CN102861331B - The application of CD146 and the diseases associated with inflammation such as antibody diagnosis and treatment autoimmune disease thereof - Google Patents
The application of CD146 and the diseases associated with inflammation such as antibody diagnosis and treatment autoimmune disease thereof Download PDFInfo
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Abstract
The present invention relates to the application of CD146 and the diseases associated with inflammation such as antibody diagnosis and treatment autoimmune disease thereof.It is the new target drone comprising the diseases associated with inflammation such as autoimmune disease that the present invention proposes CD146 first, and anti-CD146 antibody is the novel targeted medicine of this kind of disease for the treatment of.Therefore, the invention provides the antibody of CD146 or anti-CD146 or the application of the functional form of this antibody in the medicine for the preparation of diagnosis and/or treatment diseases associated with inflammation.The mechanism of action of CD146 Antybody therapy diseases associated with inflammation (as multiple sclerosis) mainly blocks inflammatory cells and passes through blood brain barrier and other vascular endothelial cell barriers, and then suppress activated lymphocyte to the damage of central nervous system's myelin and other linked groups, thus delay the process of multiple sclerosis and the damage of recurrence and linked groups, and alleviate the symptom of multiple sclerosis and the development of related inflammation.Compared with the glucocorticoid medicine of conventional therapy autoimmune disease, the side effect of anti-CD146 antibody is little, can not cause the damage of the immunologic function of systemic body-wide.
Description
Technical field
The invention belongs to immunologic diagnosis and Biotherapeutics field.Specifically, the present invention relates to the application at Diagnosis and Treat diseases associated with inflammation of CD146 molecule and antibody thereof.More specifically, the CD146 monoclonal antibody AA98 that the present invention relates to and the function of functional form thereof be to block autoimmune sexual cell and inflammatory cells and vascular endothelial cell adhesion, move and traverse to tissue site, and then block autoimmune sexual cell and inflammatory cell killing and wounding central nervous system and linked groups, thus delay and block generation and the development of autoimmune disease and diseases associated with inflammation.
Background technology
Multiple sclerosis (multiple sclerosis, MS) is a kind of autoimmune disease involving brain and spinal cord, is also a kind of diseases associated with inflammation, can causes nerve demyelination and axonal injury.Think at present, the lymphocyte of activation crosses the early stage important step that blood brain barrier is MS inflammatory damage.The inflammatory cell of activation, through the blood brain barrier of malfunction, infiltrates to central nervous system, causes demyelination and other inflammatory damage.Under normal circumstances, the permeability of blood brain barrier to inflammatory cell is low, seldom or seldom has inflammatory cell to enter into central nervous system.But in multiple sclerosis, blood brain barrier functional disorder, its permeability greatly increases under the stimulation of inflammatory factor, causes inflammatory cell to enter into central nervous system easily, causes inflammatory damage.Therefore, the permeability of blood brain barrier plays important role in this course.
Large quantity research report, the permeability of adhesion molecule to blood brain barrier plays important regulating action, as ICAM-1, integrin (integrin) etc.Existing research report, α 4 beta 1 integrin is a kind of lymphocytic cell surface membrane molecule, its part VCAM-1 expresses on brain and spinal cord vascular endothelial cell, the adhesion of mediated lymphocytes and vascular endothelial cell and migration, the interaction blocking α 4 beta 1 integrin and VCAM-1 can alleviate the inflammatory damage of MS.Natalizumab (Natalizumab) (anti-α 4 beta 1 integrin) is first monoclonal antibody being approved for treatment MS.It is by the adhesion of blocking leukocyte and vascular endothelial cell thus reduce leukocyte delays MS development to the infiltration of central nervous system.At present, block the adhesion of inflammatory cell and vascular endothelial cell and move the new method having become and treated MS and other diseases associated with inflammation.
Current clinical treatment MS mainly glucocorticoid medicine, this kind of medicine has obvious antiphlogistic effects and immune suppression function, but its side effect widely limits its use, as adrenal function suppresses, cardiovascular dysfunction etc.Use comparatively generally biological species preparation in addition, such as the use of multiple monoclonal antibody.Except natalizumab (anti-α 4 beta 1 integrin), the monoclonal antibody used clinically at present or enter clinical trial also has Rituximab (Rituximab) (anti-CD 20), alemtuzumab (Alemtuzumab) (anti-CD 52), daclizumab (Daclizumab) (anti-IL2R), these are all the antibody for immunocyte itself, the functional defect of the side effect that these antibody directly cause mainly immunocyte, and then cause other Ia diseases.
Summary of the invention
It is the new target drone comprising the diseases associated with inflammation such as autoimmune disease that the present invention proposes CD146 first, and anti-CD146 antibody is the novel targeted medicine of this kind of disease for the treatment of.Compared with glucocorticoid medicine, the side effect of anti-CD146 antibody is little, can not cause the damage of the immunologic function of systemic body-wide.CD146 and antibody thereof are based on following important scientific discovery comprising the application in the diseases associated with inflammation Diagnosis and Treat such as autoimmune disease: (1) sMe1-CAM significantly increases in the cerebrospinal fluid of multiple sclerosis patient.(2) cell adhesion molecule CD146 overexpression on the blood-brain barrier endothelial cell of people and mice, can be expressed by inflammatory factor inducible up regulation such as TNF-α and IFN-γ; (3) CD146 overexpression on the blood vessel endothelium of many inflammation diseases, the new vessels of the new vessels of rheumatoid arthritis synovial tissue, atherosclerotic blood vessel theca interna new vessels and inflammatory bowel such as, can detect the overexpression of CD146; (4) on vascular endothelial cell, the CD146 of overexpression is relevant to pathogenesis, passes through blood vessel endothelium barrier play an important role at mediated lymphocytes; (5) at mouse model experimental autoimmune encephalo myelitis (the Experimentalautoimmune encephalomyelitis of MS, EAE), in experiment, we find that anti-CD146 antibody A A98 significantly slows down morbidity and the symptom of experimental autoimmune encephalo myelitis mice.Study mechanism shows, CD146 antibody can stop the infiltration of inflammatory cell, reduces neural axon impaired loci and damaged area; (6) CD146 antibody can treat rheumatoid arthritis (Rheumatoid arthritis, RA) equally, slows down progression of disease, ameliorate osteoarthritis symptom and joint injury.
CD146 plays an important role in the adhesion regulating inflammatory cell and vascular endothelial cell and migration.The anti-CD146 Functional antibody AA98 of our independent development is the cell function experiment migration cell monolayer layer that activated lymphocyte can be suppressed preferably to pass through cerebrovascular endothelial cell in measuring to be formed in vitro.Therefore, we think that CD146 may as a kind of target on blood-brain barrier endothelial cell, and its antibody A A98 can block the adhesion of inflammatory cell and endotheliocyte, thus block inflammatory cell infiltration further and cause demyelinating to damage to central nervous system.Anti-CD146 antibody can be applicable to the Diagnosis and Treat of MS.Similar, CD146 also can as the new target drone of other diseases associated with inflammation Diagnosis and Treat, and anti-CD146 antibody can block the adhesion of inflammatory cell and vascular endothelial cell, and blocks inflammatory cell infiltration and to cause inflammation damage to local organization.The specificity of this kind of antibody is better, can not cause the damage of the immunologic function of systemic body-wide.
Therefore, one aspect of the present invention relates to the application of CD146 in the medicine for the preparation of diagnosis and/or treatment diseases associated with inflammation.
Further aspect of the present invention relates to the antibody of anti-CD146 or the application of the functional form of this antibody in the medicine for the preparation of diagnosis and/or treatment diseases associated with inflammation.
In the present invention, diseases associated with inflammation can be autoimmune disease.
In the present invention, diseases associated with inflammation can comprise multiple sclerosis, rheumatoid arthritis, acute peritonitis, atherosclerosis.According to one embodiment of the invention, diagnosis and/or treatment diseases associated with inflammation are multiple sclerosis.According to another embodiment of the present invention, diagnosis and/or treatment diseases associated with inflammation are rheumatoid arthritiss.According to another embodiment of the present invention, diagnosis and/or treatment diseases associated with inflammation are acute peritonitiss.According to another embodiment of the present invention, diagnosis and/or treatment diseases associated with inflammation are atherosclerosiss.
In the present invention, the antibody of anti-CD146 or the functional form of this antibody can comprise the monoclonal antibody of anti-CD146, genetic engineering antibody and humanized antibody.
In the present invention, the antibody of anti-CD146 or the functional form of this antibody are the Function Coupling things of the antibody of anti-CD146, can be wherein medicine, toxin, radioactivity agent, enzyme, cytokine or another kind of antibody with the material of antibodies.
In the present invention, the antibody of anti-CD146 is preferably monoclonal antibody AA98.
Another aspect of the invention relates to the antibody of CD146 or anti-CD146 or the application of the functional form of this antibody in the medicine preparing diagnosing multiple sclerosis disease, it is characterized in that the level detecting sMe1-CAM in experimenter's cerebrospinal fluid.In this one side of the present invention, medicine can be prepared into the form of test kit.
Another aspect of the invention relates to the antibody of anti-CD146 or the application of the functional form of this antibody in the medicine for the preparation of human body inflammatory cell and blood vessel injury location and targeted therapy.Preferably, the described antibody of anti-CD146 or the functional form of this antibody comprise the monoclonal antibody of anti-CD146, genetic engineering antibody and humanized antibody.More preferably, the antibody of described anti-CD146 is monoclonal antibody AA98.
In order to comprehend and application the present invention, provide the following example.
Accompanying drawing explanation
Below in conjunction with in the detailed description of accompanying drawing, above-mentioned feature and advantage of the present invention will be more obvious, wherein:
Fig. 1. clinical samples: in multiple sclerosis patient cerebrospinal fluid, sMe1-CAM significantly increases (patient VS is normal: 0.31 ± 0.206nM vs, 0.04 ± 0.047nM, p < 0.0001).
Fig. 2. clinical samples: CD146 molecule overexpression on multiple sclerosis Blood of Patients brain barrier endothelial cell, in the low expression of normal person's blood-brain barrier endothelial cell.(CD31 is the marker molecule of vascular endothelial cell).
The expression of Fig. 3 .CD146, wherein, A: the low expression of CD146 on normal mouse myeloid tissue blood vessel, and B: mice multiple sclerosis: myeloid tissue vascular endothelia CD146 high expressed.
The expression of Fig. 4 .CD146, wherein, A-B: on normal rat articular tissue blood vessel, CD146 is less, and C-F: high expressed CD146 on the new vessels of rat kind rheumatic arthritis synovial tissue.
Fig. 5. clinical samples SABC shows, wherein, A: the low expression of CD146 (antibody A A4) on the carotid inner membrance of normal person, B: CD146 high expressed on the carotid inner membrance of atherosclerosis.
Fig. 6. clinical samples SABC shows, CD146 (antibody: AA4) high expressed on the new vessels in atherosclerosis carotid artery adventitia district.
Fig. 7. Cell migration assay shows, TNF-α can obviously increase leukocytic migration, and anti-CD146 antibody A A98 (50 μ g/ml) significantly suppresses human peripheral leucocytes (to comprise CD3
+, CD4
+, CD8
+, CD19
+deng) pass through blood brain endothelial barrier.
Fig. 8. anti-CD146 antibody A A98 significantly alleviates multiple sclerosis model mice: A, mean clinical scores and C, the order of severity, slows down disease time but do not affect B, the sickness rate of disease.
Fig. 9. anti-CD146 antibody A A98 is remarkable, and inflammation-inhibiting cell (comprises CD45
+, CD4
+, CD8
+, CD19
+, F4/80
+and Gr-1
+cell) infiltration in multiple sclerosis model mice myeloid tissue, wherein A: SABC; B: statistical result.
Figure 10. anti-CD146 antibody A A98 significantly reduces the damage of multiple sclerosis mouse spinal cord myelin neural axon, wherein A: SABC; B: statistical result.
Detailed description of the invention
Embodiment one: sMe1-CAM significantly increases in the cerebrospinal fluid of multiple sclerosis patient
Adhesion molecule can split away off from endotheliocyte under the stimulation of inflammatory factor, in order to detect the relation of sMe1-CAM level and multiple sclerosis in cerebrospinal fluid, we find to have detected sMe1-CAM in multiple sclerosis patient and normal brain spinal fluid by the method for ELISA, and we find that sMe1-CAM significantly increases in multiple sclerosis patient cerebrospinal fluid.
Main material: the cerebrospinal fluid (26 example) of active stage multiple sclerosis patient, normal brain spinal fluid (22 example), the antibody A A98 used in this description, AA4, AA1 etc. can obtain according to the description of Chinese Patent Application No. 99107586.2, Chinese Patent Application No. 200810057260.7.
Main agents: 0.02M PB (pH 7.25), anti-CD146 antibody A A1, biotin labeled anti-CD146 antibody A A98, streptavidin-HRP, tmb substrate (200ng/ml TMB, 0.03%H
2o
2, pH4.5)
Main method:
1) antibody A A1 is diluted to 1 μ g/ml with 0.02M PB (pH 7.25), 50 μ l/ holes add 96 orifice plates, and 4 DEG C of bags are spent the night.
2) every hole adds 200 μ l 2%BSA room temperatures and closes 2h.
3) every hole adds patient or normal person's spinal fluid samples 50 μ l/ hole, incubated at room 2h.PBST washes 5 times, washes away non-specific binding.
4) AA98 detecting antibody biotin labelling is diluted to 0.5 μ g/ml with 2%BSA/PB, 50ml/ hole incubated at room 2h.
5) wash away antibody, add the streptavidin-HR of suitable concn, 50 μ l/ holes, incubated at room 1h.
6) wash away antibody, with tmb substrate (200ng/ml TMB, 0.03%H2O2, pH4.5) colour developing, sulphuric acid stops, 450nm reading.
Result display (Fig. 1): the sMe1-CAM in multiple sclerosis patient cerebrospinal fluid is significantly higher than normal person's cerebrospinal fluid levels (0.31 ± 0.206nM vs, 0.04 ± 0.047nM, p < 0.0001), in cerebrospinal fluid, sMe1-CAM can be thought abnormal higher than 0.134nM.
Embodiment two: CD146 overexpression on diseases associated with inflammation new vessels
In chronic inflammatory diseases, angiogenesis is an important pathological process, and a large amount of adhesion molecules all relates to this process of angiogenesis.CD146 is the adhesion molecule that an important angiogenesis is relevant, and we all observe the high expressed of CD146 in inflammation diseased tissue.
Main material: the myeloid tissue of multiple sclerosis model mice, the arthritic tissues of model of rheumatoid arthritis rat.Clinical samples comes from normal person and multiple sclerosis patient cerebral tissue, and the atherosclerosis of people strips off internal film tissue
Main agents: OCT, 4% paraformaldehyde, dimethylbenzene, dehydrated alcohol, absolute methanol, hydrogen peroxide, PBS, anti-CD146 antibody (the anti-CD146 of rabbit, little mouse-anti CD146 monoclonal antibody AA4)
Main method: (1) frozen section makes: with OCT directly embed the myeloid tissue of multiple sclerosis mice, the atherosclerosis of the arthritic tissues of model of rheumatoid arthritis and people strips off internal film tissue, freezes in-80 DEG C of refrigerators; (2) paraffin section makes: fixing flesh tissue after 24 hours with 4% paraformaldehyde, paraffin embedding, is below the SABC process of paraffin section:
1) take out slice, thin piece, enter xylene solution 37 DEG C dewaxing twice, each 30 minutes;
2) aquation in dehydrated alcohol × 2-95%-80%-70%-50%-30% and distilled water is entered, each 5 minutes of room temperature;
3) 0.3% hydrogen peroxide/methanol solution, 37 DEG C of lucifuge process 30 minutes, eliminate the activity of endogenous peroxydase, PBS washes three times;
4) pH6.0 citric acid repair liquid 100 DEG C of water-baths antigen hot repair in 30 minutes is multiple, natural cooling;
5) normal sheep serum 37 DEG C of 5% closes 1 hour;
5) primary antibodie (the anti-CD146 multi-resistance of rabbit or AA4) of PBS dilution is added, 4 DEG C of overnight incubation;
6) PBS washes three times; Anti-rabbit-the biotin of goat or goat-anti-mouse-biotin two anti-(1:1000) hatch 1 hour at 37 DEG C, and PBS washes three times;
7) Avidin-HRP (1: 1000) hatches 45 minutes at 37 DEG C;
7) with the DAB lucifuge colour developing 2-7 minute now joined, then carry out haematoxylin and redye.
8) dewater step by step: 50-70-80-90-100-100% ethanol-xylenes, dry, resinene mounting.
9) make film in micro imaging system.
Experimental result: as shown in figures 2-6, no matter be clinical samples (the atherosclerosis internal film tissue of multiple sclerosis patient cerebral tissue and people), or animal model (multiple sclerosis mouse spinal cord tissue and rheumatoid arthritis in rats synovial tissue of joint), we observe the overexpression on the new vessels of inflammation part of CD146 molecule.
Embodiment three: CD146 antibody suppression inflammatory cell passes through people's blood brain barrier
The infiltration of inflammatory cells plays very important effect in the generation and evolution of diseases associated with inflammation, and these inflammatory cells mainly comprise T cell, B cell, macrophage, neutrophilic granulocyte etc.These cells play antiinflammatory and proinflammatory effect at tissue local.The damage organized mainly causes due to its proinflammatory effect.The infiltration blocking inflammatory cell has important effect to the damage alleviating tissue.The migration of inflammatory cell and infiltration relate to the adjustment of a large amount of adhesion molecule.The high expressed of CD146 on vascular endothelial cell plays very important effect to the adhesion of inflammatory cell and rolling and migration.Anti-CD146 antibody A A98 can suppress CD146 to the effect of Inflammatory cell emigration to a great extent.
Application Transwell technology (Leukocyte transmigration through vascularendothelium.An in vitro method.Allavena P, Del Maschio A.Methods MolBiol.1999; 96:171-6), we have detected CD146 antibody A A98 in the effect of inflammatory cell being passed through to vascular endothelial cell barrier.This Introduction on Technology is as follows: be laid on by people's cerebrovascular endothelial cell on 96 transwell holes, hole indoor, cultivate in the culture medium of 5% serum, hatch 24 hours, allow it form cell monolayer (artificial blood brain barrier) closely.Afterwards, the culture medium of 10% serum is added in lower room.Human peripheral lymphocyte is added, every hole 2 × 10 in upper room
4individual, add antibody (mIgG or AA98), every hole 50 μ g/ml simultaneously.Often organize each 3 multiple holes.Cultivate after 10 hours, collect the lymphocyte that lower room is passed through, with the number of each lymphocyte subgroup of flow cytometry.In addition, we also observe cytokine TNF-α (every hole 50ng/ml) and pass through the impact of blood brain barrier and the inhibitory action of CD146 antibody to lymphocyte.
As shown in Figure 7, TNF-α can increase the permeability of blood brain barrier to experimental result, promotes that inflammatory cell (comprises CD3 through vascular endothelial cell layer
+, CD4
+, CD8
+t cell and CD19
+b cell), compared with mIgG matched group, CD146 antibody A A98 obviously can reduce the infiltration of inflammatory cell to inflammatory loci, and suppression ratio is about: total leukocyte: 35.5%; CD3:42.9%; CD4:37.5%; CD8:66.3%; CD19:39.9%.
Embodiment four: CD146 Antybody therapy mice multiple sclerosis
The important pathological characters of multiple sclerosis is a large amount of inflammatory cell infiltration central nervous tissue, can delay and alleviate its symptom by the infiltration blocking inflammatory cell.We are by zoopery, find that CD146 antibody A A98 can slow down symptom, treatment multiple sclerosis.
Experimental technique: build mice multiple sclerosis model (Active induction ofexperimental allergic encephalomyelitis.Stromnes IM, Goverman JM.NatProtoc.2006; 1 (4): 1810-9.).With antigenic peptides MOG35-55 immunity C57BL/6J mice, mice was divided into two groups at random in the 7th day after immunity, matched group irrelevant antibody mIgG and treatment group CD146 antibody A A98.Often organize 10 mices, every mouse peritoneal injection of antibodies 200 μ g, the next day administration, amount to four times.The next day observe the disease progression situation of mice, and the incidence of mice to be marked.Concrete standards of grading are as follows:
0.5 point: tail point can not be curling or curling unable
1.0 points: afterbody is completely sagging
2.0 points: afterbody is completely sagging, hind leg one or two unable
3.0 points: afterbody is completely sagging, two hind limb paralysis
4.0 points: afterbody is completely sagging, two hind limb paralysis, front myasthenia of limbs
5.0 points: be at death's door
Observe and terminate for the 25th day to immunity.Statistical analysis adopts T-test inspection.
Experimental result: according to clinical score, we find compared with mIgG matched group, and antibody A A98 obviously alleviates symptom and the development (Fig. 8) of mice multiple sclerosis.Slow down disease time but do not affect its sickness rate.Can find that there are less inflammatory cell infiltration and the damage of less neural axon in the myeloid tissue of AA98 processed group by groupization and neural axon specific stain.
Embodiment five: CD146 antibody suppression multiple sclerosis mouse machinery research I
--suppress the infiltration of inflammatory cell
In order to observe the impact of CD146 antibody on the infiltration of inflammatory cell in multiple sclerosis mouse spinal cord tissue, we set up multiple sclerosis disease mouse model, the myeloid tissue of separating mouse, make frozen section or paraffin section, for SABC.
Infiltrate a large amount of inflammatory cell in the myeloid tissue of multiple sclerosis mice, comprise T, B cell, macrophage etc.
Experimental result: the Infiltrating observing inflammatory cell in experimental autoimmune encephalo myelitis mouse spinal cord tissue, mainly CD45
+the infiltration of cell, comprises CD4
+, CD8
+t cell, CD19
+b cell and Gr-1
+granulocyte and F4/80
+macrophage.Found that (Fig. 9), compared with mIgG processed group, there is less inflammatory cell infiltration (mIgG vsAA98, Mean ± SD) (CD45:47 ± 17.2 vs 202.2 ± 78.1 in the substantia alba medullae spinalis district of AA98 treatment group; CD4:25 ± 4.5 vs 134 ± 19.2; CD8:27 ± 8.5 vs 98.7 ± 19.1; CD19:29.3 ± 6.7 vs 55.3 ± 17.3; Vs66.3 ± 24.2, Gr-1:15 ± 7; F4/80:10.7 ± 6.2 vs 41.8 ± 15.8).
Embodiment six: CD146 antibody suppression multiple sclerosis mouse machinery research II
--reduce the damage of spinal nerves aixs cylinder
Another important pathological characters of multiple sclerosis mice is the damage that inflammatory cell infiltration causes neural axon, and we utilize Luxol Fast Blue method to detect the degree of impairment of multiple sclerosis mouse Nerve aixs cylinder.Its principle be Luxol Fast Blue dyestuff in alcoholic solution, can in be combined with myelin phospholipid.Normal neuronal aixs cylinder outer wrapping complete myelin, and therefore dyeing is dark, and after loss, myelin is destroyed, painted shallow.Mouse spinal cord tissue after separation antibody treatment, paraffin embedding after fixing 24 hours with 4% paraformaldehyde, makes paraffin section, and Luxol Fast Blue dyes, and concrete grammar is as follows:
1) xylene solution 37 DEG C of cutting into slices dewaxing twice, each 10 minutes;
2) section is inserted 100% ethanol 5 minutes, in 95% alcoholic solution 5 minutes;
3) in 0.1% Luxol Fast Blue liquid 56 DEG C spend the night;
4) 95% alcoholic solution 5 minutes;
5) 70% alcoholic solution 3 minutes;
6) distilled water 3 minutes;
7) 0.05% Lithium carbonate solution breaks up 1 minute, and 70% alcoholic solution continues differentiation 30 seconds;
8) distilled water 3 minutes;
9) Microscopic observation spinal cord ash, white matter boundary whether clear, if it is unintelligible to demarcate, then need repetition (6), (7) two steps, until break up clear till;
10) 70% alcoholic solution 3 minutes;
11) 95% alcoholic solution 5 minutes;
12) transparent, the neutral gum mounting of conventional dehydration.Make film in micro imaging system.
As shown in Figure 10, compared with mIgG processed group, the mouse spinal cord neural axon impaired loci of AA98 treatment group seldom (2 ± 1 vs 8.7 ± 0.58) for experimental result.
Claims (6)
1. the antibody of anti-CD146 or the application of the functional form of this antibody in the medicine for the preparation for the treatment of diseases associated with inflammation, wherein said diseases associated with inflammation is selected from multiple sclerosis, rheumatoid arthritis, acute peritonitis, atherosclerosis and inflammatory bowel, and the antibody of wherein said anti-CD146 is monoclonal antibody AA98.
2. the application of functional form in the medicine for the preparation of diagnosis diseases associated with inflammation of sMe1-CAM or its antibody or this antibody, wherein said diseases associated with inflammation is multiple sclerosis.
3. application according to claim 2, the wherein said antibody of anti-CD146 or the functional form of this antibody comprise the monoclonal antibody of anti-CD146, genetic engineering antibody and humanized antibody.
4. according to the application in claim 1-3 described in any one, the wherein said antibody of anti-CD146 or the functional form of this antibody are the Function Coupling things of the antibody of anti-CD146, can be wherein medicine, toxin, radioactivity agent, enzyme, cytokine or another kind of antibody with the material of antibodies.
5., according to the application in Claims 2 or 3 described in any one, the antibody of wherein said anti-CD146 is monoclonal antibody AA98.
6. the antibody of anti-CD146 or the functional form of this antibody are for the preparation of the application in the location of human body inflammatory cell infiltration and the medicine of targeted therapy, and the antibody of wherein said anti-CD146 is monoclonal antibody AA98.
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