CN111000983A - Medicinal use of new recombinant human interleukin-1 receptor antagonist - Google Patents
Medicinal use of new recombinant human interleukin-1 receptor antagonist Download PDFInfo
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- CN111000983A CN111000983A CN201911360903.XA CN201911360903A CN111000983A CN 111000983 A CN111000983 A CN 111000983A CN 201911360903 A CN201911360903 A CN 201911360903A CN 111000983 A CN111000983 A CN 111000983A
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- receptor antagonist
- human interleukin
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- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/1703—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
- A61K38/1709—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/06—Antigout agents, e.g. antihyperuricemic or uricosuric agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
Abstract
The invention relates to a recombinant human interleukin-1 receptor antagonist which has a treatment effect on inflammation and pain of acute gout, and discloses a recombinant human interleukin-1 receptor antagonist which can effectively control the acute arthritis symptom of acute gout and relieve the pain of patients. In addition, the invention does not have serious adverse reaction of three common medicines of colchicine, non-steroidal anti-inflammatory drugs and glucocorticoid for controlling gout symptoms.
Description
Technical Field
The invention relates to a new medicinal application of a recombinant human interleukin-1 receptor antagonist, in particular to a therapeutic effect of the recombinant human interleukin-1 receptor antagonist on inflammation and pain of acute gout.
Background
The recombinant interleukin-1 receptor antagonist (rhIL-1Ra) is a protein cytokine receptor antagonist existing in human body, and can competitively prevent the combination of the recombinant interleukin-1 and the receptor thereof by specifically combining with the interleukin-1 receptor, so that the recombinant interleukin-1 can not exert biological effect. The recombinant interleukin-1 receptor antagonist is a recombinant product of human interleukin-1 receptor antagonist, consists of 153 amino acids, and has a molecular weight of 17.3 KD.
rhIL-1Ra plays a very critical initiating role in the inflammatory response of the body. In the process of occurrence and development of many human diseases, rhIL-1Ra participates, and the rhIL-1Ra itself not only can chemotaxis inflammatory reaction cells in vivo to gather to an inflammation occurrence position, but also can stimulate the generation of various inflammatory mediation media in vivo to further aggravate the inflammatory reaction. Therefore, how to eliminate the effect of rhIL-1Ra plays an important role in curing certain inflammatory diseases. rhIL-1Ra is an antagonist of rhIL-1Ra that occurs naturally in vivo. It can specifically bind to rhIL-1Ra receptor on cell surface without activating target cell, thereby blocking the biological activity of rhIL-1 Ra. rhIL-1Ra is the only cytokine antagonist discovered to date. Since the discovery of rhIL-1Ra, attempts have been made to develop rhIL-1Ra as a clinically applicable drug, and a number of basic and preliminary clinical studies have shown that rhIL-1Ra is effective in a number of inflammatory diseases in humans. Such reports have further fueled the promise of rhIL-1Ra as a new drug.
Phase Data of network registration and follow-up research of a national Rheumatism Data Center (CRDC) show that the number of hyperuricemia patients in China currently reaches 1.7 hundred million, wherein the number of gout patients exceeds 8000 ten thousand, the prevalence rate of gout is 1-3%, and the gout is in a trend of rising year by year. The average age of gout patients in China is 48 years old. With a gradual trend towards younger age, men have a higher incidence than women, and over 50% of gout patients are overweight or obese. Developed countries have a higher prevalence of gout than developing countries worldwide. Gout is common in North America and Western Europe, and the prevalence rate is 1-4%.
Gout is a common and complex arthritis type syndrome caused by increased blood uric acid and deposition of urate crystals on joints and kidney tissues, which includes arthritis, tophus, urinary tract uric acid stones, gouty nephropathy and the like, gout is caused by the fact that the final product of purine metabolism in the body, namely uric acid is excessive and higher than normal, which can be increased due to the lack of urate oxidase (or uricase), uric acid excretion can be reduced due to renal insufficiency, both can cause hyperuricemia, basic research proves that urate crystals deposited in joint cavities of gouty arthritis patients can activate neutral granulocyte alkaline phosphatase 3 (natrolitic alkaline phosphatase-3, NALP3) inflammation, promote the maturation and secretion of IL-1 β, finally cause gout inflammation reaction, generally, the main causes of gout include but are not limited to ① dietary reasons, eating meat and seafood, after drinking seafood, the human body has increased levels of seafood, the human body can cause excessive deposition and secretion of IL-1, the gout inflammation reaction can cause gout inflammation, even if the kidney fails to cause excessive urate, the kidney metabolism is damaged, the kidney fails to cause severe, the kidney erosion, the kidney metabolism of uric acid is damaged, the kidney erosion of the kidney is damaged, the kidney 23 is damaged, the kidney erosion of the kidney is damaged, the kidney erosion is damaged, the kidney erosion of the kidney erosion is damaged, the kidney is damaged.
Aiming at different clinical stages of gout, the anti-gout drugs can be divided into two major drugs of controlling acute arthritis symptoms and anti-hyperuricemia, the drugs for controlling the gouty arthritis symptoms mainly comprise colchicine, non-steroidal anti-inflammatory drugs, glucocorticoids and the like, the anti-hyperuricemia drugs mainly comprise drugs for inhibiting uric acid production (such as allopurinol) and drugs for promoting uric acid discharge (such as benzbromarone, probenecid and the like), the drugs can generate certain adverse reactions, mainly comprise ① gastrointestinal symptoms including diarrhea, nausea, vomiting, abdominal pain and the like, occasionally causing gastric ulcer, gastrorrhagia and gastric perforation, ② muscle and peripheral nervous system symptoms including headache, fever, somnolence, dizziness, weakness, abnormal spirit and the like, ③ anaphylactic reactions including dyspnea, alopecia, skin itch, papule or urticaria and the like, and ④ occasionally causing leucopenia, thrombocytopenia, anemia, bone marrow inhibition, liver and kidney function damage, diabetes, hypertension and the like.
In summary, the existing medicines for treating gout are not ideal and have some adverse reactions, so that the development of an ideal medicine for treating acute gout is an important subject.
Disclosure of Invention
The invention aims to solve the defect that the use of the medicine for treating acute gout in the prior art has certain adverse reaction, thereby providing a novel recombinant human interleukin-1 receptor antagonist for treating inflammation and pain of acute gout for patients.
The recombinant human interleukin-1 receptor antagonist can effectively control the acute arthritis symptom of acute gout, can relieve the pain of patients, and has no other serious adverse reactions except that individual patients have injection site stimulation reaction and red swelling.
The recombinant human interleukin-1 receptor antagonist is prepared by constructing recombinant plasmid containing interleukin-1 receptor antagonist gene by using an escherichia coli expression technology, converting the recombinant plasmid into escherichia coli to obtain stable engineering bacteria, fermenting the engineering bacteria, purifying to obtain a recombinant human interleukin-1 receptor antagonist stock solution, and adding auxiliary materials to prepare the recombinant human interleukin-1 receptor antagonist injection.
The recombinant human interleukin-1 receptor antagonist is characterized in that: the preparation is an injection, the specification is 80mg/0.8ml, and the injection can be stored for at least 24 months at the temperature of 2-8 ℃ in the dark.
The packaging material adopted by the recombinant human interleukin-1 receptor antagonist injection is a pre-encapsulated injector assembly with an injection needle, and the injection is directly injected, so that the chance of secondary pollution is reduced, and a patient can realize self-injection administration under the guidance of a doctor.
Compared with the traditional medicine, the recombinant human interleukin-1 receptor antagonist has the advantages of small adverse reaction, safety, effectiveness, stable quality, good patient compliance and the like for treating acute gout.
Advantageous effects
The invention provides a new application of a recombinant human interleukin-1 receptor antagonist, the recombinant human interleukin-1 receptor antagonist has certain effect on acute gout of various degrees, and compared with the existing two major medicines for controlling acute arthritis symptoms and resisting hyperuricemia, the effect is obvious, and in addition to the fact that individual patients can have injection part stimulation reaction and have red swelling when treating acute gout, no other serious adverse reactions exist, and a new indication is found for the recombinant human interleukin-1 receptor antagonist.
Detailed Description
The present invention is described in more detail below to facilitate an understanding of the present invention.
It should be understood that the terms or words used in the specification and claims should not be construed as having meanings defined in dictionaries, but should be interpreted as having meanings that are consistent with their meanings in the context of the present invention on the basis of the following principles: the concept of terms may be defined appropriately by the inventors for the best explanation of the invention.
Example 1:
the amino acid sequence of the rhIL-1Ra is shown as SEQ ID NO:1, and the preparation method is as follows: the recombinant human interleukin-1 receptor antagonist is prepared by constructing recombinant plasmid containing interleukin-1 receptor antagonist gene by using an escherichia coli expression technology, converting the recombinant plasmid into escherichia coli to obtain stable engineering bacteria, fermenting the engineering bacteria, purifying to obtain a recombinant human interleukin-1 receptor antagonist stock solution, and adding auxiliary materials to prepare the recombinant human interleukin-1 receptor antagonist injection.
Example 2: pharmacodynamic test
The inventor observes the treatment effect of rhIL-1Ra on acute gout of rats caused by sodium urate by using 60 female SD rats.
The method comprises the following steps:
and measuring the thermal pain threshold value and the base value of the diameter of the right hind limb ankle joint after the quarantine period of 60 female SD rats is finished, and carrying out balanced grouping according to the thermal pain threshold value to separate 10 normal control group animals and 50 model group animals. On the next day, the model building group is anesthetized by isoflurane, then 50 mu L of sodium urate (25mg/mL, prepared by normal saline) is injected into the joint cavity by puncturing the rear side of the right hind limb ankle joint along the inner side of the achilles tendon in the direction of 30-40 degrees, the normal control group is injected with the same volume of normal saline, the diameter of the right hind limb ankle joint and the thermal pain threshold are measured after 3h of model building, and the swelling degree is calculated. And selecting 36 animals of the building module group, and performing layering random grouping according to the swelling degree to obtain a solvent control model group, a raw material medicine low-dose group (9mg/kg) and a raw material medicine high-dose group (18 mg/kg). The medicine is administered by subcutaneous injection at neck part according to body weight 1 time per day for three days. The normal control group and the solvent control model group were administered with vehicle (placebo), and the bulk drug low dose group and the bulk drug high dose group were administered with rhIL-1Ra concentrations of 9mg/mL and 18mg/mL, respectively, in a volume of 1 mL/kg. Ankle diameters and thermal pain thresholds at 4h, 24h and 72h after administration were measured, and swelling degree and swelling inhibition rate and thermal pain threshold increase rate were calculated.
As a result:
the statistical results of swelling degrees are shown in table 1, and as shown in table 1, after 3h of molding, the swelling degrees of the other groups except the normal control group are obviously increased (P is less than 0.01); after administration, compared with a solvent control model group, swelling degrees of the raw material medicine low-dose group and the raw material medicine high-dose group at 4h, 24h and 72h after administration are reduced, and the bulk medicine high-dose group is reduced at 4h and 24h after administration and has significant difference (P is less than 0.05). The statistics of the inhibition rates of swelling of the drug-administered groups showed that the inhibition rates of swelling at 4h, 24h and 72h after drug administration were (19.62%, 8.99% and 11.23%) and (26.67%, 31.90% and 9.57%) respectively for the drug-administered groups.
TABLE 1 influence of rhIL-1Ra on ankle swellings of acute gout rats
Remarking: aa, P < 0.01, compared to the normal control group; compared with the solvent control model group, b and P are less than 0.05.
The results of the thermal pain threshold test are shown in tables 2 and 3. As shown in table 2, compared with the solvent control model group, the thermal pain thresholds of the bulk drug low dose group at 4h and 72h after administration tended to increase without statistical difference, while the thermal pain thresholds of the bulk drug high dose group at different time points after administration all increased, and the increases at 4h and 72h after administration were significantly different (P < 0.01, P < 0.05); comparison between low-dose and high-dose groups of the raw material medicines shows that the thermal pain threshold of the high-dose group is higher than that of the low-dose group at different time points after administration, and the thermal pain threshold of the high-dose group is very significant difference (P is less than 0.01) at 4h after administration, which indicates that the pain of animals in the high-dose group of the raw material medicines is reduced compared with that in the solvent control model group and the low-dose group of the raw material medicines.
As shown in table 3, compared with the baseline value before molding, the thermal pain threshold of the normal control group was decreased at both post-molding and at different time points of administration, wherein the decrease was significantly different at 24h and 72h after administration (P <0.05 ); the thermal pain threshold values of the solvent control model group, the bulk drug low-dose group and the bulk drug high-dose group are increased firstly in the acute stage of 3 hours after the model is made, and then are reduced at different time points after the drug is administered, and in addition, the thermal pain threshold value of the bulk drug high-dose group is not reduced and is slightly increased any more at 72 hours after the drug is administered. Compared with a solvent control model group, pain thresholds of the bulk drug high-dose group at different time points after molding and after administration are increased, and the increase is significantly different at 4h and 72h after administration (P is less than 0.01 and P is less than 0.05).
TABLE 2 influence of rhIL-1Ra on the thermal pain threshold in acute gout rats
Remarking: compared with a normal control group, a is less than 0.05, aa and P is less than 0.01; compared with the solvent control model group, b, P is less than 0.05, bb, P is less than 0.01; compared with the low-dose group of the raw material medicines, c and P are less than 0.05, cc and less than 0.01.
Table 3 Effect of rhIL-1Ra on the rate of increase of the thermal pain threshold in rats with acute gout (%)
And (4) conclusion:
the high-dose rhIL-1Ra can obviously reduce the ankle joint swelling of rats induced by sodium urate and relieve the pain sensation of acute gout rats, and the rhIL-1Ra is suggested to have a treatment effect on inflammation and pain in acute gout.
Example 3: pharmacological testing
The inventor observes other wide pharmacological effects of the rhIL-1Ra in addition to the biological drug effect of the acute gout in mice and cats.
The method comprises the following steps:
1. taking mice with the weight of 18-22g, dividing the mice into 4 groups with 10 mice in each group, and dividing the mice into a solvent control model group, a raw material medicine low dose group (4.5mg/kg), a raw material medicine medium dose group (9mg/kg) and a raw material medicine high dose group (18 mg/kg). After subcutaneous injection, the mice were observed for general behavior, posture, gait, presence or absence of tremor or paralysis, appetite, and incontinence of urine and feces. And recording the walking time and the lifting times of the double forelimbs of the mice 2 minutes before and 30 minutes after the administration respectively.
2. The method comprises the steps of taking cats weighing 2-3kg, dividing male and female halves randomly into 4 groups, wherein each group comprises 5 cats, and dividing the groups into a solvent control model group, a raw material medicine low dose group (4.5mg/kg), a raw material medicine medium dose group (9mg/kg) and a raw material medicine high dose group (18 mg/kg). Firstly, 30mg/kg sodium pentobarbital of 3 percent is anesthetized by intraperitoneal injection and fixed in a supine position, a common carotid artery is inserted into a tube, a mercury tonometer is connected, a limb II-lead electrocardiogram is connected, and blood pressure, QRS waves, ST segment, T waves and heart rhythm are recorded. After subcutaneous administration, the electrocardiogram of the sphygmomanometer was continuously recorded for 2 hours. Changes before and after administration were compared.
3. The method comprises the steps of taking cats weighing 2-3kg, dividing male and female halves randomly into 4 groups, wherein each group comprises 5 cats, and dividing the groups into a solvent control model group, a raw material medicine low dose group (4.5mg/kg), a raw material medicine medium dose group (9mg/kg) and a raw material medicine high dose group (18 mg/kg). Firstly, 30mg/kg sodium pentobarbital of 3 percent is anesthetized by intraperitoneal injection and fixed in a supine position, a line is drawn at the most obvious part of chest respiratory motion to be connected with a pulley and a tracing pen, and the respiratory motion frequency and the depth of a cat are recorded on a tattooing drum. After subcutaneous administration, respiratory movement frequency and depth were continuously recorded over 2 hours. Changes in respiratory movements before and after administration were compared.
As a result:
after the conscious mice are injected with rhIL-1Ra subcutaneously, the general behavior of the conscious mice is shown, and the posture, the gait, the muscle tension, the appetite and the excrement and urine of the conscious mice are not obviously changed. The results show that the rhIL-1Ra has no adverse reaction on the mental and nervous systems of mice, and has no excitation and inhibition effects. The rhIL-1Ra has no obvious change before and after administration for the observation of indexes such as blood pressure, electrocardiogram, respiratory movement and the like of anesthetized cats.
And (4) conclusion:
therefore, rhIL-1Ra has no other broad pharmacological effects except anti-inflammatory and analgesic effects.
Example 4: toxicology test-acute toxicity test the inventors observed the toxic response of a single administration of large doses of rhIL-1Ra in mice.
The method comprises the following steps:
a mouse with the weight of 18-22g is taken, each half of male and female is divided into 2 groups at random, each group comprises 10 mice, and the groups are divided into a solvent control model group and a bulk drug high dose group (400mg/kg, which is equivalent to 20 times of the drug effect high dose of the mouse and is equivalent to 200 times of the clinical application dose). After once subcutaneous injection, the mice were continuously observed for 14 days to see whether the mice had tremor, convulsion, stiffness, salivation, loose stools, lethargy, coma, abnormal breathing and limb movements, death, etc.
As a result:
all mice survived with no abnormalities in general behavioral manifestations, appetite, etc., and increased body weight. No significant toxicity or abnormal reaction was observed.
And (4) conclusion:
the single administration of rhIL-1Ra at a dose 200 times that of clinical human is nontoxic to mice, which indicates the LD of rhIL-1Ra to mice50More than 400 mg/kg.
Second, long-term toxicity test the inventors observed long-term toxicity of rhIL-1Ra injected subcutaneously for 180 days continuously in rhesus monkeys.
The method comprises the following steps:
the male and female of 32 healthy rhesus monkeys were randomly divided into 4 groups according to body weight, and the test was conducted with 8 control groups, low, medium and high dose groups, each group, and each half of male and female. According to the clinical recommended dose of 100 mg/person day, the administration dose is respectively set as 5, 30 and 180mg/kgd, the administration dose is respectively 2.5, 15.0 and 90.0 times of the recommended clinical dose according to the body weight, the subcutaneous injection is carried out before the morning feeding, and the solvent is equivalent to the sc solvent of the solvent control group. After 180 days of dosing, 2 animals (male and female halves) were sacrificed each group for pathological dissection, and dosing was continued for the remaining animals. Observation of symptoms and detection of indicators include: (1) general symptoms and indices: the appearance, behavior, activity, gait, spirit, appetite, stool and urine, fur, presence or absence of salivation, nausea, vomiting, presence or absence of death, etc. of the monkeys were observed. The general indexes include 5 items of body weight, food intake, anal temperature, respiration and pupils. (2) Electrocardiogram: the heart rate, P-R interval, QRS complex, S-T interval and Q-T interval of limb II electrocardiogram are guided by limbs II. (3) The hematology index is as follows: 16 items in total are red blood cell (RBC count, hemoglobin (Hb) quantification, hematocrit (HC, mean volume of red blood cells MCV), mean hemoglobin content of red blood cells MCH, mean hemoglobin concentration of red blood cells MCHC, platelet (Plat) count, White Blood Cell (WBC) count and classification (lymphocytes and granulocytes), plasma thrombin time (T), plasma prothrombin time PT), activated partial thromboplastin time aPTT, plasma fibrinogen (Fig) content platelet aggregation rate. (4) Biochemical indexes of blood: alanine Aminotransferase (ALT), aspartate Aminotransferase (AST), alkaline phosphatase (ALP), total bilirubin (Tbi), urea nitrogen BUN), Creatinine (CT), Total Protein (TP), Albumin (AB), blood Glucose (GIU), Total Cholesterol (TCH), Lactate Dehydrogenase (LDH), Fibrin (FIB), pH, serum K+、Na+、Cr-、iCa2+、TCa2+、Mg2+、TCO2P and the Anion Gap (AG). (5) Urine test items: nitrite, pH, protein, occult blood, glucose, ketone body, bilirubin and urobilinogen are 8 items. (6) Antibody determination: ELISA method detects antibody titer and biological activity method determines whether the antibody is a neutralizing antibody. (7) Bone marrow examination: observing the change and proliferation degree of cells in each stage of each line. (8) And (3) pathological examination: the presence or absence of positive lesions in the respective organs was generally observed. The heart, liver, spleen, lung, kidney, brain, adrenal gland, thymus, thyroid gland, prostate, testis, uterus and ovary were weighed for 13 organs, and the relative weights of each were calculated. Histological examination: the pathological changes of heart, liver, spleen, lung, kidney, brain, stomach, duodenum, ileum colon, pituitary gland, thyroid gland, adrenal gland, thymus, pancreas, mesenteric lymph node, prostate gland, bladder, testis, epididymis, uterus, ovary, eyeball, optic nerve and subcutaneous tissue at the injection position are observed.
As a result:
(1) in the initial high dose group of rhIL-1Ra, 1 monkey (monkey 26) showed an hyperphagic reduction and gradually recovered after the second week, which was not observed in the other 31 monkeys. After administration, the animals have no abnormal physical signs and behavior activities, no glandular secretion and abnormal respiration, no nausea, vomiting, salivation, fever, diarrhea and other symptoms. (2) Weight change: the weight change of the monkeys in each group was not significantly different during the administration period, and the weight average of the animals in each group increased normally during the administration period, compared to the control group. (3) And (3) electrocardiogram detection and display: compared with the control group, the electrocardio of each group is basically normal and has no obvious change. (4) The biochemical examination result of the blood shows that: compared with a control group, the serum biochemical indexes AST and ALT of the high-dose group are slightly reduced, but no significant difference is seen (p is more than 005), ALB is obviously increased (p is less than 0.05), and other indexes fluctuate in a normal range without significant change. (5) The hematology examination result shows that all indexes of all groups of animals fluctuate in a normal range without obvious change; (6) the antibody assay data indicated that: the serum of the animals in the group given 1 month after administration was detectable as anti-drug antibodies, and the animals in the low, medium and high dose groups all had antibodies present, but no neutralizing antibodies were detected. This is consistent with literature reports. (7) Urine examination: compared with the control group, all indexes fluctuate in a normal range, and no obvious abnormality is seen. (8) Histopathological results: compared with the control group, in the high-dose group, 1 monkey lung slightly suffered from local punctate hemorrhage, 2 monkey kidneys were individually vacuolated to the proximal convoluted tubule, 2 monkey liver cytoplasm was slightly loosened, and 1 monkey myocardium was slightly inflamed. No obvious pathological changes are observed in the other organs. No obvious pathological changes are found in the organs of the medium and low dose groups.
And (4) conclusion:
(1) rhIL-1Ra had no significant adverse effects on the general condition of monkeys. (2) rhIL-1Ra had no significant effect on the monkey coagulation system, but high doses (180mgkg) may have some effect on protein metabolism. (3) Anti-drug antibodies were detected in the serum of the animals in the group administered 1 month after administration, and antibodies were present in the animals in the low, medium and high dose groups, but no neutralizing antibodies were detected. (4) The rhIL-1Ra high dose may have slight influence on liver and kidney functions of monkeys, and has no influence on middle and low dose groups.
Third, immunotoxicity test the present inventors observed the time, titer and presence or absence of neutralizing effect of anti-IL-1 Ra antibody after injection of rhIL-1Ra in monkeys.
The method comprises the following steps:
the anti-IL-1 Ra antibody was assayed by ELISA and the presence or absence of neutralizing antibody was assayed by IL-1Ra bioactivity assay.
As a result:
anti-IL-1 Ra antibodies were detected in the serum of the animals in the group administered 1 month after administration, and antibodies were present in all of the animals in the low, medium and high dose groups, with no dose-dependency, but no neutralizing antibodies were detected.
Fourth, hemolytic test the inventors of the present invention observed the hemolytic and agglutination effect of rhIL-1Ra injection on rabbit red blood cells with blank as control.
The method comprises the following steps:
taking 1 male New Zealand rabbit, extracting 5ml of rabbit blood, removing fibrinogen, adding physiological saline, centrifuging until the supernatant is colorless, taking red blood cells, and adding physiological saline to dilute into 2% suspension. Taking 6 test tubes, adding 0.1, 0.2, 0.3, 0.4 and 0.5ml (80mg/ml) of rhIL-1Ra injection respectively, adjusting to 2.5ml with physiological saline, adding 2.5ml of rabbit erythrocyte suspension respectively, placing in a water-proof constant temperature incubator, observing hemolysis and agglutination of each tube after administration for 0.5, 1, 2 and 3 hours respectively, and observing rupture of blood cells by a microscope.
As a result:
when 0.1, 0.2, 0.3, 0.4, 0.5ml rhIL-1Ra injection is given, no hemolysis and agglutination phenomenon can be observed after 0.5, 1, 2, 3hr of action with rabbit blood, and no difference exists between the observed results and the control group.
And (4) conclusion:
the rhIL-1Ra injection has no hemolytic effect when the concentration reaches 80 mg/ml.
Fifth, local irritation test the inventors observed the local irritation toxicity reaction of rhIL-1Ra in rhesus monkeys.
The method comprises the following steps:
the rhesus monkeys are randomly divided into 4 groups, namely a solvent control model group, a raw material medicine low-dose group (5mg/kg), a raw material medicine medium-dose group (30mg/kg) and a raw material medicine high-dose group (180 mg/kg). The injection is administered once daily, and the four limbs are injected subcutaneously alternately for 180 days.
As a result:
no abnormality appeared in the control group and the low-dose group, while red swelling of the skin at the injection site was observed in some animals in the medium-and high-dose groups after administration, some were accompanied by scratch, but no rupture or infection appeared, and the skin almost disappeared within two months.
And (4) conclusion:
after subcutaneous administration to monkeys, the injection site showed red swelling at the medium and high doses, but the administration continued. The symptoms disappear, and the local tolerance condition is good.
Sequence listing
<110> Changchun biological products institute, LLC
<120> medicinal use of a novel recombinant human interleukin-1 receptor antagonist
<141>2019-12-25
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Asp Gln Pro Val Ser Leu Thr Asn Met Pro Asp Glu Gly Val MetVal
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Claims (5)
1. The application of the recombinant human interleukin-1 receptor antagonist in preparing the medicines for treating the inflammation and pain of acute gout is disclosed, wherein the amino acid sequence of the human interleukin-1 receptor antagonist is shown as SEQ ID NO. 1.
2. The recombinant human interleukin-1 receptor antagonist of claim 1 effective for controlling the symptoms of acute arthritis of acute gout and alleviating pain in a patient, except that the individual patient may experience injection site irritation, redness, and no other serious adverse effects.
3. The use of the recombinant human interleukin-1 receptor antagonist according to claim 1, wherein the human interleukin-1 receptor antagonist is prepared by constructing a recombinant plasmid containing interleukin-1 receptor antagonist genes by using an escherichia coli expression technology, transforming the recombinant plasmid into escherichia coli to obtain stable engineering bacteria, fermenting the engineering bacteria, purifying to obtain a recombinant human interleukin-1 receptor antagonist stock solution, and adding an auxiliary material to prepare the recombinant human interleukin-1 receptor antagonist injection.
4. The use of a recombinant human interleukin-1 receptor antagonist according to claim 1, wherein: the preparation is an injection, the specification is 80mg/0.8ml, and the injection can be stored for at least 24 months at the temperature of 2-8 ℃ in the dark.
5. The use of a recombinant human interleukin-1 receptor antagonist according to claim 1, wherein: the packaging material is a pre-filling and sealing injector assembly with an injection needle, and can be directly injected, so that the chance of secondary pollution is reduced, and a patient can realize self-injection administration under the guidance of a doctor.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113842448A (en) * | 2020-11-04 | 2021-12-28 | 深圳前海鹰岗生物科技有限公司 | Polymer microneedle for treating acute gout attack and preparation method thereof |
Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1175213A (en) * | 1994-12-12 | 1998-03-04 | 奥默罗斯医学系统有限公司 | Irrigation solution and method for inhibition of pain, inflammation |
| CN1471968A (en) * | 2002-07-29 | 2004-02-04 | 北京北医联合生物工程公司 | Medicinal use of recombined human interleukin-1 receptor antagonist |
| US20060094663A1 (en) * | 2004-05-05 | 2006-05-04 | Sylvain Chemtob | Interleukin-1 receptor antagonists, compositions, and methods of treatment |
| US20090123446A1 (en) * | 2006-10-20 | 2009-05-14 | Regeneron Pharmaceuticals, Inc. | Use of IL-1 Antagonists to Treat Gout |
| CN101781364A (en) * | 2010-01-22 | 2010-07-21 | 上海抗体药物国家工程研究中心有限公司 | Interleukin-1 receptor antagonist |
| US20130178425A1 (en) * | 2010-09-03 | 2013-07-11 | Biomet Biologics, LLC. | Methods and compositions for delivering interleukin-1 receptor antagonist |
| AU2015203141A1 (en) * | 2007-12-20 | 2015-07-09 | Xoma (Us) Llc | Methods for the treatment of gout |
| CN105367663A (en) * | 2014-08-31 | 2016-03-02 | 复旦大学 | Long-acting interleukin-1 receptor antagonist recombinant fusion protein and a preparation method and application thereof |
-
2019
- 2019-12-25 CN CN201911360903.XA patent/CN111000983A/en active Pending
Patent Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1175213A (en) * | 1994-12-12 | 1998-03-04 | 奥默罗斯医学系统有限公司 | Irrigation solution and method for inhibition of pain, inflammation |
| CN1471968A (en) * | 2002-07-29 | 2004-02-04 | 北京北医联合生物工程公司 | Medicinal use of recombined human interleukin-1 receptor antagonist |
| US20060094663A1 (en) * | 2004-05-05 | 2006-05-04 | Sylvain Chemtob | Interleukin-1 receptor antagonists, compositions, and methods of treatment |
| US20090123446A1 (en) * | 2006-10-20 | 2009-05-14 | Regeneron Pharmaceuticals, Inc. | Use of IL-1 Antagonists to Treat Gout |
| AU2015203141A1 (en) * | 2007-12-20 | 2015-07-09 | Xoma (Us) Llc | Methods for the treatment of gout |
| CN101781364A (en) * | 2010-01-22 | 2010-07-21 | 上海抗体药物国家工程研究中心有限公司 | Interleukin-1 receptor antagonist |
| US20130178425A1 (en) * | 2010-09-03 | 2013-07-11 | Biomet Biologics, LLC. | Methods and compositions for delivering interleukin-1 receptor antagonist |
| CN105367663A (en) * | 2014-08-31 | 2016-03-02 | 复旦大学 | Long-acting interleukin-1 receptor antagonist recombinant fusion protein and a preparation method and application thereof |
Non-Patent Citations (1)
| Title |
|---|
| ＲICHETTE P等: "2016 updated EULAＲ evidence-based recommendations for the management of gout", 《ANNALS OF THE ＲHEUMATIC DISEASES》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113842448A (en) * | 2020-11-04 | 2021-12-28 | 深圳前海鹰岗生物科技有限公司 | Polymer microneedle for treating acute gout attack and preparation method thereof |
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