CN106267192A - A kind of medicine for treating mesangial proliferative nephritis - Google Patents
A kind of medicine for treating mesangial proliferative nephritis Download PDFInfo
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- CN106267192A CN106267192A CN201610827292.5A CN201610827292A CN106267192A CN 106267192 A CN106267192 A CN 106267192A CN 201610827292 A CN201610827292 A CN 201610827292A CN 106267192 A CN106267192 A CN 106267192A
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- medicine
- cxcl10
- pharmaceutical composition
- antibody
- nephritis
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
- A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
- A61K39/39566—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against immunoglobulins, e.g. anti-idiotypic antibodies
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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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
- C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding
Abstract
The present invention provides a kind of medicine for treating mesangial proliferative nephritis, and the effective ingredient of described medicine is anti-CXCL10 monoclonal antibody, specially CXCL10/IP 10/CRG 2 antibody.Present invention firstly discovers that anti-CXCL10 monoclonal antibody can substantially alleviate glomerule pathological change, reduce the propagation of mesangial cell, alleviate renal dysfunction.New drug development for treatment mesangial proliferative nephritis provides precious resources.
Description
Technical field
The invention belongs to field of medicaments, specifically, relate to a kind of medicine for treating mesangial proliferative nephritis.
Background technology
Treatment mesangial proliferative nephritis mainly uses hormone therapy and cytotoxic drug treatment at present, and hormone therapy is passed through
Suppression transcription factor NF-KB activity and then suppression can promote brightic proinflammatory factor (IL-1 β, TNF-α), and to multiple
The glomerulonephritis of type has therapeutic effect.But, hormone therapy generally entails side effect in various degree, and cytotoxicity medicine
The toxic and side effects of thing is bigger, thus limits the application of hormone and cytotoxic drug.Therefore, scientist is just having tried to animal
And clinical trial, it is desirable to be able to find regulation immunity, reduce the new Therapeutic Method damaging, promote to repair, reduce toxic and side effects.
Summary of the invention
It is an object of the invention to provide a kind of novel medicine for treating mesangial proliferative nephritis.
The present invention is also called interferon gamma induced protein based on following design, IFN-GAMMA-inducible protein 10 (CXCL 10)
10, it has chemotactic, activates the functions such as T cell, the expression of regulation adhesion molecule, promotion cell proliferation and suppression angiogenesis.
Research finds, there is the high table of CXCL10 in mesangial proliferative glomerulonephritis (MesPGN) patient's mesangial cell
Reach, and CXCL10 can promote that the propagation of mesangial cell, the most anti-CXCL10 monoclonal antibody have treatment mesangial matrix * kidney
Scorching possible and application prospect.
In order to realize the object of the invention, the present invention provides anti-CXCL10 monoclonal antibody to increase for treating mesentery in preparation
Application in natural disposition nephritis medicine.Wherein, described anti-CXCL10 monoclonal antibody is CXCL10/IP-10/CRG-2 antibody, i.e.
Mouse CXCL10/IP-10/CRG-2Antibody, R&D SYSTEM, article No.: AF-466-NA.
The present invention also provides for what above-mentioned anti-CXCL10 monoclonal antibody was caused by Trimeresurus stejnegeri toxin for treatment in preparation
Application in acute mesangial proliferative glomerulonephritis medicine.
The present invention, first with C57BL/6 mice, sets up acute mesangial matrix * by tail vein injection trimeresurus stejnegeri venom
Glomerulonephritis (Habu nephritis) animal model, after model sets up 1 day, using anti-CXCL10 monoclonal antibody as controlling
Treatment medicine is with in 50-100mg/kg body weight tail vein injection to Mice Body, and then the different time points after model is set up is put to death
Mice obtains mouse kidney tissue, and after preparing pathology sample, section carries out pathological staining, immunohistochemical staining, and extracts
Histone carries out Western Blot experiment, observes anti-CXCL10 mab treatment effect.
The present invention also provides for a kind of medicine for treating mesangial proliferative nephritis or pharmaceutical composition, described medicine or medicine
The effective ingredient of compositions is above-mentioned CXCL10/IP-10/CRG-2 antibody.
The present invention further provides a kind of acute mesangial matrix * glomerule caused for treatment by Trimeresurus stejnegeri toxin
The medicine of nephritis or pharmaceutical composition, the effective ingredient of described medicine or pharmaceutical composition is above-mentioned CXCL10/IP-10/CRG-2
Antibody.
In described medicine or pharmaceutical composition, the single dose unit of effective ingredient is 50-100mg/kg body weight.Use
Time, the lyophilized injectable powder of CXCL10/IP-10/CRG-2 antibody is dissolved in normal saline, by intravenous injection to internal.
Described medicine or pharmaceutical composition are lyophilized injectable powder.Possibly together with medicinal auxiliary in described medicine or pharmaceutical composition
Material.
Present invention firstly discovers that anti-CXCL10 monoclonal antibody can substantially alleviate glomerule pathological change, reduce glomerule
The propagation of mesangial cell, alleviates renal dysfunction.New drug development for treatment mesangial proliferative nephritis provides precious resources.
Have turned out CXCL10 albumen at present at the important physiology of physical exertion and pathologic effect, participate in inflammation, tumor, from
The multiple diseases such as body immunological diseases develop.In nephropathy field, CXCL10 albumen is at kidney to have a large amount of clinical evidence to prove
Expression showed increased in transplanting, diabetic nephropathy, lupus nephritis, acute injury of kidney, and there are some researches show that anti-CXCL10 resists
Body can effectively reduce the infiltration of renal tubular interstitium T cell, reduce inflammation reaction.Present invention Effect of Anti-CXCL10 monoclonal first
The antibody effect to MsPGN, chmice acute mesangial proliferative glomerulonephritis (Habu nephritis) animal
It will be seen that proliferation period (7D) treatment group glomerule inner cell quantity, proliferating cell nuclear antigen (PCNA) positive rate are equal in model
Less than matched group, illustrate that anti-CXCL10 monoclonal antibody can substantially alleviate glomerule pathological change, reduce mesangial cell
Propagation, alleviate renal dysfunction.New drug development for treatment mesangial proliferative nephritis provides precious resources.
Accompanying drawing explanation
Fig. 1 is Western Blot method detection Nephritis Model group murine glomerular CXCL10 albumen in the embodiment of the present invention 1
Expression.
Fig. 2 is that in the embodiment of the present invention 1, anti-CXCL10 monoclonal antibody intervenes Habu mesangial proliferative nephritis mouse kidney
Pathological staining result.(observing under 400 power microscopes)
Fig. 3 is that in the embodiment of the present invention 1, anti-CXCL10 monoclonal antibody intervenes Habu mesangial proliferative nephritis mice PCNA
Immunohistochemical staining result.(observing under 400 power microscopes)
Fig. 4 is that in the embodiment of the present invention 1, Western Blot method detects anti-CXCL10 mab treatment group and nephritis
The expression of model group murine glomerular CXCL10 albumen.
Fig. 5 is that in the embodiment of the present invention 1, anti-CXCL10 monoclonal antibody intervenes Habu mesangial proliferative nephritis mice PCNA
Positive rate comparative result.
Fig. 6 is the kidney that in the embodiment of the present invention 1, anti-CXCL10 monoclonal antibody intervenes Habu mesangial proliferative nephritis mice
Bead hardenability value.
Detailed description of the invention
Following example are used for illustrating the present invention, but are not limited to the scope of the present invention.If not specializing, embodiment
In the conventional means that is well known to those skilled in the art of technological means used, raw materials used be commercial goods.
The anti-CXCL10 monoclonal antibody used in following example is Mouse CXCL10/IP-10/CRG-
2Antibody, R&D SYSTEM, article No.: AF-466-NA.
The application in treatment mesangial proliferative nephritis of the embodiment 1 anti-CXCL10 monoclonal antibody
1, the foundation of Habu mesangial proliferative nephritis model
Choose the C57BL/6 mice that body weight is 25～30g, in the way of tail vein injection in model group Mice Body single
Saline injection dissolves Trimeresurus stejnegeri toxin soiutions, and dosage is 2.5mg/kg body weight, and control group mice injects isopyknic life
Reason saline.
Western Blot method detects the expression of Nephritis Model group murine glomerular CXCL10 albumen and compares with matched group.
Kidney of mouse carries out cracking extract albumen, survey protein concentration, protein denaturation, SDS-PAGE (polyacrylamide) gel electricity
Swimming, protein electrotransfer, Ponceaux dyeing, the closing of film and hybridization.Many grams of the Anti-IP10 rabbit of one anti-use 1:1000 dilution
Grand antibody (abcam), overnight incubation under the conditions of 4 DEG C.Result is as it is shown in figure 1, at Habu mesangial proliferative nephritis model mice kidney
CXCL10 albumen high expressed in bead mesangial cell.
2, anti-CXCL10 mab treatment Habu nephritis
After trimeresurus stejnegeri venom is injected 1 day, model group mice is randomly divided into Nephritis Model group and anti-CXCL10 monoclonal
Antybody therapy group, anti-CXCL10 mab treatment group gives anti-CXCL10 mab treatment, and dosage is 50-
100mg/kg body weight, is expelled in Mice Body by the way of tail vein injection.At the 3rd, 7 and 14 days that whole model is set up
Dead mice also obtains kidney sample, cuts into slices, carry out PAS dyeing (Fig. 2) and immunohistochemical staining after histopathology embeds
, and extract histone by Western Blot method detection model group and treatment group murine glomerular CXCL10 albumen (Fig. 3)
Content, result as shown in Figure 4, after injecting anti-CXCL10 monoclonal antibody, treatment group mouse CXC L10 expression relatively model group
Substantially reduce.
Figure it is seen that model mice is after accepting anti-CXCL10 mab treatment, anti-CXCL10 monoclonal
The wide array of pathologies such as in Antybody therapy group murine glomerular, mesentery dissolves, mesangial cell proliferation are substantially lighter than Nephritis Model group；Propagation
Cell nuclear antigen (PCNA) immunohistochemical staining result also indicates that anti-CXCL10 mab treatment group murine glomerular
Inner cell propagation degree is less than Nephritis Model group (Fig. 3), and anti-CXCL10 mab treatment can alleviate mesangial matrix * kidney
Scorching mouse kidney pathology damage, suppresses glomerule inner cell hyper-proliferative.
3, statistical analysis and pathological score
3.1 PCNA positive rates compare
By proliferating cell nuclear antigen (PCNA) immunohistochemical observation glomerule inner cell proliferative conditions, result is shown in Fig. 3.High
The 7th day glomerule PCNA positive rate of proliferation period, 20 glomerule of every mice random counter are counted under power microscope (× 400).
Treatment group murine glomerular PCNA positive rate is 25 ± 1.77%, and control group mice is 30.00 ± 1.31%.With Nephritis Model group
Mice is compared, and anti-CXCL10 Antybody therapy group murine glomerular PCNA positive rate substantially reduces, p < 0.05 (Fig. 5).
The comparison of 3.2 glomerular sclerosis indexes
The two groups of kidney of mouse pathological changes of optical microphotograph Microscopic observation, and in terms of glomerular sclerosis pathological changes, it is carried out
Sxemiquantitative is marked, two Pathology Doctors 's use double-blind method to be analyzed.Concrete standards of grading are:
Glomerular sclerosis index (Glomerulosclerosis Index):
Score 0: normal glomerule
Score 1: there is mesangial cell proliferation in glomerule, mesangial region expansion or hardening account for whole glomerular filtration area
25%
Score 2: in glomerule, mesangial region expansion or hardening account for the 25%-50% of whole glomerular filtration area
Score 3: in glomerule, mesangial region expansion or hardening account for the 50%-75% of whole glomerular filtration area
Score 4: in glomerule, mesangial region expansion or hardening exceed the 75% of whole glomerular filtration area
Matched group and model group murine glomerular hardenability value all reached peak value at the 7th day.Treatment group murine glomerular is hard
Changing index is 0.876 ± 0.244, and control group mice is 1.218 ± 0.208.Compared with Nephritis Model group mice, anti-CXCL10
Antybody therapy group murine glomerular hardenability value substantially reduces, p < 0.05 (Fig. 6).
Although, the present invention is described in detail the most with a general description of the specific embodiments, but
On the basis of the present invention, can make some modifications or improvements it, this will be apparent to those skilled in the art.Cause
This, these modifications or improvements without departing from theon the basis of the spirit of the present invention, belong to the scope of protection of present invention.
Claims (10)
- The most anti-CXCL10 monoclonal antibody is used for treating the application in mesangial proliferative nephritis medicine in preparation, wherein said anti- CXCL10 monoclonal antibody is CXCL10/IP-10/CRG-2 antibody.
- The acute mesangial matrix * kidney that the most anti-CXCL10 monoclonal antibody is caused by Trimeresurus stejnegeri toxin for treatment in preparation is little Application in ball nephritis medicine, wherein said anti-CXCL10 monoclonal antibody is CXCL10/IP-10/CRG-2 antibody.
- 3. medicine or the pharmaceutical composition being used for treating mesangial proliferative nephritis, it is characterised in that described medicine or medicine The effective ingredient of compositions is CXCL10/IP-10/CRG-2 antibody.
- Medicine the most according to claim 3 or pharmaceutical composition, it is characterised in that the single dose list of described effective ingredient Unit is 50-100mg/kg body weight.
- 5. according to the medicine described in claim 3 or 4 or pharmaceutical composition, it is characterised in that described medicine or pharmaceutical composition For lyophilized injectable powder.
- 6. according to the medicine described in any one of claim 3-5 or pharmaceutical composition, it is characterised in that described medicine or medicine group Possibly together with pharmaceutic adjuvant in compound.
- 7. the medicine being used for the acute mesangial proliferative glomerulonephritis that treatment is caused by Trimeresurus stejnegeri toxin or medicine group Compound, it is characterised in that the effective ingredient of described medicine or pharmaceutical composition is CXCL10/IP-10/CRG-2 antibody.
- Medicine the most according to claim 7 or pharmaceutical composition, it is characterised in that the single dose list of described effective ingredient Unit is 50-100mg/kg body weight.
- 9. according to the medicine described in claim 7 or 8 or pharmaceutical composition, it is characterised in that described medicine or pharmaceutical composition For lyophilized injectable powder.
- 10. according to the medicine described in any one of claim 7-9 or pharmaceutical composition, it is characterised in that described medicine or medicine Possibly together with pharmaceutic adjuvant in compositions.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610827292.5A CN106267192A (en) | 2016-09-14 | 2016-09-14 | A kind of medicine for treating mesangial proliferative nephritis |
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| CN201610827292.5A CN106267192A (en) | 2016-09-14 | 2016-09-14 | A kind of medicine for treating mesangial proliferative nephritis |
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| CN201610827292.5A Pending CN106267192A (en) | 2016-09-14 | 2016-09-14 | A kind of medicine for treating mesangial proliferative nephritis |
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101595212A (en) * | 2006-10-12 | 2009-12-02 | 伊西康公司 | Kidney-derived cells and the using method in tissue repair and regeneration |
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2016
- 2016-09-14 CN CN201610827292.5A patent/CN106267192A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101595212A (en) * | 2006-10-12 | 2009-12-02 | 伊西康公司 | Kidney-derived cells and the using method in tissue repair and regeneration |
Non-Patent Citations (2)
| Title |
|---|
| 吴玲玲: "小鼠系膜增生性肾炎模型的建立及相关机制的研究", 《万方数据》 * |
| 文君: "竹叶青蛇毒诱导不同品系小鼠系膜增生性肾炎模型的比较研究", 《中国优秀硕士学位论文全文数据库》 * |
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