CN1565631A - Usage of fused protein of TNF receptor and globin in acute lung injury treating medicine - Google Patents
Usage of fused protein of TNF receptor and globin in acute lung injury treating medicine Download PDFInfo
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Abstract
The invention relates to drug field, more specifically relates to the usage of confluent protein of tumor necrosin receptor-immune global protein(TNFR-Ig confluent protein) for treating acute lung injury. Pharmaceutical composition contained TNFR-Ig confluent protein can effectively treating acute lung injury occurred by SARS virus and other factors.
Description
Technical field
The present invention relates to drug world, relate more specifically to the purposes of fusion rotein (abbreviating " TNFR-Ig fusion rotein " as) aspect the treatment acute lung injury of tumor necrosis factor receptor-immunoglobulin.
Background technology
(Severe Acute Respiratory Syndromes SARS) after the generation, once involved the whole world more than 30 individual countries, and total number of the infected is above 7500 people, and is dead above 600 people since severe acute respiratory syndrome.SARS has intensive infectiousness, can send out and outbreak of epidemic to the surrounding area rapidly, and mortality rate can influence the politics and the expanding economy of countries in the world up to 14%-15%.
SARS is a kind of new pathogen, the fatality rate height, and infectiousness is strong.Understanding to aspects such as its epidemiology, nosetiology, immunologys is also very limited, and clinical treatment does not also have the definite effective medicine, and developing vaccines is also at the early-stage.Therefore, WHO and various countries scientist think that all this situation obviously also will continue significant period of time, and do not get rid of the probability of outburst once more.Therefore, development SARS prevents and treats medicine, particularly can effectively reduce the medicine of mortality rate, has become the focus that the whole world is paid close attention to.
Most of SARS the infected can show acute respiratory distress syndrome (ARDS after sb.'s illness took a turn for the worse, Acute Respiratory Distress Syndrome) and acute lung injury (ALI, Acute Lung Injury), shock or multiple organ dysfunction syndrome (MODS) also can appear in the patient of some serious symptoms.The acute pathological changes of these pulmonarys and major injury have caused SARS patient's final death just.
Therefore, this area presses for the medicine of the new effective treatment acute lung injury of exploitation.
Tumor necrosis factor (Tumor Necrosis Factor alpha, TNF-α) be that the intravital a kind of multifunction immunity of machine is regulated molecule, it can play a role with the receptors bind on the cell membrane, often cause the dead of target cell or attract immune effector cell, participate in multiple physiology, pathology and immunologic process in partial gathering.
(TNF receptor, studies show that TNFR) has I type, two kinds of Tumor Necrosis Factor Receptors of II type, is I type transmembrane glycoprotein to the TNF receptor.It is more extensive wherein to distribute with the II type, stronger with the affinity of tumor necrosis factor.Just can bring into play function from signal to cell that transmit on the cell membrane though two kinds of receptors need be positioned at, still have part to drop in the body fluid, be called soluble recepter from cell surface.Further studies show that, the receptor of this solubility can in and TNF, the activity to TNF plays down regulation in vivo.
The TNFR-Ig fusion rotein is that genetic engineering and immunological technique are combined, and utilizes receptor-immunoglobulin integration technology (claiming " immune adherence " technology (Immunoadhesion Technology) again), produces recombined human II type TNFR-Ig fusion rotein.Its principle is to utilize technique for gene engineering, and (Immunoglobulin, Fc fragment gene Ig) merges, and goes out corresponding fusion proteins at vivoexpression with the cell outskirt of receptor and immunoglobulin.
Yet, still the TNFR-Ig fusion rotein is not used for the treatment of the report of acute lung injury up to now.
Summary of the invention
Purpose of the present invention is exactly a kind of medicine of effective treatment acute lung injury, and the active component of described medicine is the TNFR-Ig fusion rotein.
In a first aspect of the present invention, a kind of purposes of fusion rotein of tumor necrosis factor receptor-immunoglobulin is provided, be used to prepare the medicine for the treatment of acute lung injury.
In a preference, described acute lung injury is infected by sars coronavirus and is caused.
In another preference, the weight content of TNFR-Ig fusion rotein is 1-99% in the described medicine.
In another preference, the sequence of 235 amino acid residue behaviour II type Tumor Necrosis Factor Receptors extracellular sections of the N-end of described TNFR-Ig fusion rotein, 232 amino acid residues of its C-end are the FC sequence of human normal immunoglobulin γ 1 chain.
In another preference, the route of administration of described medicine is intravenous injection or intravenous drip.
In another preference, the dosage of described medicine is 0.1-3mg TNFR-Ig fusion rotein/kg body weight every day.More preferably, the dosage of described medicine is 0.5-2mg TNFR-Ig fusion rotein/kg body weight every day.
The specific embodiment
The inventor is the extensive studies discovery through going deep into, and the TNFR-Ig fusion rotein can be treated acute lung injury very effectively, has finished the present invention on this basis.
As used herein, term " TNFR-Ig fusion rotein " refers to by the extracellular section of Tumor Necrosis Factor Receptors and the formed fusion rotein of Fc fragment of immunoglobulin.Preferred TNFR is an II type Tumor Necrosis Factor Receptors.In addition, should have length between TNFR and Ig part is 10-30 amino acid whose peptide linker.
The method for making of TNFR-Ig fusion rotein and structure are known, for example the product E nbrel of American I mmunex company
TMBe exactly a kind of people II type TNFR-Ig fusion rotein, the sequence of 235 amino acid residue behaviour II type Tumor Necrosis Factor Receptors extracellular sections of its N-end; 232 amino acid residues of its C-end are the FC sequence (IgG1 Fc) of human normal immunoglobulin γ 1 chain, preparation method for the TNFR-Ig fusion rotein, can be referring to Chinese patent application 01132074.5 (application on October 31 calendar year 2001, applicant: Shanghai CP Guojian Pharmaceutical Co.,Ltd).
Technology, method, some indication of the TNFR-Ig fusion rotein being mixed with medicine all are as known in the art.For example, in the art, the TNFR-Ig fusion rotein has been used for the treatment of rheumatoid arthritis.
As used herein, term " pharmaceutical composition of the present invention " refers to be used for the treatment of acute lung injury, contains the compositions of TNFR-Ig fusion rotein and pharmaceutically acceptable carrier.
When making pharmaceutical composition, be that TNFR-Ig fusion rotein with safe and effective amount is applied to mammal, wherein this safe and effective amount is usually at least about 10 micrograms/kg body weight, and in most of the cases be no more than about 8 mg/kg body weight, preferably this dosage is about 10 micrograms/kg body weight-Yue 1 mg/kg body weight.Certainly, concrete dosage also should be considered factors such as route of administration, patient health situation, and these all are within the skilled practitioners skill.
The pharmaceutical composition for preparing can carry out administration by conventional route, comprising (but being not limited to): intravenous drip, intramuscular, intravenous, subcutaneous, Intradermal or topical.
The TNFR-Ig fusion rotein can effectively be treated the mechanism of acute lung injury may be as described below.However, it should be understood that scope of the present invention is not subjected to the restriction of this treatment mechanism.
By TNF-α and the good malignant disease relation of breast lung be studies have shown that the generation of TNF and the good malignant disease of breast lung, development all have certain relation.Research shows that pulmonary alveolar macrophage can produce TNF, and the generation of TNF and Lung and Chest Diseases, development have comparatively confidential relation.On the other hand, TNF plays an important role to the release of other Secondary cases cytokines.Overweight of a specified duration excessively when various TNF effects, PCEC, interstitial lung and alveolar epithelial cells grievous injury finally produce ARDS.The level of TNF plays an important role to the control of injury of lung in the regulation and control body.SARS causes patient pulmonary acute injury the most at last, and TNF-α unusual rising of level in human body has directly caused the inflammation of pulmonary just.Therefore, if can lower the immune reaction of SARS patient and reduce the damage that pulmonary is caused, reduce the intravital TNF-alpha levels of SARS patient to normal amplitude, can correctly handle and effectively treat and alleviate the pulmonary lesion symptom degree of ARDS and ALI, can farthest reduce simultaneously medicine again may be to the side effect of patient's generation, this will be of great advantage to the treatment of SARS, help to improve therapeutic effect, reduce the SARS mortality.
The TNFR-Ig fusion rotein can be in conjunction with the material of TNF as a kind of long half time, TNF around can combining competitively with the TNFR on the cell surface in vivo, thereby reduce the number that is incorporated into the TNF of TNFR on the cell, thereby reduce or eliminate the inflammatory reaction that causes by TNF, thereby the acute lung injury that effective inhibition is caused by factors such as SARS.
Result of the test of the present invention shows that the TNFR-Ig fusion rotein can be treated acute lung injury very effectively.In addition, by too high TNF in effectively and in the body, can alleviate the clinical disease of SARS greatly, therefore, use recombined human II type TNFR-Ig fusion rotein and treat SARS, of great advantage to the treatment of SARS, help to improve therapeutic effect, reduce the SARS mortality.Therefore pharmaceutical composition of the present invention is a kind of medicine of effective reduction SARS mortality rate.
Below in conjunction with specific embodiment, further set forth the present invention.Should be understood that these embodiment only to be used to the present invention is described and be not used in and limit the scope of the invention.The experimental technique of unreceipted actual conditions in the following example, usually according to normal condition, or the condition of advising according to manufacturer.
Embodiment 1
Pharmacodynamic study before clinical
The TNFR-Ig fusion rotein that uses in the present embodiment (being also referred to as " rh-TNFR:Fc "), the sequence of 235 amino acid residue behaviour II type Tumor Necrosis Factor Receptors extracellular sections of its N-end; 232 amino acid residues of its C-end are the FC sequence (IgG1 Fc) of human normal immunoglobulin γ 1 chain.These goods are to adopt Chinese hamster ovary cell (Chinese hamster ovary celI) serum-free continous pouring fermentation technique to produce, and obtain the albumen of purification behind ultrafiltration and concentration, multistep purification by chromatography, and final lyophilizing is a clinical research preparation (referring to CN01132074.5).This product and the product E nbrel of American I mmunex company
TMHave identical molecular structure and external activity, immunoreactivity.
These goods are lyophilized injectable powder, and every contains 12.5mg TNFR-Ig fusion rotein.Should keep in Dark Place in 2～8 ℃, avoid moist.Contain the sterile water for injection dissolving with 1 milliliter before using, usage is intravenous drip.
(a) acute lung injury test
Rh-TNFR:Fc is carried out clinical preceding pharmacodynamic study.Use endogenous toxin usually to induce rat, make it to produce the acute lung injury symptom, use rh-TNFR:Fc fusion rotein intravenous injection rat then.
The result shows that in this test, this medicine is minimum can to produce tangible drug action when the 1mg/kg body weight.
(b) test of injected in mice fatal dose TNF-α and TNFR-Ig fusion rotein
In this test, by injected in mice fatal dose TNF-α model, studied in the body of subcutaneous injection TNFR:Fc in and the situation of TNF α.
The result shows, gives mouse peritoneal injection reorganization humanTNF-(R﹠amp; D systems) 1 μ g/, mice is in 24h dead (20/20) all.Subcutaneous injection rhTNFR:Fc fusion rotein before the 24h (50 μ g/ only) group mice does not then have animal dead (0/20).This result proves, during the rhTNFR:Fc fusion rotein can play really in vivo and the effect of TNF-α, and this medicine percutaneous still has pharmacological action behind the 24h down after the injection at least.Other two treated animal TNF-α dosages are increased to 2 μ g, dead 8 of rhTNFR:Fc treated animal (survival rate 60%) as a result, Enbrel
TMDead 7 of treated animal (survival rate 65%); Through χ
2Check, two treated animal survival rates do not have significant difference.
In sum, intravenous injection TNFR-Ig fusion rotein can play preventive and therapeutic effect to the Acute Lung Injury of endotaxin induction, and its effect is proportionate with dosage.
Embodiment 2
Safety detects
The general pharmacology that utilizes cat that pilot product is carried out is learned and be studies show that, the TNFR-Ig fusion rotein of subcutaneous injection 4mg/kg or 12mg/kg, and animal is not having obvious change aspect ensuing 6 hours internal respirations, blood pressure, the rhythm of the heart, heart rate, the electrocardiogram.Use four kinds of methods such as Irwin behavior staging, pole-climbing method, open method, gradient method, observe subcutaneous injection rh-TNFR:Fc20mg/kg and 40mg/kg the neural influence of mice spirit.
TNFR-Ig fusion rotein and excipient negative control group do not have marked difference as a result.Illustrate that it is safe using method of the present invention to carry out the acute lung injury treatment.
Embodiment 3
Pharmacokinetics test
Entrust new drug Research on Safety Assessment center, national Shanghai, utilize rat to carry out the TNFR-Ig fusion rotein and (comprise TNFR-Ig fusion rotein and Enbrel among the CN01132074.5
TM) the pharmacokinetics comparative study.Subcutaneous rat this medicine of 3mg/kg or the Enbrel of giving
TM, the different time blood sampling utilizes sandwich ELISA to detect the drug level in the rat blood serum then and analyzes after administration.
Results suggest, TNFR-Ig fusion rotein and Enbrel among the CN01132074.5
TMAll do not have significant difference on indexs such as area under the drug-time curve, half-life, peak concentration, curve is near overlapping during both medicines.This presentation of results, this product are approaching with Enbrel ten minutes on pharmacokinetic property.
Give the research medicine of mice disposable vein injection 160mg/kg (recommend clinical practice dosage 400 times), in 14 days observation period, all animals survival and weight increase, no abnormal toxic reaction phenomenon.
Embodiment 4
Long term toxicity test
In addition, carried out the long-term toxicity test of 4 weeks of this product with Rhesus Macacus, to observe the toxic reaction and the order of severity thereof that Rhesus Macacus subcutaneous injection rh-TNFR:Fc 4 week back produces body, the target organ of toxic reaction and the reversibility of infringement thereof are provided, determine the dosage of non-toxic reaction, provide reference for drafting the human safe dose.
The result shows, be respectively 0,1,5 and 15mg/kg giving dosage, inject weekly 2 times, injected for 4 weeks continuously, the general symptom of animal, hematology and serum biochemistry index, urinalysis, electrocardiogram and pathologic finding etc. all find no obviously unusual, and antibody produces in rarely seen administration 2 all rear sections animal serums.The above results and U.S. FDA announce about ENBREL
TMMonkey 4 week long-term toxicity tests the result very approaching.Therefore under this experimental condition, 4 weeks of monkey administration, safe dose was 15mg/kg than safety.
Embodiment 5
Dosage and mode
What be used for that rheumatoid arthritis adopts in view of rh-TNFR:Fc is subcutaneous administration, in order to make its onset quickly, preferably adopts intravenous drip to be used for the acute lung injury that SARS, wound etc. cause, recommended dose be hypodermic half.
Pharmacokinetics and bioavailability test method are as follows: sc gives 10mg and iv gives 10mg (N=6 in the healthy volunteer; Two groups of each 3 people).Individual 10mg for 70kg is equivalent to 5.7mg/m
2This research is considered to the crossing research of route of administration, follows by iv because the experimenter gives sc earlier.Injection interval 28 days.Measure the pharmacokinetics terminal point with non-compartment model method.Calculate AUC with trapezoidal rule; Half-life is-log (2)/β.For the later time of iv administrable 72h, and sc is with the later time estimation regression coefficient (β) of 144h.Ratio (sc/iv) by different approaches AUC calculates bioavailability.
The result shows that hypodermic peak time is 66h, and the half-life is 92h, and the intravenous injection peak time is 0.8h, and the half-life is 72h; Hypodermic bioavailability is 58%.As seen, adopt quiet notes 12.5mg/ time, semiweekly dosage is feasible, also is safe.
All quote in this application as a reference at all documents that the present invention mentions, just quoted as a reference separately as each piece document.Should be understood that in addition those skilled in the art can make various changes or modifications the present invention after having read above-mentioned teachings of the present invention, these equivalent form of values fall within the application's appended claims institute restricted portion equally.
Claims (7)
1. the purposes of the fusion rotein of a tumor necrosis factor receptor-immunoglobulin is characterized in that, is used to prepare the medicine for the treatment of acute lung injury.
2. purposes as claimed in claim 1 is characterized in that, described acute lung injury is infected by sars coronavirus and caused.
3. purposes as claimed in claim 1 is characterized in that, the weight content of TNFR-Ig fusion rotein is 1-99% in the described medicine.
4. purposes as claimed in claim 1, it is characterized in that, the sequence of 235 amino acid residue behaviour II type Tumor Necrosis Factor Receptors extracellular sections of the N-end of described TNFR-Ig fusion rotein, 232 amino acid residues of its C-end are the FC sequence of human normal immunoglobulin γ 1 chain.
5. purposes as claimed in claim 1 is characterized in that, the route of administration of described medicine is intravenous injection or intravenous drip.
6. purposes as claimed in claim 1 is characterized in that, the dosage of described medicine is 0.1-3mg TNFR-Ig fusion rotein/kg body weight every day.
7. purposes as claimed in claim 1 is characterized in that, the dosage of described medicine is 0.5-2mg TNFR-Ig fusion rotein/kg body weight every day.
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| CN 03129569 CN1565631A (en) | 2003-06-27 | 2003-06-27 | Usage of fused protein of TNF receptor and globin in acute lung injury treating medicine |
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| CN 03129569 CN1565631A (en) | 2003-06-27 | 2003-06-27 | Usage of fused protein of TNF receptor and globin in acute lung injury treating medicine |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1309740C (en) * | 2005-10-20 | 2007-04-11 | 高基民 | Soluble tumour necrosis factor receptor II- |
| CN105039473A (en) * | 2007-04-23 | 2015-11-11 | 惠氏公司 | Use of low temperature and/or low ph in cell culture |
-
2003
- 2003-06-27 CN CN 03129569 patent/CN1565631A/en active Pending
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1309740C (en) * | 2005-10-20 | 2007-04-11 | 高基民 | Soluble tumour necrosis factor receptor II- |
| CN105039473A (en) * | 2007-04-23 | 2015-11-11 | 惠氏公司 | Use of low temperature and/or low ph in cell culture |
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