CN109400707A - A kind of antibody and its preparation method and application preventing cerebral arterial thrombosis - Google Patents
A kind of antibody and its preparation method and application preventing cerebral arterial thrombosis Download PDFInfo
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- CN109400707A CN109400707A CN201811250668.6A CN201811250668A CN109400707A CN 109400707 A CN109400707 A CN 109400707A CN 201811250668 A CN201811250668 A CN 201811250668A CN 109400707 A CN109400707 A CN 109400707A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/40—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against enzymes
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
- G01N33/573—Immunoassay; Biospecific binding assay; Materials therefor for enzymes or isoenzymes
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/10—Immunoglobulins specific features characterized by their source of isolation or production
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2800/00—Detection or diagnosis of diseases
- G01N2800/32—Cardiovascular disorders
- G01N2800/323—Arteriosclerosis, Stenosis
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Abstract
The present invention provides a kind of antibody and its preparation method and application for preventing cerebral arterial thrombosis, a kind of antibody for the stability improving atherosclerotic plaque, it is characterized by: the antibody is CHI3L1 neutralizing antibody, wherein, the CHI3L1 neutralizing antibody, for the 325th -339 amino acids of mouse CHI3L1 albumen, the sequence of the 325th -339 amino acids are as follows: n-WVGYDDQESVKSNKVQ-c.The antibody and preparation method thereof of prevention cerebral arterial thrombosis of the invention, the mouse of CHI3L1 neutralizing antibody injection is compared with control group, and Efferocytosis is relatively strong and patch is more stable.Therefore cerebral arterial thrombosis caused by falling off as carotid artery atherosclerosis plaques can effectively be prevented.
Description
Technical field
The present invention relates to a kind of antibody for preventing cerebral arterial thrombosis, the invention further relates to the preparation method of this antibody and
Using belonging to antibody drug field.
Background technique
It in recent years, with cerebral apoplexy is at present the major causes of death for representing diseases of cardiovascular and cerebrovascular systems and having become the mankind.
Diseases of cardiovascular and cerebrovascular systems has become first cause of death of China resident, and mortality is higher than 4-5 times of American-European countries,
And disease incidence cumulative year after year.Self-care ability is lost after many stroke patients, brings heavy medical treatment for family and society
Pressure.The cause of disease of statistics display about 30-50% cerebral arterial thrombosis is Extracranial carotid atherosis
(carotidatherosclerosis stenosis, CAS) is narrow.The primary treatment measure of current CAS include drug therapy and
Surgical operation therapy, to the selection of therapeutic strategy mainly according to the clinical manifestation of patient and its carotid artery stenosis in current guideline
Depending on degree.But find that numerous patients with carotid stenosis have no traditional risk factor or even absence of aura disease in clinical practice
Shape, and occur acute cerebral ischemia symptom suddenly, such case usually causes cerebral vessels embolism to cause by atherosclerotic plaque rupture.
Histology and iconography research at present it has been confirmed that, the generation of cerebral apoplexy is not only related to CAS stenosis, and with AS patch
The property of itself is related, such as plaque surface ulcer, bleeding, thrombus etc., this patch for being easy to rupture and cause acute embolic
It is referred to as Plaque Disrupt.More and more evidences show to determine that the factor of plaque stability is not luminal stenosis degree,
But atherosclerosis (atherosclerosis, AS) patch constituent.Early detection and treatment suffer from carotid artery stenosis
And with stroke high risk factor patient, cerebral arterial thrombosis event generation before carry out intervene have the function of it is very positive.
The principal element of atherosclerotic plaque stability is influenced for smooth muscle cell fibrous cap as main component and with bad
The Relationship Between Dynamic Change of dead cell necrotic cores as main component, the two plays certainly during atheromatous plaque occurrence and development
Qualitative effect, necrotic cores are larger and atherosclerotic plaque that fibrous cap is weaker is more unstable, it is easier to fall off and form blood
Bolt leads to cerebral arterial thrombosis.Therefore, the stability for improving patch just becomes the important side that prevention ischemic cerebral apoplexy is seen
To.
Summary of the invention
The purpose of the present invention is to provide a kind of antibody of stability and application thereof for improving atherosclerotic plaque, to solve
The above problem.
A kind of antibody for the stability improving atherosclerotic plaque, it is characterised in that: the antibody is in CHI3L1 and anti-
Body, wherein the CHI3L1 neutralizing antibody, for the 325th -339 amino acids of mouse CHI3L1 albumen, the described 325th -
The sequence of 339 amino acids are as follows: n-WVGYDDQESVKSNKVQ-c.
The antibody of the stability of raising atherosclerotic plaque of the invention, also has a feature in that wherein, the antibody
For use the 325th -339 amino acids segment of mouse CHI3L1 albumen be immunized animal after obtain.
The antibody of the stability of raising atherosclerotic plaque of the invention, also has a feature in that wherein, the artery
For aorta and arteria carotis.
The antibody of the stability of raising atherosclerotic plaque of the invention, also has a feature in that wherein, described immune
Animal be the acceptable animal in Antibody preparation field.
The antibody of the stability of raising atherosclerotic plaque of the invention also has a feature in that wherein, immune is dynamic
Object is new zealand white rabbit.
The antibody of the stability of raising atherosclerotic plaque of the invention, also has a feature in that wherein, the antibody
For the monoclonal antibody for the 325th -339 amino acids of mouse CHI3L1 albumen.
The present invention also provides a kind of preparation methods of CHI3L1 neutralizing antibody, which comprises the steps of:
Step 1: synthetic polypeptide antigen, the polypeptide antigen are the 325th -339 amino acids of mouse CHI3L1 albumen, sequence
It is classified as: n-WVGYDDQESVKS/NKVQ-c；
Step 2: new zealand white rabbit is repeatedly immunized using the peptide fragment；
Step 3: taking a blood sample after 10 weeks, uses the clear antibody titer of ELISA, the clear antibody specificity of Western Blot；
Step 4: taking blood, and purified blood serum removes endotoxin and concentrated antibody.
The present invention also provides a kind of CHI3L1 neutralizing antibodies in production detection atherosclerotic plaque stability kit
Using, it is characterised in that: it include: CHI3L1 neutralizing antibody, for the 325th -339 amino acids of mouse CHI3L1 albumen, institute
State the sequence of the 325th -339 amino acids are as follows: n-WVGYDDQESVKSNKVQ-c, also with report on the CHI3L1 neutralizing antibody
Accuse group.
Advantageous effect of the invention
The antibody and preparation method thereof of prevention cerebral arterial thrombosis of the invention, the mouse of CHI3L1 neutralizing antibody injection compared with
Control group, Efferocytosis is relatively strong and patch is more stable.Therefore can effectively prevent to make since carotid artery atherosclerosis plaques fall off
At cerebral arterial thrombosis.
Detailed description of the invention
Figure 1A is the result of CHI3L1 protein groups in mouse aorta root HE dyeing；
Figure 1B is the result of control group in mouse aorta root HE dyeing；
Fig. 1 C is the result of CHI3L1 neutralizing antibody group in mouse aorta root HE dyeing；
Fig. 1 D is mouse aorta root necrotic core area statistical result；
Fig. 1 E is the ration statistics result that mouse aorta root necrotic cores account for atheromatous plaque
Fig. 2A is arteria carotis Vulnerable plaque materials, slice, the result dyed, wherein Fig. 2A -1, Fig. 2A -2, figure
2A-3 be HE dyeing as a result, Fig. 2 B-1, Fig. 2 B-2, Fig. 2 B-3 be MASSON dyeing as a result,
Fig. 2 C is that mouse arteria carotis necrotic cores account for atheromatous plaque ration statistics result；
Fig. 2 D is that mouse arteria carotis fibrous cap accounts for atheromatous plaque ration statistics result；
Fig. 3 is the horizontal testing result of symptomatic arteria carotis patient arteria carotis change of serum C HI3L1.
Specific embodiment
Illustrate a specific embodiment of the invention below in conjunction with attached drawing.
<embodiment one>
Falling off for carotid artery stenosis Vulnerable plaque is the Important cause of disease for leading to cerebral apoplexy.The stability of atherosclerotic plaque
It is the result of necrotic cores and fibrous cap dynamic equilibrium inside patch.Efferocytosis is a kind of phagocyte, such as macrophage
Or Dendritic Cells etc., the physiology course of clear program dead cell.In atherosclerotic plaque, the born of the same parents of macrophage are buried
The Scavenging activity of effect can directly affect the size of necrotic cores in patch, and the decline of Efferocytosis level will lead to atheromatous plaque
Block stability reduces.3 sample albumen 1 (CHI3L1) of chitinase is a kind of and the highly relevant molecular labeling of cerebral arterial thrombosis
Object.A kind of antibody of stability improving atherosclerotic plaque, i.e. CHI3L1 neutralizing antibody are provided in present embodiment.
Experimental section:
The preparation of CHI3L1 neutralizing antibody
(1) synthetic polypeptide antigen, the peptide fragment are the 325th -339 amino acids (n- of mouse CHI3L1 albumen
WVGYDDQESVKSNKVQ-c)；
(2) new zealand white rabbit is repeatedly immunized using the peptide fragment；
It takes a blood sample after (3) 10 weeks, uses the clear antibody titer of ELISA, the clear antibody specificity of Western Blot；
(3) blood is taken after clear immune effect, purified blood serum removes endotoxin and concentrated antibody in case animal model injection makes
With.
The administration of CHI3L1 neutralizing antibody
The generally acknowledged mouse for establishing arteria carotis Vulnerable plaque model method that this part experiment uses is with health
Ldlrtm1HerIt is constructed based on/J public affairs mouse.
(1) health Ldlr is chosentm1Her/ J public affairs mouse, in termination breast-feeding in the 3rd week；
(2) it after normal diet is fed 3 weeks, is fed 10 weeks using High cholesterol diet, High cholesterol diet: containing protein
22%, fat 21%, carbohydrate 40%, cholesterol 0.15%；
(3) mouse is randomly divided into 3 groups, injects CHI3L1 recombinant protein, CHI3L1 neutralizing antibody and IgG, injection respectively
Time point is the 13rd, 15,17,19,21 week after mouse birth, by the way that CHI3L1 recombinant protein 500ng/ml is injected intraperitoneally,
CHI3L1 neutralizing antibody 1mg/ml and IgG 1mg/ml, three kinds of reagents are dissolved in PBS, and injection volume is according to mouse circulating meter
It calculates, mouse circulating blood volume is estimated by mouse weight 8%.
(4) it performs the operation in the 16th week progress mouse arteria carotis constriction, establishes unstable plaque block models.Use yellow Jackets
60mg/Kg intraperitoneal injection of anesthesia.The row stringer notch on the right side of mouse neck, layer-by-layer blunt separation tissue, sufficiently exposure right side neck
Total artery avoids damage to peripheral nerve and blood vessel.The titanium silk that a piece diameter is 150um is fixed on arteria carotis with the silk thread of 6-0
Bifurcated with remote 1mm-4mm at, then titanium silk is removed；
(5) surgical effect confirms, postoperative 1st week and the 3rd week, randomly selects mouse and carries out carotid artery vascular color ultrasound examination,
Specify surgical effect.Attention action is soft, avoids squeezing patch, patch is caused to fall off；
(6) mouse weighs weekly and calculates food-intake, observes mouse state change；
(7) materials experiment, is euthanized to mouse in postoperative 7th week, and acquisition respective organization is observed.
Experimental result
Statistical method and drawing:
All data are drawn using Graphpad Prsim7, for statistical analysis using its plug-in.Picture each section
The statistics of area is indicated in the form of mean ± standard error with (Fiji editions) analysis statistics of Image J software, continuous variable.Two groups
Between comparison examined using t, compare using variance analysis between multiple groups.There is statistical difference if P < 0.05.
(1) CHI3L1 can increase necrotic cores in aortic root patch, and CHI3L1 neutralizing antibody has inhibition to make to it
With.
It is observation CHI3L1 and its neutralizing antibody for mouse aorta root atheromatous plaque as shown in Figure 1A to Fig. 1 E
The influence of necrotic cores in block has carried out paraffin section HE dyeing to mouse aorta root, and to necrotic cores therein, face
Product is statisticallyd analyze, and necrotic cores are dotted line circled portion in Fig. 1, is found after injecting CHI3L1 albumen, and mouse is actively
Necrotic core area increases compared with control group in arteries and veins patch.And inject downright bad core in the mouse aorta patch of CHI3L1 neutralizing antibody
Heart area is reduced compared with control group.In addition we have also counted necrotic cores in the slice of mouse aorta root and have accounted for atheromatous plaque simultaneously
The ratio of area, discovery CHI3L1 protein groups rise compared with control group necrotic cores ratio, and two value < 0.05 group difference P have system
Meter learns meaning.And CHI3L1 neutralizing antibody group declines compared with control group necrotic cores ratio, two group difference P values are < 0.05, are had
Statistical significance.The result shows CHI3L1, and necrotic cores in the patch of mouse aorta root can be made to increase, and in CHI3L1
It can inhibit the expansion of necrotic cores with antibody.
(2) fibrous cap ratio reduces in CHI3L1 group carotid plaques, and the patch ratio of necrotic cores increases, and is added
CHI3L1 neutralizing antibody fibrous cap ratio increases, and necrotic cores ratio reduces
Fig. 2A is mouse arteria carotis HE dyeing, and Fig. 2 B is mouse arteria carotis Masson dyeing
The neutralizing antibody of influence for clear CHI3L1 and its to(for) atherosclerotic plaque stability, we are small to three groups respectively
The paraffin section of mouse arteria carotis sample has carried out HE (uplink, Fig. 2A -1, Fig. 2A -2, Fig. 2A -3), MASSON dyeing (under
Row, Fig. 2 B-1, Fig. 2 B-2, Fig. 2 B-3), the ratio that necrotic cores in slice account for atheromatous plaque area has been counted, has found CHI3L1
Protein groups rise compared with control group necrotic cores ratio, two value < 0.05 group difference P, have statistical significance.And CHI3L1 is neutralized
Antibody group declines compared with control group necrotic cores ratio, two value < 0.05 group difference P, has statistical significance, such as Fig. 2 C.In addition
It was found that CHI3L1 protein groups, compared to control group, fibrous cap ratio reduces (P < 0.05), CHI3L1 neutralizing antibody group, compared to right
According to group, fibrous cap ratio increases (P < 0.01), as shown in Figure 2 D.These data illustrate that CHI3L1 can improve it in Mice Body
The ratio of necrotic cores in arteria carotis unstable atheromatous plaque can further decrease the stability of atherosclerotic plaque, and
CHI3L1 neutralizing antibody can reduce the ratio of necrotic cores in its arteria carotis unstable atheromatous plaque, improve atherosclerotic plaque
Stability.
As a result
It is detected by the histotomy and RNA of clinical sample, specifies CHI3L1 in unstable atherosclerotic plaque
Expression is higher, and is mainly distributed near patch necrotic cores.Extract Bone Marrow Macrophage and human peripheral macrophage
After cell, prove that CHI3L1 can inhibit the Efferocytosis of macrophage by flow cytometry and laser confocal microscope.?
In the arteria carotis Vulnerable plaque mouse model of building, inject the mouse of CHI3L1 compared with the control group, Efferocytosis weaken and
Patch is more unstable, and gives the mouse of neutralizing antibody injection compared with control group, and Efferocytosis is relatively strong and patch is more stable.Pass through analysis
Clinical sample and proteomic techniques, filtering out CHI3L1 influences the target gene MFGE8 of Efferocytosis, and passes through cell experiment
It is verified.Pass through observation macrophage Efferocytosis variation after covering MFGE8, it was demonstrated that CHI3L1 is by inhibiting MFGE8
It expresses and inhibits macrophage Efferocytosis.
<embodiment two>
Based on CHI3L1 neutralizing antibody obtained in embodiment one and its improve atherosclerotic plaque stability in
Remarkable effect, present embodiment provide a kind of detection atherosclerotic plaque stability kit: it include: CHI3L1 neutralizing antibody,
For the 325th -339 amino acids of mouse CHI3L1 albumen, the sequence of the 325th -339 amino acids are as follows: n-
WVGYDDQESVKS/NKVQ-c also has reporter group on the CHI3L1 neutralizing antibody.
Take peripheral blood sample to be measured.It is detected using kit provided by the present invention.
Symptomatic arteria carotis patient arteria carotis change of serum C HI3L1 level is higher than asymptomatic patient.
In Fig. 3, ELISA detection has been carried out to CHI3L1 protein content in patient's artery serum of carotid artery stenosis, wherein
Asymptomatic carotid stenosis 39, symptom carotid artery stenosis patient 38.Artery serum ELISA detection can reflect by
The content of inspection person's intra-arterial correlation secreted protein.Each point represents the CHI3L1 protein content of corresponding sample in figure.?
In Fig. 3, the CHI3L1 albumen average content of asymptomatic group patients with carotid stenosis is 82.4ng/ml, has symptom group arteria carotis narrow
Narrow patient is 247.7ng/ml, and asymptomatic group, which is substantially less than, symptom group, value < 0.001 P between two groups, and difference is anticipated with statistics
Justice.
Sequence table
<110>Second Military Medical University, PLA
<120>a kind of antibody and its preparation method and application for preventing cerebral arterial thrombosis
<130> 111111111111111111
<160> 1
<170> SIPOSequenceListing 1.0
<210> 1
<211> 16
<212> PRT
<213> mouse
<400> 1
Trp Val Gly Tyr Asp Asp Gln Glu Ser Val Lys Ser Asn Lys Val Gln
1 5 10 15
Claims (8)
1. a kind of antibody for the stability for improving atherosclerotic plaque, it is characterised in that:
The antibody is CHI3L1 neutralizing antibody,
Wherein, the CHI3L1 neutralizing antibody, for the 325th -339 amino acids of mouse CHI3L1 albumen, the described 325th -
The sequence of 339 amino acids are as follows: n-WVGYDDQESVKSNKVQ-c.
2. improving the antibody of the stability of atherosclerotic plaque as described in claim 1, it is characterised in that:
Wherein, the antibody is to obtain after animal is immunized using the 325th -339 amino acids segment of mouse CHI3L1 albumen.
3. improving the antibody of the stability of atherosclerotic plaque as described in claim 1, it is characterised in that:
Wherein, the artery is aorta and arteria carotis.
4. improving the antibody of the stability of atherosclerotic plaque as claimed in claim 2, it is characterised in that:
Wherein, the immune animal is the acceptable animal in Antibody preparation field.
5. improving the antibody of the stability of atherosclerotic plaque as claimed in claim 2, it is characterised in that:
Wherein, immune animal is new zealand white rabbit.
6. improving the antibody of the stability of atherosclerotic plaque as described in claim 1, it is characterised in that:
Wherein, the antibody is the monoclonal antibody for the 325th -339 amino acids of mouse CHI3L1 albumen.
7. a kind of preparation method of CHI3L1 neutralizing antibody, which comprises the steps of:
Step 1: synthetic polypeptide antigen, the polypeptide antigen are the 325th -339 amino acids of mouse CHI3L1 albumen, sequence are as follows:
n-WVGYDDQESVKSNKVQ-c；
Step 2: new zealand white rabbit is repeatedly immunized using the peptide fragment；
Step 3: taking a blood sample after 10 weeks, uses the clear antibody titer of ELISA, the clear antibody specificity of Western Blot；
Step 4: taking blood, and purified blood serum removes endotoxin and concentrated antibody.
8. a kind of application of CHI3L1 neutralizing antibody in production detection atherosclerotic plaque stability kit, feature exist
In:
It include: CHI3L1 neutralizing antibody, for the 325th -339 amino acids of mouse CHI3L1 albumen, described 325th -339
The sequence of amino acid are as follows: n-WVGYDDQESVKSNKVQ-c,
Reporter group is also had on the CHI3L1 neutralizing antibody.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111197040A (en) * | 2020-01-21 | 2020-05-26 | 福建亿彤生物科技有限公司 | Chitinase 3-like protein 1(CHI3L1) epitope peptide, antigen, antibody, application and kit |
-
2018
- 2018-10-25 CN CN201811250668.6A patent/CN109400707A/en active Pending
Non-Patent Citations (4)
| Title |
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| EMIKO MIZOGUCHI: "Chitinase 3–Like-1 Exacerbates Intestinal Inflammation by Enhancing Bacterial Adhesion and Invasion in Colonic Epithelial Cells", 《GASTROENTEROLOGY》 * |
| ZUSHUN GONG ET AL: "ncreased Expression of Chitinase 3-Like 1 in Aorta of Patients with Atherosclerosis and Suppression of Atherosclerosis in Apolipoprotein E-Knockout Mice by Chitinase 3-Like 1 Gene Silencing", 《MEDIATORS INFLAMM》 * |
| 李祥波: "几丁质酶样3蛋白1及基质金属蛋白酶-9在人颈动脉粥样硬化斑块中表达的相关研究", 《中国优秀硕士学位论文全文数据库》 * |
| 钟海: "甲壳质酶3类似物1在非小细胞肺癌中促血管生成及机制研究", 《中国优秀硕士学位论文全文数据库》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111197040A (en) * | 2020-01-21 | 2020-05-26 | 福建亿彤生物科技有限公司 | Chitinase 3-like protein 1(CHI3L1) epitope peptide, antigen, antibody, application and kit |
| CN111197040B (en) * | 2020-01-21 | 2023-08-08 | 福建亿彤生物科技有限公司 | Chitinase 3-like protein 1 (CHI 3L 1) epitope peptide, antigen, antibody, application and kit |
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