway Compounds capable of directly activating plasminogen or indirectly activating plasminogen by activating upstream components of the plasminogen activation pathway, compounds that mimic the activity of plasminogen or plasmin, Compounds that up-regulate plasminogen or plasminogen activator expression, plasminogen analogs
- the components of the plasminogen activation pathway are selected from the group consisting of plasminogen, recombinant human plasmin, Lys-plasminogen, Glu-plasminogen, fiber Protease, plasminogen and plasmin variants and analogs containing plasminogen and one or more kringle domains and protease domains of plasmin, small plasminogen (mini-plasminogen), small plasmin (mini-plasmin), micro-plasminogen (micro-plasminogen), micro-plasmin (micro-plasmin), delta-plasminogen, delta-plasmin (delta-plasmin), plasminogen activator, tPA and uPA.
- the antagonist of the fibrinolysis inhibitor is an inhibitor of PAI-1, complement C1 inhibitor, alpha2 antiplasmin, or alpha2 macroglobulin, eg, an antibody.
- the compound is plasminogen.
- the present application provides a method of treating a tumor comprising administering an effective amount of plasminogen to a tumor subject.
- the tumor is a malignant tumor.
- the tumor is cancer.
- the tumor is a solid tumor.
- the tumor is a tumor of the digestive system or a tumor of the respiratory system.
- the tumor is selected from one or more of the following: oral cancer, esophageal cancer, gastric cancer, small bowel cancer, colon cancer, rectal cancer, lung cancer, liver cancer, hepatocellular carcinoma, pancreatic cancer, gallbladder cancer, Non-Small Cell Lung (NSCL) Cancer, Bronchoalveolar Cell Lung Cancer, Breast Cancer, Ovarian Cancer, Cervical Cancer, Fallopian Tube Cancer, Endometrial Cancer, Vaginal Cancer, Prostate Cancer, Urethral Cancer, Penile Cancer, Kidney Cancer, Ureteral Cancer, Kidney Cancer Cell carcinoma, renal pelvis, bladder, head and neck, skin, melanoma, mesothelioma, bone, thyroid, parathyroid, adrenal, soft tissue sar
- the plasminogen described herein has one or more effects selected from the group consisting of: reducing tumor volume, improving general survival of tumor subjects, delaying tumor progression, inhibiting tumor cell proliferation growth, improve survival rate, prolong the survival of tumor subjects, reduce cancer pain, inhibit tumor angiogenesis, promote tumor cell necrosis or apoptosis, promote anti-tumor immune response, regulate the expression of tumor-associated antigens or lymphocyte surface molecules, Reduce the damage of cancer cells to tissues and organs, and promote the recovery of tumor tissue structure or function.
- the subject's plasminogen level or plasminogen level in tumor tissue or tissue without tumor is higher, equal to or lower than healthy subject plasminogen level or plasminogen levels in corresponding tissues without tumors.
- the subject's fibrin level or fibrin level in tumor tissue or in tumor-free tissue is greater than, equal to, or lower than a healthy subject's fibrin level or the corresponding tumor-free tissue Fibrin levels in tissues.
- the plasminogen is administered in combination with one or more selected from the group consisting of chemotherapy, radiation therapy, surgical therapy, cell therapy, and immunotherapy.
- the chemotherapeutic drugs include, for example, alkylating agents, antimetabolites (eg, folate analogs), pyrimidine analogs, purine analogs, antimitotic drugs, antibiotics, cytokines, platinum coordination complexes, substitutions urea, hormones, adrenal corticosteroid antagonists, anti-estrogens, anti-androgens, etc.
- the plasminogen is selected from the group consisting of Glu-plasminogen, Lys-plasminogen, microplasminogen, microplasminogen, delta-plasminogen, or their conserved Substitution variant.
- the plasminogen is a plasminogen protein comprising a serine protease domain and/or a lysine binding domain.
- the plasminogen comprises at least 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% sequence identity to sequence 14, and plasminogen protein with protein level activity.
- the plasminogen has at least 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% with sequence 2, 6, 8, 10 or 12 % sequence identity and still have plasminogen activity.
- the plasminogen described herein is selected from the group consisting of Glu-plasminogen, Lys-plasminogen, microplasminogen, microplasminogen, delta-plasminogen, or their variants that retain plasminogen activity.
- the plasminogen is based on sequence 2, 6, 8, 10 or 12 with additions, deletions and/or substitutions of 1-100, 1-90, 1-80, 1-70 , 1-60, 1-50, 1-45, 1-40, 1-35, 1-30, 1-25, 1-20, 1-15, 1-10, 1-5, 1-4, 1 -3, 1-2, 1 amino acid protein that still has plasminogen activity.
- the plasminogen is natural or synthetic human plasminogen, or a variant or fragment thereof that still retains plasminogen activity.
- the plasminogen is a human plasminogen ortholog from a primate or rodent or a variant or fragment thereof that still retains plasminogen activity.
- the amino acid of the plasminogen is shown in sequence 2, 6, 8, 10 or 12.
- the plasminogen is human native plasminogen.
- the subject is a human. In some embodiments, the subject is low, deficient or deficient in plasminogen. In some embodiments, the deficiency, deficiency or deletion is congenital, secondary and/or local.
- the pharmaceutical composition comprises a pharmaceutically acceptable carrier and plasminogen for use in the aforementioned methods.
- the kit may be a prophylactic or therapeutic kit comprising: (i) plasminogen for use in the aforementioned methods and (ii) for delivering the plasminogen to the the subjects' means.
- the member is a syringe or vial.
- the kit further comprises a label or instructions for administering the plasminogen to the subject to perform any of the foregoing methods.
- the article of manufacture comprises: a container comprising a label; and comprising (i) plasminogen or a pharmaceutical composition comprising plasminogen for use in the aforementioned methods, wherein the label indicates that the plasminogen is to be The lysinogen or composition is administered to the subject to perform any of the foregoing methods.
- the kit or article of manufacture further comprises one or more additional components or containers that contain other medicaments.
- the other drug is an antineoplastic drug.
- the plasminogen can be treated by systemic or topical administration, preferably by intravenous, intramuscular, subcutaneous administration of plasminogen. In some embodiments of the foregoing methods, the plasminogen is administered in combination with a suitable polypeptide carrier or stabilizer.
- the plasminogen is administered at 0.0001-2000 mg/kg, 0.001-800 mg/kg, 0.01-600 mg/kg, 0.1-400 mg/kg, 1-200 mg/kg, 1-100 mg per day /kg, 10-100mg/kg (calculated per kilogram of body weight) or 0.0001-2000mg/cm2, 0.001-800mg/cm2, 0.01-600mg/cm2, 0.1-400mg/cm2, 1-200mg/cm2, 1-100mg/ cm2, doses of 10-100 mg/cm2 (calculated per square centimeter of body surface area) are administered, preferably repeated at least once, preferably at least daily.
- the present invention explicitly covers all combinations of technical features belonging to the embodiments of the present invention, and these combined technical solutions have been explicitly disclosed in this application, just as the above-mentioned technical solutions have been separately and explicitly disclosed.
- the present invention also explicitly covers the combination of each embodiment and its elements, and the technical solution after the combination is explicitly disclosed herein.
- Figure 2 Calculation results of tumor volume changes after plasminogen was administered to the tail vein of colon cancer model mice. The difference between the tumor volume on the 20th day and the tumor volume on the 10th and 13th days and the difference between the tumor volume on the 24th day and the tumor volume on the 10th day were calculated. The results showed that the increase in tumor volume in the plasminogen group was significantly smaller than that in the vehicle PBS control group, and the difference was statistically significant (* means P ⁇ 0.05).
- FIG. 3A-B Representative images of immunohistochemical staining of CD31 in tumor masses after 29 days of plasminogen administration in the tail vein of colon cancer model mice.
- Fig. 3A is the control group given vehicle PBS
- Fig. 3B is the group given plasminogen.
- the results showed that the expression of CD31 (marked by arrow) in the tumor tissue of the plasminogen group was significantly lower than that of the vehicle PBS control group. This indicates that plasminogen can inhibit the expression of vascular endothelial cell marker CD31 in tumor tissue, suggesting that plasminogen can inhibit the formation of new blood vessels in colon cancer tumor tissue.
- Figure 4A-B Representative pictures of LYVE-1 immunohistochemical staining in tumor tissue after 29 days of plasminogen administration in the tail vein of colon cancer model mice.
- Figure 4A is the control group given vehicle PBS
- Figure 4B is the group given plasminogen.
- the results showed that the expression of LYVE-1 (marked by arrow) in the tumor tissue of the plasminogen group was significantly lower than that of the vehicle PBS control group. It is suggested that plasminogen can inhibit the formation of lymphatic vessels in colon cancer and the metastasis of cancer tissue.
- Figure 5A-D Representative images of H&E staining of tumor mass in colon cancer model mice 29 days after plasminogen was administered to the tail vein.
- Figures 5A and C are the PBS-administered control group
- Figures 5B and D are the plasminogen-administered groups.
- the results showed that the colon cancer subcutaneous masses in the plasminogen group and the vehicle PBS group showed different degrees of necrosis, and the plasminogen group had more severe necrosis and wider necrosis area than the vehicle PBS group.
- the number of tumor cells in the non-necrotic area treated with plasminogen was significantly less than that in the control group treated with vehicle PBS.
- Figure 6A-B The results of tumor volume measurement after administration of plasminogen or vehicle to colon cancer model mice and the results of the difference in tumor volume between the two groups of mice on the 13th day and the 4th day.
- A is the measurement result of tumor volume
- B is the result of the difference in tumor volume between the two groups of mice on the 13th day and the 4th day.
- the difference in tumor volume between the vehicle group and the plasminogen-administered group on the 13th day and the 4th day was compared and analyzed.
- FIG. 7 The results of the mechanical allodynia-induced pain sensitivity test on the seventh day after plasminogen was administered to the tail vein of the lung cancer model mice.
- the results showed that the pain threshold of the mice in the blank control group was normal, and the pain threshold of the vehicle group was increased. Compared with the vehicle group, the pain perception threshold of the mice in the plasminogen group was significantly lower, and the statistical P value of the two groups was 0.003, and The pain threshold of the administration group was close to that of the blank control group.
- the results showed that plasminogen could significantly improve the pain sensitivity of lung cancer model mice.
- Figure 8A-B Representative pictures were taken of lung cancer model mice on the 20th day after plasminogen was administered to the tail vein.
- Figure A is the vehicle-administered control group
- Figure B is the plasminogen-administered group.
- the picture shows that on the 20th day, the mice in the PBS control group were given the vehicle to stand up, with slow movement, lethargy, severe rupture of the tumor, and obvious ulceration and bleeding of the tumor wound (marked by arrows); the mice in the plasminogen group moved freely and had a good mental state. , The tumor has no obvious ulceration, and there is a small amount of scab on the tumor epidermis.
- the results indicate that plasminogen can improve the general physical condition and mental state of lung cancer model mice.
- Fig. 12 Results of the boundary resting time rate in the open field experiment for 7 days after administration of plasminogen or vehicle to lung cancer model mice.
- the results showed that the blank control mice had a certain border resting time rate; the border resting time rate of the mice in the vehicle group was significantly more than that of the blank control group; the border resting time rate of the mice in the plasminogen group was significantly less Vehicle group, and the difference was statistically significant (* means P ⁇ 0.05).
- the results indicate that plasminogen can promote the recovery of activity and behavior in lung cancer model mice.
- FIG. 13 Results of tumor volume measurement in lung cancer model mice after administration of plasminogen or vehicle. The results showed that the tumor volume of mice in the plasminogen group was significantly smaller than that in the vehicle group at each measurement time point. The P value on the 10th day of the drug was 0.07. It shows that plasminogen can obviously inhibit the tumor growth of lung cancer model mice.
- FIG 14A-B Cancer pain model mice hot and cold plate pain detection results.
- A is the statistical result of the contraction and lifting temperature of the hind foot during the detection
- B is the statistical result of the contraction and lifting time of the hind foot during the detection.
- the results showed that the temperature of the mice in the vehicle group was significantly higher than that of the mice in the blank control group when the hind paws were contracted and lifted.
- the contraction and lifting time of the hind paws of the mice in the vehicle group was significantly earlier than that of the mice in the blank control group.
- the above results indicate that plasminogen can relieve pain in cancer pain model mice.
- FIG. 15 Results of clamp-type tenderness test in mice with cancer pain model after administration of plasminogen. The results showed that the pain threshold of the mice in the administration group was significantly higher than that in the vehicle group, and the statistical analysis P value was 0.006. It is suggested that plasminogen can relieve pain in cancer pain model mice.
- Fig. 16 Measurement results of tumor volume in lung cancer model mice after administration of plasminogen. The results showed that the tumor volume of the mice in the administration group was no different from the vehicle group on Day 0, and the tumor volume in the administration group was significantly smaller than that in the vehicle group on Day 4, Day 7 and Day 10, and the statistical analysis P values were 0.22, 0.003 and 0.07, respectively. It shows that plasminogen can significantly inhibit the growth of lung cancer tumor.
- Fig. 17 The results of esophageal electronic gastroscope detection in patients with esophageal cancer after treatment with plasminogen and chemotherapy. Before the first course of treatment and 4 weeks after the third course of treatment, the patients underwent electronic gastroscopic examination. The results showed that before administration, the esophagus mass (marked by arrow) was seen from 20cm-30cm away from the incisors, and the esophagus was involved for 3/4 weeks.
- Fibrinolytic system also known as fibrinolytic system, is a system composed of a series of chemical substances involved in the process of fibrinolysis (fibrinolysis), mainly including plasminogen (also known as: plasminogen) , plasmin, plasminogen activator, fibrinolysis inhibitor.
- Plasminogen activators include tissue-type plasminogen activator (t-PA) and urokinase-type plasminogen activator (u-PA).
- t-PA tissue-type plasminogen activator
- u-PA urokinase-type plasminogen activator
- t-PA activates plasminogen, which is mainly carried out on fibrin; urokinase-type plasminogen activator (u-PA) is produced by renal tubular epithelial cells and vascular endothelial cells and can directly activate plasminogen without the need for fibrin as a cofactor.
- Plasminogen (PLG) is synthesized by the liver. When blood coagulates, a large amount of PLG is adsorbed on the fibrin network, and under the action of t-PA or u-PA, it is activated to plasmin, which promotes fibrinolysis.
- Plasmin (PL) is a serine protease whose functions are as follows: degrade fibrin and fibrinogen; hydrolyze various coagulation factors V, VIII, X, VII, XI, II, etc.; convert plasminogen into fibrinolytic enzymes; hydrolysis of complement, etc.
- Fibrinolytic inhibitors including plasminogen activator inhibitor (PAI) and ⁇ 2 antiplasmin ( ⁇ 2-AP).
- PAI mainly has two forms, PAI-1 and PAI-2, which can specifically bind to t-PA in a ratio of 1:1, thereby inactivating it and activating PLG at the same time.
- ⁇ 2-AP is synthesized by the liver and combines with PL in a ratio of 1:1 to form a complex, which inhibits the activity of PL; FXIII makes ⁇ 2-AP covalently bound to fibrin, reducing the sensitivity of fibrin to PL.
- Substances that inhibit the activity of the fibrinolytic system in vivo include: PAI-1, complement C1 inhibitor; ⁇ 2 antiplasmin; ⁇ 2 macroglobulin.
- component of the plasminogen activation pathway encompasses:
- plasmin also known as: plasmin
- variants or analogs thereof are also known as: plasmin and variants or analogs thereof.
- Plasminogen activators such as tPA and uPA, and tPA or uPA variants and the like comprising one or more domains of tPA or uPA, such as one or more kringle domains and serine protease domains thing.
- variants of plasminogen, plasmin, tPA and uPA include all naturally occurring human genetic variants and other mammalian forms of these proteins, as well as by additions, deletions and/or substitutions such as 1- 100, 1-90, 1-80, 1-70, 1-60, 1-50, 1-45, 1-40, 1-35, 1-30, 1-25, 1-20, 1-15, 1-10, 1-5, 1-4, 1-3, 1-2, 1 amino acid protein that still has plasminogen, plasmin, tPA or uPA activity.
- variants of plasminogen, plasmin, tPA, and uPA include, for example, 1-100, 1-90, 1-80, 1-70, 1-60, 1-50, 1- 45, 1-40, 1-35, 1-30, 1-25, 1-20, 1-15, 1-10, 1-5, 1-4, 1-3, 1-2, 1 conservative Mutant variants of these proteins obtained by amino acid substitutions.
- a "plasminogen variant” of the invention encompasses at least 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% with sequence 2, 6, 8, 10 or 12 % sequence identity and still have plasminogen activity.
- a "plasminogen variant” of the present invention may be based on sequence 2, 6, 8, 10 or 12 with additions, deletions and/or substitutions of 1-100, 1-90, 1-80, 1- 70, 1-60, 1-50, 1-45, 1-40, 1-35, 1-30, 1-25, 1-20, 1-15, 1-10, 1-5, 1-4, 1-3, 1-2, 1 amino acid protein that still has plasminogen activity.
- the plasminogen variants of the present invention include all naturally occurring human genetic variants as well as other mammalian forms of these proteins, as well as by conservative amino acid substitutions such as 1-100, 1-90, 1-80, 1- 70, 1-60, 1-50, 1-45, 1-40, 1-35, 1-30, 1-25, 1-20, 1-15, 1-10, 1-5, 1-4, 1-3, 1-2, 1 amino acid obtained mutant variants of these proteins.
- the plasminogen of the invention may be a human plasminogen ortholog from a primate or rodent or a variant thereof that still retains plasminogen activity, eg sequences 2, 6, 8, 10 Or plasminogen shown in 12, such as human natural plasminogen shown in sequence 2.
- plasminogen, plasmin, tPA, and uPA include compounds that provide substantially similar effects to plasminogen, plasmin, tPA, or uPA, respectively.
- variants and analogs of plasminogen, plasmin, tPA and uPA encompass fibers comprising one or more domains (eg, one or more kringle domains and serine protease domains) "Variants” and “analogs” of lysinogen, plasmin, tPA and uPA.
- variants and analogs such as mini-plasminogen.
- Variants and “analogs” of plasmin encompass “variants” of plasmin that comprise one or more plasmin domains (eg, one or more kringle domains and serine protease domains) and “analogs” such as mini-plasmin and delta-plasmin.
- a "variant" or “analog” of the above-mentioned plasminogen, plasmin, tPA or uPA has the activity of plasminogen, plasmin, tPA or uPA, respectively, or does it provide Substantially similar effects of plasminogen, plasmin, tPA or uPA can be detected by methods known in the art, for example, by methods based on enzymography, ELISA (enzyme-linked immunosorbent assay) and FACS ( Fluorescence-activated cell sorting method) is measured by the level of activated plasmin activity, which can be measured, for example, with reference to a method selected from the literature described in: Ny, A., Leonardsson, G., Hagglund, AC, Hagglof, P.
- the "component of the plasminogen activation pathway" of the invention is plasminogen.
- the plasminogen is selected from the group consisting of Glu-plasminogen, Lys-plasminogen, microplasminogen, microplasminogen, delta-plasminogen.
- the plasminogen is a plasminogen protein comprising one or more kringle domains.
- the plasminogen is a plasminogen protein comprising a serine protease domain.
- the plasminogen is a plasminogen protein comprising a serine protease domain as shown in SEQ ID NO: 14.
- the plasminogen comprises at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% identity to the amino acid sequence set forth in SEQ ID NO: 14 Plasminogen protein with a serine protease domain.
- the plasminogen is natural or synthetic human full-length plasminogen.
- the amino acid of the plasminogen is shown in sequence 2, 6, 8, 10 or 12.
- the plasminogen is human native plasminogen.
- the plasminogen is human native plasminogen as shown in SEQ ID NO: 2.
- the plasminogen is at least 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98% or A protein with 99% sequence identity and still having plasminogen activity. In some embodiments, the plasminogen is a conservative substitution variant of sequence 2, 6, 8, 10 or 12.
- plasminogen activity refers to the lysine binding activity and proteolytic activity of plasminogen to its receptor or substrate.
- Plasmin is a key component of the plasminogen activation system (PA system). It is a broad-spectrum protease capable of hydrolyzing several components of the extracellular matrix (ECM), including fibrin, gelatin, fibronectin, laminin, and proteoglycans [1]. In addition, plasmin can activate some metalloproteinase precursors (pro-MMPs) to form active metalloproteinases (MMPs). Therefore, plasmin is considered to be an important upstream regulator of extracellular proteolysis [2-3] .
- ECM extracellular matrix
- MMPs active metalloproteinases
- Plasmin is formed by proteolysis of plasminogen by two physiological PAs: tissue-type plasminogen activator (tPA) or urokinase-type plasminogen activator (uPA). Due to the relatively high levels of plasminogen in plasma and other body fluids, it has traditionally been thought that the regulation of the PA system is mainly achieved through the synthesis and activity levels of PAs. The synthesis of PA system components is tightly regulated by different factors, such as hormones, growth factors and cytokines. In addition, there are specific physiological inhibitors of plasmin and PAs. The main inhibitor of plasmin is ⁇ 2-antiplasmin.
- PAI-1 uPA plasminogen activator inhibitor-1
- PAI-2 lysinogen activator inhibitor-2
- uPA-specific cell surface receptors uPAR
- Plasminogen is a single-chain glycoprotein composed of 791 amino acids with a molecular weight of about 92kDa [6-7] . Plasminogen is mainly synthesized in the liver and is abundantly present in the extracellular fluid. Plasminogen content in plasma is approximately 2 ⁇ M. Therefore, plasminogen is a huge potential source of proteolytic activity in tissues and body fluids [8-9] . Plasminogen exists in two molecular forms: glutamate-plasminogen (Glu-plasminogen) and lysine-plasminogen (Lys-plasminogen).
- the naturally secreted and uncleaved form of plasminogen has an amino-terminal (N-terminal) glutamate and is therefore referred to as glutamate-plasminogen.
- glutamate-plasminogen is hydrolyzed at Lys76-Lys77 to lysine-plasminogen.
- lysine-plasminogen has a higher affinity for fibrin and can be activated by PAs at a higher rate.
- the Arg560-Val561 peptide bond of these two forms of plasminogen can be cleaved by uPA or tPA, leading to the formation of the disulfide-linked double-chain protease plasmin [10] .
- the amino-terminal part of plasminogen contains five homologous kringles, the so-called kringles domains (kringle 1, kringle 2, kringle3, kringle 4, kringle 5), and the carboxy-terminal part contains the protease domain.
- Some kringles contain lysine-binding sites that mediate the specific interaction of plasminogen with fibrin and its inhibitor ⁇ 2-AP, and are therefore also called lysine-binding domains.
- a lysine binding domain refers to a structural region selected from any one, two, three, four or five kringle of kringle 1, kringle 2, kringle3, kringle 4 and kringle 5.
- the main substrate of plasmin is fibrin, and the dissolution of fibrin is the key to preventing pathological thrombosis [11] .
- Plasmin also has substrate specificity for several components of the ECM, including laminin, fibronectin, proteoglycans, and gelatin, suggesting that plasmin also plays an important role in ECM remodeling [7,12- 13] .
- plasmin can also degrade other components of the ECM, including MMP-1, MMP-2, MMP-3 and MMP-9, by converting certain protease precursors into active proteases. Therefore, it has been suggested that plasmin may be an important upstream regulator of extracellular proteolysis [14] .
- plasmin has the ability to activate certain latent forms of growth factors [15-17] . In vitro, plasmin also hydrolyzes components of the complement system and releases chemotactic complement fragments.
- Pulmin is a very important enzyme present in the blood that hydrolyzes fibrin clots into fibrin degradation products and D-dimers.
- “Plasminogen” is the zymogen form of plasmin. According to the sequence in swiss prot, it is composed of 810 amino acids according to the natural human plasminogen amino acid sequence (sequence 4) containing the signal peptide, and the molecular weight is about 90kD , is a glycoprotein that is mainly synthesized in the liver and can circulate in the blood.
- the cDNA sequence encoding the amino acid sequence is shown in sequence 3.
- Full-length plasminogen contains seven domains: a serine protease domain or protease domain for short at the C-terminus, a Pan Apple (PAp) domain at the N-terminus, and five Kringle domains (Kringle1-5).
- the serine protease domain includes residues Val581-Arg804.
- Glu-plasminogen is a natural full-length plasminogen composed of 791 amino acids (without a signal peptide of 19 amino acids), the amino acid sequence is shown in sequence 2, and the cDNA sequence encoding this sequence is shown in sequence 1. Show. In vivo, there is also a Lys-plasminogen formed by hydrolysis of amino acids 76-77 of Glu-plasminogen. The amino acid sequence is shown in sequence 6, and the cDNA sequence encoding the amino acid sequence is shown in Sequence 5 is shown. Delta-plasminogen is a fragment of full-length plasminogen that lacks the Kringle2-Kringle5 structure, and only contains Kringle1 and serine protease domains [18-19] .
- the amino acid sequence of delta-plasminogen has been reported in the literature. (Sequence 8) [19] , the cDNA sequence encoding the amino acid sequence is as sequence 7.
- Mini-plasminogen is composed of Kringle5 and serine protease domains, and it has been reported to include residues Val443-Asn791 (starting with the Glu residues of the Glu-plasminogen sequence without the signal peptide) amino acid) [20] , its amino acid sequence is shown in sequence 10, and the cDNA sequence encoding the amino acid sequence is shown in sequence 9.
- Micro-plasminogen contains only a serine protease domain, and it has been reported that its amino acid sequence includes residues Ala543-Asn791 (starting from the Glu residues of the Glu-plasminogen sequence without the signal peptide). starting amino acid) [21] , there are also patent documents CN102154253A reported that its sequence includes residues Lys531-Asn791 (with the Glu residues of the Glu-plasminogen sequence that does not contain the signal peptide as the starting amino acid), this patent sequence refers to the patent document CN102154253A, its amino acid sequence is shown in sequence 12, and the cDNA sequence encoding the amino acid sequence is shown in sequence 11. The amino acid sequence of the serine protease domain in this application is shown in SEQ ID NO: 14, and the cDNA sequence encoding the amino acid sequence is shown in SEQ ID 13.
- Plasminogens comprising one or more Kringle domains selected from Kringle 1, Kringle 2, Kringle 3, Kringle 4, and Kringle 5 are encompassed by the present application.
- a "serine protease domain”, also known as a protease domain, is a domain of plasminogen that performs proteolytic functions.
- the technical solutions of the present invention relating to plasminogen cover all technical solutions of plasminogen comprising a serine protease domain.
- the plasminogen fragment comprising a serine protease domain of the present invention is a protein comprising a serine protease domain of plasminogen.
- the plasminogen fragment comprising a serine protease domain described herein is a protein comprising the amino acid sequence shown in SEQ ID NO: 14.
- the plasminogen fragment comprising a serine protease domain described herein is at least 80%, 90%, 95%, 96%, 97%, 98%, 99% identical to SEQ ID NO: 14
- the plasminogen comprises conservative substitution variants of sequence 14.
- assay methods for plasminogen and its activity include: detection of tissue plasminogen activator activity (t-PAA), detection of plasma tissue plasminogen activator antigen (t-PAA) t-PAAg), detection of plasma tissue plasminogen activity (plgA), detection of plasma tissue plasminogen antigen (plgAg), detection of plasma tissue plasminogen activator inhibitor activity, plasma tissue fibrinolysis Detection of zymogen activator inhibitor antigen, detection of plasma plasmin-antiplasmin complex (PAP).
- tissue plasminogen activator activity t-PAA
- t-PAA plasma tissue plasminogen activator antigen
- plgA plasma tissue plasminogen activity
- plgAg detection of plasma tissue plasminogen antigen
- PAP plasma tissue fibrinolysis
- the most commonly used detection method is the chromogenic substrate method: streptokinase (SK) and chromogenic substrate are added to the test plasma, and the plasminogen in the test plasma is converted into plasmin under the action of SK. , the latter acts on a chromogenic substrate, which is subsequently measured by a spectrophotometer, and the increase in absorbance is proportional to plasminogen activity.
- plasminogen activity eg, proteolytic activity
- Angiostatin has a molecular weight of 38KD and is a part of plasminogen [22-23] . Its amino acid sequence has a homology of up to 98% with Kringle1-Kringle4 in the five Kringles of plasminogen.
- Angiostatin is formed by the cleavage of plasminogen by elastase, different matrix metalloproteinases and other proteolytic enzymes in vivo [24-25] .
- Angiostatin can bind to a variety of proteins including angiomotin, annexin II, tPA and CD26 [26] , and studies have shown that angiostatin can interact with these proteins to inhibit angiogenesis.
- angiostatin can specifically inhibit the proliferation, migration and apoptosis of vascular endothelial cells, and its mechanism may be closely related to the lysine-binding activity of kringle in angiostatin.
- Plasminogen Kringle5 (K5) can also significantly inhibit the growth of endothelial cells, and its activity is significantly higher than that of Angiostatin.
- K5 also has lysine binding activity, its inhibitory effect on angiogenesis does not depend on lysine binding activity, and the structure of K5 has a unique mechanism of action [27] .
- angiostatin has been expanded from a single protein to a class of proteins (angiostatin isoforms or angiostatin related proteins), including A series of fragments containing different Kingle structures of plasminogen and similar biological activities have been developed [28-29] .
- This effect is likely to be that the additional increased plasminogen in the body is degraded by proteolytic enzymes such as MMPs and elastase accumulated in the tumor microenvironment, thereby promoting the production of high amounts of Angiostatin and/or its analogs, and thereby inhibiting tumor angiogenesis. generated function. That is to say, the inhibition of angiogenesis can be achieved by directly regulating the plasminogen in the body instead of directly increasing the Angiostatin and/or its analogs in the body. This opens up a new therapeutic strategy for tumor suppression.
- proteolytic enzymes such as MMPs and elastase accumulated in the tumor microenvironment
- plasminogen encompasses plasminogen fragments having plasminogen activity, such as plasminogen fragments comprising one or more different Kingle domains, or comprising biologically similar to one or more Kingle domains Active variant plasminogen fragment.
- orthologs or orthologs refer to homologs between different species, including both protein homologs and DNA homologs, also known as orthologs and vertical homologs. It specifically refers to proteins or genes that have evolved from the same ancestral gene in different species.
- the plasminogen of the present invention includes human natural plasminogen, and also includes plasminogen orthologs or orthologs derived from different species and having plasminogen activity.
- a “conservative substitution variant” refers to one in which a given amino acid residue is altered without altering the overall conformation and function of the protein or enzyme, including but not limited to those with similar properties (eg, acidic, basic, hydrophobic, etc.)
- Amino acids replace amino acids in the amino acid sequence of the parent protein.
- Amino acids with similar properties are well known. For example, arginine, histidine and lysine are hydrophilic basic amino acids and are interchangeable.
- isoleucine is a hydrophobic amino acid and can be replaced by leucine, methionine or valine. Therefore, the similarity of two proteins or amino acid sequences of similar functions may differ.
- Constants also include polypeptides or enzymes determined to have more than 60% amino acid identity by BLAST or FASTA algorithm, if it can reach more than 75%, it is better, preferably more than 85%, or even more than 90%. is optimal and has the same or substantially similar properties or functions as the native or parent protein or enzyme.
- Plasmid and “plasmin” and “plasminase” can be used interchangeably and have the same meaning; “plasminogen” is used with “plasminogen” and “plasminogen” “Original” are used interchangeably and have the same meaning.
- plasminogen is used with “plasminogen” and “plasminogen” “Original” are used interchangeably and have the same meaning.
- Compounds capable of directly activating plasminogen or indirectly activating plasminogen by activating upstream components of the plasminogen activation pathway refers to activating plasminogen either directly or by activating plasminogen Any compound that activates upstream components of the pathway and indirectly activates plasminogen, such as tPA, uPA, streptokinase, saruplase,reteplase, reteplase, tenecteplase, anistreplase, Monteplase, lanoteplase, paamiplase, staphylokinase.
- the "antagonist of a fibrinolysis inhibitor" of the present invention is a compound that antagonizes, weakens, blocks, or prevents the action of a fibrinolysis inhibitor.
- fibrinolytic inhibitors are eg PAI-1, complement C1 inhibitor, alpha2 antiplasmin and alpha2 macroglobulin.
- Such antagonists such as PAI-1, complement C1 inhibitor, ⁇ 2 antiplasmin or ⁇ 2 macroglobulin antibodies, or block or downregulate such as PAI-1, complement C1 inhibitor, ⁇ 2 antiplasmin or ⁇ 2 macroglobulin Antisense RNA or small RNA expressed by globulin, or occupying the binding site of PAI-1, complement C1 inhibitor, ⁇ 2 antiplasmin, or ⁇ 2 macroglobulin but without PAI-1, complement C1 inhibitor, ⁇ 2 antifibrinolytic A compound that functions as a lysin or alpha2 macroglobulin", or a compound that blocks the binding and/or active domains of PAI-1, complement C1 inhibitor, alpha2 antiplasmin, or alpha2 macroglobulin.
- the "deficiency" of plasminogen means that the content or activity of plasminogen in a subject is lower than that of normal people, and is low enough to affect the normal physiological function of the subject; the The meaning of “deletion” of plasminogen is that the content or activity of plasminogen in the subject is significantly lower than that of normal people, or even the activity or expression is extremely low, and normal physiological functions can only be maintained by external supply.
- Isolated plasminogen refers to a plasminogen protein that has been isolated and/or recovered from its natural environment.
- the plasminogen will be purified (1) to greater than 90%, greater than 95%, or greater than 98% purity (by weight), as determined by Lowry's method, eg, greater than 99% (by weight), (2) to a degree sufficient to obtain at least 15 residues of the N-terminal or internal amino acid sequence by use of a spinning cup sequencer, or (3) to homogeneity as determined by using Determined by Coomassie blue or silver staining by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) under reducing or non-reducing conditions.
- Isolated plasminogen also includes plasminogen prepared from recombinant cells by bioengineering techniques and isolated by at least one purification step.
- polypeptide refers to a polymeric form of amino acids of any length, which may include genetically encoded and non-genetically encoded amino acids, chemically or biochemically modified or derivatized modified amino acids, and polypeptides with modified peptide backbones.
- the term includes fusion proteins including, but not limited to, fusion proteins with heterologous amino acid sequences, fusions with heterologous and homologous leader sequences (with or without N-terminal methionine residues); and the like.
- Percent (%) amino acid sequence identity with respect to a reference polypeptide sequence is defined as, after gaps have been introduced as necessary to achieve maximum percent sequence identity, and no conservative substitutions are considered part of sequence identity, the Percentage of amino acid residues that are identical to amino acid residues in a reference polypeptide sequence. Alignment for purposes of determining percent amino acid sequence identity can be accomplished in a variety of ways that are within the skill in the art, eg, using publicly available computer software such as BLAST, BLAST-2, ALIGN or Megalign (DNASTAR) software. Those skilled in the art can determine appropriate parameters for aligning sequences, including any algorithms needed to achieve maximal alignment over the full length of the sequences being compared. However, for the purposes of the present invention, percent amino acid sequence identity values were generated using the sequence comparison computer program ALIGN-2.
- % amino acid sequence identity of a given amino acid sequence A relative to a given amino acid sequence B (or can be expressed as having or comprising relative to, with, or against a given amino acid sequence A given amino acid sequence A) for a certain % amino acid sequence identity of B is calculated as follows:
- the terms “treating” and “treating” refer to obtaining a desired pharmacological and/or physiological effect.
- the effect may be complete or partial prevention of the disease or symptoms thereof, and/or partial or complete cure of the disease and/or symptoms thereof, and includes: (a) preventing the occurrence of the disease in a subject, who may have Predisposing to the disease, but not yet diagnosed as having the disease; (b) inhibiting the disease, ie, blocking its development; and (c) alleviating the disease and/or its symptoms, ie, causing regression of the disease and/or its symptoms.
- mammals including, but not limited to, murine (rat, mouse), non-human primate, human, canine, feline , hoofed animals (eg horses, cattle, sheep, pigs, goats), etc.
- murine rat, mouse
- non-human primate human
- canine feline
- hoofed animals eg horses, cattle, sheep, pigs, goats
- a “therapeutically effective amount” or “effective amount” refers to an amount of plasminogen sufficient to effect said prevention and/or treatment of a disease when administered to a mammal or other subject to treat the disease.
- a “therapeutically effective amount” will vary depending on the plasminogen used, the severity of the disease and/or its symptoms in the subject to be treated, as well as age, weight, and the like.
- Plasminogen can be isolated from nature and purified for further therapeutic use, or it can be synthesized by standard chemical peptide synthesis techniques. When the polypeptide is synthesized chemically, the synthesis can be carried out via liquid phase or solid phase.
- Solid-phase polypeptide synthesis SPPS
- SPPS Solid-phase polypeptide synthesis
- Various forms of SPPS such as Fmoc and Boc, can be used to synthesize plasminogen.
- Techniques for solid-phase synthesis are described in Barany and Solid-Phase Peptide Synthesis; pp. 3-284 in The Peptides: Analysis, Synthesis, Biology.
- Plasminogen of the present invention can be produced using standard recombinant methods.
- a nucleic acid encoding plasminogen is inserted into an expression vector operably linked to regulatory sequences in the expression vector.
- Expression control sequences include, but are not limited to, promoters (eg, naturally associated or heterologous promoters), signal sequences, enhancer elements, and transcription termination sequences.
- Expression control may be a eukaryotic promoter system in a vector capable of transforming or transfecting eukaryotic host cells (eg, COS or CHO cells). Once the vector is incorporated into a suitable host, the host is maintained under conditions suitable for high-level expression of the nucleotide sequence and collection and purification of plasminogen.
- Suitable expression vectors typically replicate in the host organism as episomes or as an integral part of the host chromosomal DNA.
- the expression vector contains a selectable marker (eg, ampicillin resistance, hygromycin resistance, tetracycline resistance, kanamycin resistance, or neomycin resistance) to facilitate transformation of the exogenous with the desired DNA sequence of those cells were detected.
- a selectable marker eg, ampicillin resistance, hygromycin resistance, tetracycline resistance, kanamycin resistance, or neomycin resistance
- Escherichia coli is an example of a prokaryotic host cell that can be used to clone a subject protein-encoding polynucleotide.
- Other microbial hosts suitable for use include bacilli such as Bacillus subtilis and other enterobacteriaceae such as Salmonella, Serratia, and various Pseudomonas Genus (Pseudomonas) species.
- expression vectors can also be generated, which will typically contain expression control sequences (eg, origins of replication) that are compatible with the host cell.
- promoters such as the lactose promoter system, the tryptophan (trp) promoter system, the beta-lactamase promoter system, or the promoter system from bacteriophage lambda.
- a promoter will typically control expression, optionally in the case of operator sequences, and have ribosome binding site sequences, etc., to initiate and complete transcription and translation.
- yeast can also be used for expression.
- Yeast eg, S. cerevisiae
- Pichia are examples of suitable yeast host cells, with suitable vectors having expression control sequences (eg, promoters), origins of replication, termination sequences, etc., as desired.
- Typical promoters contain 3-phosphoglycerate kinase and other saccharolytic enzymes.
- Inducible yeast are initiated from promoters that include, inter alia, alcohol dehydrogenase, isocytochrome C, and enzymes responsible for maltose and galactose utilization.
- mammalian cells eg, mammalian cells grown in in vitro cell culture
- Suitable mammalian host cells include CHO cell lines, various Cos cell lines, HeLa cells, myeloma cell lines, and transformed B cells or hybridomas.
- Expression vectors for use in these cells may contain expression control sequences, such as origins of replication, promoters and enhancers (Queen et al., Immunol. Rev.
- RNA splicing sites sites for necessary processing information
- sites for necessary processing information such as ribosome binding sites, RNA splicing sites, polyadenylation sites, and transcription terminator sequences.
- suitable expression control sequences are promoters derived from leukoimmunoglobulin genes, SV40, adenovirus, bovine papilloma virus, cytomegalovirus, and the like. See Co et al, J. Immunol. 148:1149 (1992).
- the compounds described herein can be purified according to standard procedures in the art, including ammonium sulfate precipitation, affinity columns, column chromatography, high performance liquid chromatography (HPLC), gel electrophoresis, and the like Plasminogen.
- the plasminogen is substantially pure, eg, at least about 80% to 85% pure, at least about 85% to 90% pure, at least about 90% to 95% pure, or 98% to 99% pure or purer, eg, free of contaminants such as cellular debris, macromolecules other than compounds of the invention such as plasminogen, and the like.
- Lyophilized formulations can be formed by mixing plasminogen of the desired purity with optional pharmaceutical carriers, excipients, or stabilizers (Remington's Pharmaceutical Sciences, 16th edition, Osol, A. ed. (1980)) or aqueous solutions to prepare therapeutic formulations.
- Acceptable carriers, excipients, stabilizers are non-toxic to recipients at the dosages and concentrations employed, and include buffers such as phosphates, citrates and other organic acids; antioxidants including ascorbic acid and methionine; preservatives (such as octadecyldimethylbenzylammonium chloride; hexanediamine chloride; benzalkonium chloride, benzethonium chloride; phenol, butanol or benzyl alcohol; alkyl parahydroxybenzoic acid Esters such as methyl or propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol; m-cresol); low molecular weight polypeptides (less than about 10 residues) ; proteins such as serum albumin, gelatin or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine
- the formulations of the present invention may also contain more than one active compound as required for the particular condition to be treated, preferably those which are complementary in activity and which do not have side effects with each other.
- active compound for example, antitumor drugs, liver protective drugs, hormone drugs, etc.
- the plasminogen of the present invention can be encapsulated in microcapsules prepared by techniques such as coacervation or interfacial polymerization, for example, can be placed in colloidal drug delivery systems (eg, liposomes, albumin microspheres, microemulsions, nanoparticles and nanocapsules) or in hydroxymethyl cellulose or gel-microcapsules and poly-(methyl methacrylate) microcapsules in macroemulsions.
- colloidal drug delivery systems eg, liposomes, albumin microspheres, microemulsions, nanoparticles and nanocapsules
- hydroxymethyl cellulose or gel-microcapsules and poly-(methyl methacrylate) microcapsules in macroemulsions are disclosed in Remington's Pharmaceutical Sciences 16th edition, Osol, A. Ed. (1980).
- the plasminogen of the present invention for in vivo administration must be sterile. This can be easily achieved by filtration through sterile filters before or after lyophilization and reconstitution.
- the plasminogen of the present invention can be prepared as a sustained-release preparation.
- sustained release formulations include semipermeable matrices of solid hydrophobic polymers having a shape and containing glycoproteins, such as membranes or microcapsules.
- sustained release matrices include polyesters, hydrogels such as poly(2-hydroxyethyl-methacrylate) (Langer et al., J. Biomed. Mater. Res., 15:167-277 (1981); Langer, Chem. .Tech., 12:98-105 (1982)) or poly(vinyl alcohol), polylactide (US Pat. No.
- Polymers such as ethylene -Vinyl acetate and lactic acid-glycolic acid can continuously release molecules for more than 100 days, while some hydrogels release proteins for shorter periods of time. Rational strategies to stabilize proteins can be designed based on the relevant mechanisms. For example, if the mechanism of aggregation is discovered Intermolecular SS bonds are formed through the exchange of thiodisulfide bonds, which can be achieved by modifying sulfhydryl residues, lyophilizing from acidic solutions, controlling humidity, using appropriate additives, and developing specific polymer matrix compositions. Stablize.
- compositions of the present invention can be accomplished by different means, eg, intravenously, intraperitoneally, subcutaneously, intracranally, intrathecally, intraarterally (eg, via the carotid artery), intramuscularly.
- Preparations for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions and emulsions.
- non-aqueous solvents are propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate.
- Aqueous carriers include water, alcoholic/aqueous solutions, emulsions or suspensions, including saline and buffered media.
- Parenteral vehicles include sodium chloride solution, Ringer's dextrose, dextrose and sodium chloride, or fixed oils.
- Intravenous vehicles include fluid and nutrient replenishers, electrolyte replenishers, and the like. Preservatives and other additives may also be present, such as, for example, antimicrobials, antioxidants, chelating agents, and inert gases, among others.
- Dosing regimens will be determined by healthcare professionals based on various clinical factors. As is well known in the medical arts, the dosage for any patient depends on a variety of factors, including the patient's size, body surface area, age, the particular compound to be administered, sex, number and route of administration, general health, and other concomitantly administered drugs .
- the dosage range of the pharmaceutical composition comprising plasminogen of the invention may be, for example, about 0.0001 to 2000 mg/kg per day, or about 0.001 to 500 mg/kg (eg, 0.02 mg/kg, 0.25 mg/kg, 0.5 mg/kg, 0.75 mg/kg) per day mg/kg, 10 mg/kg, 50 mg/kg, etc.) subject body weight.
- the dose may be 1 mg/kg body weight or 50 mg/kg body weight or in the range of 1-50 mg/kg, or at least 1 mg/kg. Dosages above or below this exemplary range are also contemplated, especially in view of the factors set forth above. Intermediate doses within the above ranges are also included within the scope of the present invention. Subjects may be administered such doses daily, every other day, weekly, or according to any other schedule determined by empirical analysis. An exemplary dosage schedule includes 1-10 mg/kg on consecutive days. Real-time evaluation of therapeutic efficacy and safety is required during the administration of the drug of the present invention.
- the article of manufacture preferably includes a container, label or package insert.
- Suitable containers are bottles, vials, syringes, etc.
- the container can be made of various materials such as glass or plastic.
- the container contains a composition effective to treat the disease or condition of the present invention and has a sterile access port (eg, the container may be an intravenous solution pack or vial containing a stopper penetrable by a hypodermic needle) of).
- At least one active agent in the composition is plasminogen/plasmin.
- the label on or attached to the container states that the composition is used to treat the tumors of the present invention.
- the article of manufacture may further comprise a second container containing a pharmaceutically acceptable buffer, such as phosphate buffered saline, Ringer's solution, and dextrose solution. It may further contain other materials required from a commercial and user standpoint, including other buffers, diluents, filters, needles and syringes.
- a pharmaceutically acceptable buffer such as phosphate buffered saline, Ringer's solution, and dextrose solution.
- the article of manufacture comprises a package insert with instructions for use, including, for example, instructing the user of the composition to administer the plasminogen composition to the patient along with other drugs for the treatment of concomitant diseases.
- the plasminogen used in the following examples is human plasminogen, which is obtained from the plasma of donors. Based on the purification methods described in the literature [37-39] , part of the process optimization is carried out, and it is obtained from the purification of human plasma. Among them, human Lys-plasminogen (Lys-plasminogen) and Glu-plasminogen (Glu-plasminogen)>98%.
- CT26.WT mouse colon cancer cells are undifferentiated colon cancer cell lines induced by N-nitroso-N-methylurethane-(NNMU). Its cloned cell line was named CT26.WT (ATCC CRL-2638).
- CT26.WT mouse colon cancer cells were purchased from Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, hereinafter referred to as CT26.
- CT26 cells were placed in PRIM-1640 (GIBCO, Cat. No. 31800022) medium containing 10% fetal bovine serum, and cultured in a 37°C, 5% carbon dioxide incubator. After the cells in the culture flask had grown to 90%, they were digested with trypsin (0.05% trypsin with 0.02% EDTA) (Sigma, 74799), then washed three times with normal saline, and resuspended in normal saline at a concentration of 10 7 pcs/ml.
- trypsin 0.05% trypsin with 0.02% EDTA
- mice Fourteen male Balb/c mice aged 7-9 weeks were anesthetized by intraperitoneal injection of sodium pentobarbital at 50 mg/kg body weight. After anesthesia, mice were subcutaneously inoculated with 10 6/100 ⁇ l CT26 resuspension on the back with a 27-gauge needle, and then the volume of the mouse subcutaneous tumor (length x width 2 x 0.52) was measured with a vernier caliper every day for seven consecutive days [40-41] . According to the tumor volume on the seventh day, the mice were randomly divided into two groups, 7 mice each in the plasminogen group and the PBS control group. The administration of CT26 started on the eighth day of inoculation, and was designated as the first day.
- Human plasminogen 1 mg/0.1 mL/mice/day was injected into the tail vein of the mice in the plasminogen group, and the vehicle PBS (20 mM citric acid-lemon sodium, 2% arginine hydrochloride, 3% mannitol, pH 7.4, the same below) the control group was injected with the same volume of PBS through the tail vein for 23 consecutive days. On the 1st, 4th, 7th, 10th, 13th, 17th, 20th, and 24th days, the length and width of the tumor were measured, and the tumor volume was calculated.
- mice 14 male Balb/c mice aged 7-9 weeks.
- the mice were anesthetized by intraperitoneal injection of sodium pentobarbital at 50 mg/kg body weight. After anesthesia, the mice were subcutaneously inoculated on the back with a 27-gauge needle. Suspension, and then the volume of the mouse subcutaneous tumor (length x width 2 x 0.52) was measured with a vernier caliper every day [40-41] for seven consecutive days. According to the volume of the tumor on the seventh day, the mice in the model group were randomly divided into two groups, the plasminogen group and the PBS control group, with 7 mice in each group. The administration of CT26 began on the eighth day of inoculation and was designated as the first day.
- Human plasminogen 1 mg/0.1 mL/mice/day was injected into the tail vein of the plasminogen group, and the same as the tail vein injection of the vehicle PBS control group. volume of PBS for 29 consecutive days.
- the mice were sacrificed on the 30th day, and the tumor tissues were fixed in 10% neutral formaldehyde for 24-48 hours, and then dehydrated and embedded.
- the fixed tissue samples were dehydrated in an alcohol gradient and cleared with xylene before paraffin-embedding.
- the thickness of tumor tissue sections was 4 ⁇ m, and the sections were deparaffinized and rehydrated, and washed once with water. Repair with citric acid for 30 minutes, cool at room temperature for 10 minutes and rinse gently with water.
- the color was developed according to the DAB kit (Vector laboratories, Inc., USA), washed with water for 3 times, counterstained with hematoxylin for 30 seconds, returned to blue under running water for 5 minutes, and then washed once with PBS. Gradient dehydration was made transparent and mounted, and the sections were observed under a 200-fold optical microscope.
- CD31 is usually located in vascular endothelial cells, platelets, macrophages and kuffer cells, granulocytes, T/NK cells, lymphocytes, megakaryocytes, osteoclasts, and neutrophils. In immunohistochemistry, CD31 is a marker of vascular endothelial cells and can be used to assess tumor angiogenesis [42-43] .
- mice 14 male Balb/c mice aged 7-9 weeks.
- the mice were anesthetized by intraperitoneal injection of sodium pentobarbital at 50 mg/kg body weight. After anesthesia, the mice were subcutaneously inoculated on the back with a 27-gauge needle. Suspension, and then the volume of the mouse subcutaneous tumor (length x width 2 x 0.52) was measured with a vernier caliper every day [40-41] for seven consecutive days. According to the volume of the tumor on the seventh day, the mice in the model group were randomly divided into two groups, the plasminogen group and the PBS control group, with 7 mice in each group. The administration of CT26 began on the eighth day of inoculation and was designated as the first day.
- Human plasminogen 1 mg/0.1 mL/mice/day was injected into the tail vein of the plasminogen group, and the same as the tail vein injection of the vehicle PBS control group. volume of PBS for 29 consecutive days.
- the mice were sacrificed on the 30th day, and the tumor tissues were collected and fixed in 10% neutral formaldehyde for 24-48 hours, then dehydrated and embedded.
- the fixed tissue samples were dehydrated in an alcohol gradient and cleared with xylene before paraffin-embedding.
- the thickness of tumor tissue sections was 4 ⁇ m, and the sections were deparaffinized and rehydrated, and washed once with water. Repair with citric acid for 30 minutes, cool at room temperature for 10 minutes and rinse gently with water.
- the color was developed according to the DAB kit (Vector laboratories, Inc., USA), washed with water for 3 times, counterstained with hematoxylin for 30 seconds, returned to blue under running water for 5 minutes, and then washed once with PBS. Gradient dehydration was made transparent and mounted, and the sections were observed under a 400-fold optical microscope.
- Lymphatic vessel endothelial hyaluronan receptor 1 (LYVE-1) is a receptor on the surface of lymphatic endothelial cells and can be used as a marker of lymphatic endothelial cells [44-45] .
- LYVE-1 (marked by arrow) in the plasminogen group (Fig. 4B) was significantly lower than that in the vehicle PBS control group (Fig. 4A).
- plasminogen could inhibit the expression of LYVE-1, a marker of intratumoral lymphatic endothelial cells, suggesting that plasminogen inhibits the formation of lymphatic vessels in colon cancer tissue.
- the mice were anesthetized by intraperitoneal injection of sodium pentobarbital at 50 mg/kg body weight. After anesthesia, the mice were subcutaneously inoculated with 10 6/100 ⁇ l CT26 on the back with a 27-gauge needle. After resuspension, the volume of mouse subcutaneous tumors (length x width 2 x 0.52) was measured with a vernier caliper every day [40-41] for seven consecutive days. According to the volume of the tumor on the seventh day, the mice in the model group were randomly divided into two groups, 7 mice in the plasminogen group and 7 mice in the PBS control group, with 7 mice in each group.
- CT26 The administration of CT26 began on the eighth day of inoculation and was designated as the first day.
- Human plasminogen 1 mg/0.1 mL/mice/day was injected into the tail vein of the plasminogen group, and the same as the tail vein injection of the vehicle PBS control group. volume of PBS for 29 consecutive days.
- the mice were sacrificed on the 30th day, and the tumor tissues were fixed in 10% neutral formaldehyde for 24-48 hours.
- the fixed tumor tissue was dehydrated in alcohol gradient and cleared with xylene before being embedded in paraffin.
- the thickness of the tissue section was 3 ⁇ m.
- FIG. 5C and FIG. 5D are enlarged pictures of the block area in FIG. 5A and FIG. 5B , respectively.
- mice Twenty-seven 9-week-old Balb/c female mice were randomly divided into 2 groups after weighing, 9 mice in the blank control group and 18 mice in the model group. After the grouping was completed, all mice in the model group were anesthetized with 2% isoflurane, sterilized one armpit and injected subcutaneously with 1 ⁇ 10 6 cells of CT-26 cell suspension, and observed for 7 days. On the 8th day of tumor cell inoculation, all mice were tested for tumor volume. When the tumor volume of the mice reached more than 100 mm 3 , all mice were weighed and randomly divided into groups according to the results of the detected body weight and tumor volume. There were 9 mice in the vehicle group. Mice, 9 mice in the administration group.
- mice in the administration group were injected with human plasminogen in the tail vein of 1 mg/0.1ml/mouse/day, and the mice in the vehicle group and the mice in the blank control group were injected with the same volume of vehicle PBS in the tail vein, on the first day of administration. Defined as day 1, dosing for 13 consecutive days. The volume of mouse subcutaneous tumors (length x width 2 x 0.52) was measured with vernier calipers on days 0 (pre-dose), 4, 7, 10, and 13 of dosing [40-41] .
- Mouse Lewis lung cancer cells (Lewis lung cancer cells, LLC) were purchased from Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, hereinafter referred to as LLC.
- LLC was placed in DMEM (GIBCO, Cat. No. 15140122) medium containing 10% fetal bovine serum, and cultured in a 37°C, 5% carbon dioxide incubator. After the cells in the culture flask had grown to 90%, they were digested with trypsin (0.02% EDTA added to 0.05% trypsin) (Sigma, 74799), and then washed three times with normal saline. Cells were resuspended in physiological saline and counted under a microscope to confirm that the cells were in single suspension. Finally, the cells were resuspended with physiological saline, the cell concentration was 10 7 cells/ml, and the cells were kept on ice for use.
- DMEM fetal bovine serum
- mice in the model group were selected and randomly divided into 2 groups after weighing, 6 mice in the blank control group and 24 mice in the model group. After the grouping was completed, the mice were anesthetized with 2% isoflurane using a respiratory anesthesia machine; the left leg was depilated, and the skin of the distal condyle of the femur was disinfected with iodine solution, and a 0.5 cm shallow incision was made; then a blunt ligament was made on the patella Sexual dissection to expose the distal condyle of the femur with minimal damage; mice in the model group were slowly injected with 10ul LLC cell suspension (2 ⁇ 10 5 cells/ul) into the distal medullary cavity of the left femur with a 50ul sterile microsyringe.
- mice in the control group were injected with 10 ul of sterile saline into the bone cavity; after the injection was completed, the syringe was placed for 90 s to allow cells to fill the bone cavity, and the injection hole was sealed with sterile bone wax to prevent cell leakage after removing the syringe, and then injected with 5.0
- the wound was sutured with silk thread; the mice after surgery were placed on a heating pad to keep warm, and returned to the cage after the mice recovered.
- all mice were weighed and electronic pain detection was performed.
- the mice in the model group were divided into groups according to the results of pain and body weight, with 12 mice in the vehicle group and 12 mice in the administration group.
- mice in the administration group were injected with human plasminogen in the tail vein of 50 mg/kg/mouse/day, and the mice in the vehicle group and the mice in the blank control group were injected with the vehicle in the tail vein of 5ml/kg/mouse/day.
- the first day of the drug was defined as the first day of dosing.
- Von-Frey filaments (Stoelting, USA) were used to detect the sensitivity of animals to mechanical damage. With 2.0g force as the starting force, test its left foot first. If 4 times out of 5 stimulations, the paw withdrawal response is positive, which is recorded as the threshold of the animal to mechanical damage.
- mice Eleven female C57 mice aged 6-7 weeks were randomly divided into two groups according to body weight, the plasminogen group (5 mice) and the vehicle control group (6 mice). Two groups of mice were injected intraperitoneally with sodium pentobarbital at 50 mg/kg body weight, and after anesthesia, mice were subcutaneously inoculated with 2 x 10 6 mice/200 ⁇ l LLC resuspension [46,47] . The mice were given cells on the day of inoculation, which was recorded as the first day. Human plasminogen 1 mg/0.1 mL/mice/day was injected into the tail vein of the mice in the plasminogen group, and the same volume was injected into the tail vein of the vehicle control group every day. The vehicle PBS was observed and photographed every day to record the tumor situation and the mental state of the mice.
- mice in the control group who were given the vehicle PBS had erect hair, slow movement, lethargy, severe rupture of the tumor, and obvious ulceration and bleeding of the tumor wound (marked by arrows);
- the mice in the plasminogen group (Fig. 8B) The mice move freely and have good mental state.
- the tumor has no obvious rupture phenomenon, and the tumor epidermis has a small amount of scab. This observation suggests that plasminogen can improve general physical and mental status in lung cancer model mice.
- mice Eleven female C57 mice aged 6-7 weeks were randomly divided into two groups according to body weight, the plasminogen group (5 mice) and the vehicle control group (6 mice). Two groups of mice were injected intraperitoneally with sodium pentobarbital at 50 mg/kg body weight, and after anesthesia, mice were subcutaneously inoculated with 2 x 10 6 mice/200 ⁇ l LLC resuspension [46,47] . The day after the mice were inoculated with cells, the administration started, which was recorded as the first day.
- Human plasminogen 1 mg/0.1 mL/mice/day was injected into the tail vein of the mice in the plasminogen (PLG) group, and 1 mg/0.1 mL/mice/day was injected into the tail vein of the mice in the vehicle control group. The same volume of vehicle PBS was injected. The survival of the mice was observed and recorded every day for 24 consecutive days. During the observation period, the animals were administered daily according to the protocol.
- mice Thirty male C57 mice aged 13-14 weeks were randomly divided into two groups according to body weight, 6 in the blank control group and 24 in the model group. Two groups of mice were anesthetized with 2% isoflurane. After the mice were anesthetized, the back skin of 4 to 6 lumbar vertebrae was sterilized and 1 x 10 6 LLC resuspension was subcutaneously inoculated [46,47] . After the cell injection was completed, the tumor growth status of the mice was observed. Seven days after tumor cell inoculation, all mice were tested for body weight, tumor volume and open field. The mice in the model group were randomly divided into two groups according to the test results, the vehicle control group and the fibrinolytic group.
- mice in the zymogen group there were 12 mice in each group, and the administration was started, which was recorded as the first day.
- the mice in the plasminogen group were injected with human plasminogen 1 mg/0.1 mL/mice/day through the tail vein, and the mice in the vehicle control group were given 1 mg/0.1 mL/mouse/day.
- mice Thirty male C57 mice aged 13-14 weeks were randomly divided into two groups according to body weight, 6 in the blank control group and 24 in the model group. Two groups of mice were anesthetized with 2% isoflurane. After the mice were anesthetized, the back skin of 4 to 6 lumbar vertebrae was sterilized and 1 x 10 6 LLC resuspension was subcutaneously inoculated [46,47] . After the cell injection was completed, the tumor growth status of the mice was observed. Seven days after tumor cell inoculation, all mice were tested for body weight, tumor volume and open field. The mice in the model group were randomly divided into two groups according to the test results, the vehicle control group and the fibrinolytic group.
- mice in the zymogen group there were 12 mice in each group, and the administration was started, which was recorded as the first day.
- the mice in the plasminogen group were injected with human plasminogen 1 mg/0.1 mL/mice/day through the tail vein, and the mice in the vehicle control group were given 1 mg/0.1 mL/mouse/day.
- the same volume of vehicle PBS was injected into the tail vein and administered continuously for 7 days. Open field experiments were performed on the 8th day of dosing.
- the Smart System is a complete and easy-to-use video tracking system for evaluating the behavior of laboratory animals. It allows to record trajectories, activities, specific behaviors (such as rotation, stretching and feeding) and events, and to perform calculations of various analytical parameters.
- the Smart3.0 system was used to record and analyze the movement of the mice, and the boundary resting time rate of the mice was recorded. The box was wiped with 70% alcohol to prevent olfactory preference in each experiment.
- mice severe combined immunodeficiency mice (NOD.CB17-Prkdcscid/NcrCrl, referred to as NOD SCID, purchased from Weitong Lihua Laboratory Animal Technology Co., Ltd., strain code 40624) were taken from 7 to 10 weeks old, and were called The mice were randomly divided into 2 groups, 8 mice in the blank control group and 16 mice in the model group. After grouping, all mice in the model group were anesthetized with 2% isoflurane, sterilized their backs and inoculated subcutaneously with 1 ⁇ 10 6 Lewis lung carcinoma cells-GFP cells (mouse lung cancer cells stably transduced with green fluorescent protein GFP, LLC- for short).
- NOD SCID severe combined immunodeficiency mice
- mice in the model group was randomly divided into 2 groups, 8 mice in the vehicle group, 8 mice in the administration group, and blank control. The mice in the group were not treated. After the mice were grouped, the mice in the administration group were injected with human plasminogen in the tail vein of 1 mg/0.1ml/mouse/day, the mice in the vehicle group were injected with the same volume of PBS in the tail vein, and the mice in the blank control group were not given administration. Treatment, continuous administration for 10 days. The volume of mouse subcutaneous tumors (length x width 2 x 0.52) was measured with a caliper on day 0 (pre-dose), day 4, day 7 and day 10 of administration [40-41] .
- mice 18 female and 18 male Balb/c mice aged 8-9 weeks were selected and randomly divided into 2 groups after weighing, 12 mice in the blank control group and 24 mice in the model group. After the grouping was completed, the mice were anesthetized with 2% isoflurane using a respiratory anesthesia machine; the left leg was depilated, and the skin of the distal condyle of the femur was disinfected with iodine solution, and a 0.5 cm shallow incision was made; then a blunt ligament was made on the patella Sexual dissection to expose the distal condyle of the femur with minimal damage; mice in the model group were slowly injected with 5 ⁇ l of CT-26 cell suspension (2 ⁇ 10 4 cells/ ⁇ l) into the medullary cavity of the left distal femur with a 50 ⁇ l sterile microsyringe .
- mice in the control group were injected with 5 ⁇ l of sterile normal saline into the bone cavity; after the injection was completed, the syringe was placed for 90 s to allow cells to fill the bone cavity, and the injection hole was sealed with sterile bone wax to prevent cell leakage after removing the syringe, and then with 5.0
- the wound was sutured with silk thread; the mice after surgery were placed on a heating pad to keep warm, and returned to the cage when the mice were awake. All mice were weighed on the 8th day of surgical modeling. Mice in model group were randomly divided into vehicle group and administration group according to the results of body weight, with 12 mice in each group.
- mice in the administration group were injected with human plasminogen in the tail vein of 50 mg/kg/mouse/day, and the mice in the vehicle group and the blank control group were injected with the vehicle PBS in the tail vein of 5ml/kg/mouse/day.
- the first day of dosing was defined as day 1, and the dosing was continued for 7 days.
- hot and cold disk pain detection was performed, and the mice began to show pain response.
- the temperature of the equipment was set to a constant temperature of 20 °C, and the mice were put in one by one to adapt for 5 min.
- the hot and cold plate RAMP mode select the hot and cold plate RAMP mode, set the initial temperature to 20°C and the final temperature to 4°C, and set the time from initial temperature to final temperature of 5 minutes. After the device temperature reaches the initial temperature, place the mouse to be tested on the cold plate and click Start. Start timing and cooling, observe the mouse's hind foot contraction and lift and stop, record the time and display temperature of the mouse's hind foot contraction and lift, the longest detection time is 6 minutes, and the measurement is performed 3 times in a row. Note that after each mouse experiment, the hot and cold plates need to be cleaned and wiped with disinfectant before starting the next mouse to avoid mutual interference.
- mice in the vehicle group was significantly higher than that of the mice in the blank control group when the hind paws were contracted and lifted.
- mice in the model group were selected and randomly divided into 2 groups after weighing, 6 mice in the blank control group and 24 mice in the model group. After the grouping was completed, the mice were anesthetized with 2% isoflurane using a respiratory anesthesia machine; the left leg was depilated, and the skin of the distal condyle of the femur was disinfected with iodine solution, and a 0.5 cm shallow incision was made; then a blunt ligament was made on the patella Sexual dissection to expose the distal condyle of the femur with minimal damage; mice in the model group were slowly injected with 10ul LLC cell suspension (2 ⁇ 10 5 cells/ul) into the distal medullary cavity of the left femur with a 50ul sterile microsyringe.
- mice in the control group were injected with 10 ul of sterile saline into the bone cavity; after the injection was completed, the syringe was placed for 90 s to allow cells to fill the bone cavity, and the injection hole was sealed with sterile bone wax to prevent cell leakage after removing the syringe, and then injected with 5.0
- the wound was sutured with silk thread; the mice after surgery were placed on a heating pad to keep warm, and returned to the cage when the mice were awake.
- all mice were weighed and electronic pain detection was performed.
- the mice in the model group were divided into groups according to the results of pain and body weight. There were 12 mice in the vehicle group and 12 mice in the administration group.
- mice in the administration group were injected with human plasminogen in the tail vein of 50 mg/kg/mouse/day, and the mice in the vehicle group and the mice in the blank control group were injected with the vehicle in the tail vein of 5ml/kg/mouse/day.
- the first day of the drug was defined as the first day of dosing, and the drug was administered for 20 consecutive days.
- a clamp-type tenderness test was performed. The specific steps are as follows: the animal to be tested is placed on the fixing frame, and the left and right paws are exposed. Use forceps to clamp the mouse's hind paw and measure the maximum pressure. Record the desired measured pressure value. The measurements were repeated 4 times on the left and right hind paws of each mouse.
- mice Twenty-one 7-10-week-old SCID (Severe Combined Immunodeficiency) mice (NOD.CB17-Prkdcscid/NcrCrl, referred to as NOD SCID, purchased from Weitong Lihua Laboratory Animal Technology Co., Ltd., strain code 40624) were selected. The mice were randomly divided into two groups, 7 mice in the blank control group and 14 mice in the model group. After the grouping was completed, all mice in the model group were anesthetized with 2% isoflurane (purchased from Lunan Beite Pharmaceutical Co., Ltd.), sterilized their backs and injected subcutaneously with 1 ⁇ 10 6 Lewis lung carcinoma cells-GFP cells (stable to green fluorescence).
- NOD SCID severe Combined Immunodeficiency mice
- mice were suspended and observed for 7 days.
- All mice were tested for body weight, and mice in the model group were tested for tumor volume.
- the model group was randomly divided into 2 groups, 7 mice in the vehicle group, 7 mice in the administration group, and blank control. The mice in the group were not treated.
- mice in the administration group were injected with human plasminogen in the tail vein of 1 mg/0.1ml/mouse/day, the mice in the vehicle group were injected with the same volume of PBS in the tail vein, and the mice in the blank control group were not given administration. Dosing for 10 consecutive days. The first day of dosing was designated as day 0, and tumor volume was measured on day 0, day 4, day 7 and day 10.
- Example 15 Therapeutic effect of plasminogen on patients with esophageal cancer
- the patient was a 72-year-old male with clear consciousness, no history of diabetes and heart disease, and a history of hypertension. Diagnosed with esophageal cancer six months ago and started chemotherapy.
- the patient signed an informed consent form and voluntarily received human plasminogen therapy, which was approved by the hospital ethics committee. Human plasminogen was started after the fourth chemotherapy, and human plasminogen therapy was also used after the fifth, sixth, and seventh chemotherapy.
- Human plasminogen dosing regimen The mode of administration is intravenous bolus. Dosing for 21 days is a course of treatment, and the frequency of dosing is twice a day for the first 5 days and once a day thereafter. Daily dose: 40 mg on day 1, then gradually increased to 190 mg on day 21.
- the curative effect on patients after administration was recorded on a scale of 1-10, and the condition without administration on the first day was recorded as 10. If the symptom aggravation score increases, the symptom relief score decreases, and 1 is the lightest.
- the patient's condition improved, the overall impression score was 7 points, the mental state score was 8 points, the appetite score was 7 points, the nausea subsidence score was 0 points, the lower lip ulceration was scabbed, and the hair basically did not fall out .
- the patient's condition was further improved.
- the overall impression score was 4 points, the mental state score was 5 points, the appetite score was 6 points, and the color scores of the left and right palms were both 8 points.
- the lower lip ulceration was basically healed, and the hair basically did not fall out.
- the overall impression score was 1, the mental state score was 0, the appetite score was 0, and the left and right palm color scores were 3 and 4, respectively.
- Dosing regimen for the second course of human plasminogen The mode of administration is intravenous bolus injection. The dosing period is 21 days, the frequency of dosing is once a day, and the dose is 100-120 mg.
- Efficacy The patient's mental state is good, his appetite is good, his sleep is good, his body softens and improves, and he has no other discomfort.
- the sixth chemotherapy was performed 5 days after the end of the second course of administration. After the chemotherapy, the patient reported no discomfort.
- Other drugs taken at the same time are: thymosin enteric-coated tablets.
- the dosing regimen of the third course of human plasminogen is intravenous bolus.
- the dosing period is 7 days, the frequency of dosing is once a day, and the dose is 100-115 mg.
- Angiostatin a novel angiogenesis inhibitor that mediates the suppression of metastases by a Lewis lung carcinoma. Cell. 1994 Oct 21;79(2):315-28.
- Angiostatin a circulating endothelial cell inhibitor that suppresses angiogenesis and tumor growth. Cold Spring Harb Symp Quant Biol. 1994;59:471-82.
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Abstract
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Claims (14)
- 一种治疗肿瘤的方法,包括给药肿瘤受试者有效量的选自如下的一种或多种化合物:纤维蛋白溶酶原激活途径的组分、能够直接激活纤维蛋白溶酶原或通过激活纤维蛋白溶酶原激活途径上游组分而间接激活纤维蛋白溶酶原的化合物、模拟纤维蛋白溶酶原或纤维蛋白溶酶之活性的化合物、能够上调纤维蛋白溶酶原或纤维蛋白溶酶原激活剂表达的化合物、纤维蛋白溶酶原类似物、纤维蛋白溶酶类似物、tPA或uPA类似物和纤溶抑制剂的拮抗剂。
- 权利要求1的方法,其中所述纤维蛋白溶酶原激活途径的组分选自纤维蛋白溶酶原、重组人纤维蛋白溶酶、Lys-纤维蛋白溶酶原、Glu-纤维蛋白溶酶原、纤维蛋白溶酶、含有纤维蛋白溶酶原和纤维蛋白溶酶的一个或多个kringle结构域和蛋白酶结构域的纤维蛋白溶酶原和纤维蛋白溶酶变体及类似物、小纤维蛋白溶酶原(mini-plasminogen)、小纤维蛋白溶酶(mini-plasmin)、微纤溶酶原(micro-plasminogen)、微纤溶酶(micro-plasmin)、delta-纤溶酶原、delta-纤溶酶(delta-plasmin)、纤维蛋白溶酶原激活剂、tPA和uPA。
- 权利要求1或2的方法,其中所述纤溶抑制剂的拮抗剂为PAI-1、补体C1抑制物、α2抗纤溶酶或α2巨球蛋白的抑制剂,例如抗体。
- 权利要求1-3任一项的方法,其中所述化合物为纤溶酶原。
- 权利要求1-4任一项的方法,其中其中所述肿瘤为癌症。
- 权利要求1-5任一项的方法,其中所述肿瘤选自如下的一种或多种:口腔癌、食管癌、胃癌、小肠癌、结肠癌、直肠癌、肺癌、肝癌、肝细胞癌、胰腺癌、胆囊癌、非小细胞肺(NSCL)癌、支气管肺泡细胞肺癌、乳腺癌、卵巢癌、宫颈癌,输卵管癌、子宫内膜癌、阴道癌、前列腺癌、尿道癌、阴茎癌、肾癌、输尿管癌、肾细胞癌、肾盂癌、膀胱癌、头颈部癌、皮肤癌、黑素瘤、间皮瘤、骨癌、甲状腺癌、甲状旁腺癌、肾上腺癌、软组织肉瘤、胶质瘤、多形性成胶质细胞瘤、星形细胞瘤、施旺细胞瘤、室管膜瘤、髓母细胞瘤、脑脊膜瘤、鳞状细胞癌、垂体腺瘤。
- 权利要求1-6任一项的方法,其中所述纤溶酶原具有选自如下的一种或多种作用:减小肿瘤体积、改善肿瘤受试者的一般生存状况、延迟肿瘤的进展、抑制肿瘤细胞的生长、提高存活率、延长肿瘤受试者生存期、减轻癌性疼痛、抑制肿瘤血管形成、促进肿瘤细胞坏死或凋亡、促进抗肿瘤免疫应 答、调节肿瘤相关抗原或淋巴细胞表面分子的表达、减轻癌细胞对组织器官的损伤、促进肿瘤损伤组织结构或功能恢复。
- 权利要求1-7任一项的方法,其中所述受试者血纤溶酶原水平或肿瘤组织中或未患肿瘤的组织中纤溶酶原水平高于、等于或低于健康受试者血纤溶酶原水平或未患肿瘤的相应组织中的纤溶酶原水平。
- 权利要求1-8任一项的方法,其中所述受试者血纤维蛋白水平或肿瘤组织中或未患肿瘤的组织中纤维蛋白水平高于、等于或低于健康受试者血纤维蛋白水平或未患肿瘤的相应组织中的纤维蛋白水平。
- 权利要求1-9任一项的方法,本申请所述纤溶酶原与选自如下的一项或多项联合施用:化疗、放疗、手术疗法、细胞疗法和免疫疗法。
- 权利要求1-10任一项的方法,其中所述纤溶酶原选自Glu-纤溶酶原、Lys-纤溶酶原、小纤溶酶原、微纤溶酶原、delta-纤溶酶原或它们的保守取代变体。
- 权利要求1-10任一项的方法,其中所述纤溶酶原是包含丝氨酸蛋白酶结构域和/或赖氨酸结合结构域的纤溶酶原蛋白。
- 权利要求1-10任一项的方法,其中所述纤溶酶原是包含与序列14具有至少75%、80%、85%、90%、95%、96%、97%、98%或99%的序列同一性,并具有蛋白水平活性的纤溶酶原蛋白。
- 权利要求1-10任一项的方法,其中所述纤溶酶原与序列2、6、8、10或12具有至少75%、80%、85%、90%、95%、96%、97%、98%或99%的序列同一性,并且仍然具有纤溶酶原活性。
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US20230302102A1 (en) | 2023-09-28 |
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