CN108484768A - Neutralizing antibody and the application in treating breast cancer is immunized in a kind of anti-phylaxin - Google Patents
Neutralizing antibody and the application in treating breast cancer is immunized in a kind of anti-phylaxin Download PDFInfo
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- CN108484768A CN108484768A CN201810227299.2A CN201810227299A CN108484768A CN 108484768 A CN108484768 A CN 108484768A CN 201810227299 A CN201810227299 A CN 201810227299A CN 108484768 A CN108484768 A CN 108484768A
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- 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
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
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- A—HUMAN NECESSITIES
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- A—HUMAN NECESSITIES
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- 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
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- 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
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Abstract
The invention discloses a kind of anti-phylaxins, and neutralizing antibody and the application in treating breast cancer is immunized, and belongs to biomedicine field.The present invention passes through the selection of antigen polypeptide, the selection of immunization ways, the purifying of antibody serum and the measurement of antibody concentration and the detection of antibody effects, has obtained anti-phylaxin and neutralizing antibody is immunized, which can be used for treating breast cancer under obese model.
Description
Technical field
The present invention relates to a kind of anti-phylaxins, and neutralizing antibody and the application in treating breast cancer is immunized, and belongs to biological medicine
Field.
Background technology
Breast cancer is the significant problem of the global women's health of puzzlement, and there are about 1,400,000 people to be diagnosed as mammary gland in the annual whole world
Cancer, and about 500,000 people die of the disease, breast cancer is first cause of death of 40-55 Sui women.The year of China's breast cancer
Equal growth rate is 3%-4%, becomes the fastest-rising cancer of the death rate in city, especially with Shanghai, Beijing, Tianjin and coastal
Area is the hotspot of China's breast cancer, has accounted for the first place of female malignant incidence.
The occurrence and development key factor of breast cancer is in following three kinds of reasons：1. inherent cause.Breast cancer has apparent family
Genetic predisposition, for example, it is to pass through special gene (BRCA1/BRCA2 genes) by its parent that some patientss, which suffer from breast cancer,
It hands down by heredity.2. female hormone is disorderly.Since breast is for a long time by the abnormal stimulation of female hormone, lead to breast tissue canceration,
High fat diet is to lead to the extremely increased one of the main reasons of female hormone.3. such environmental effects.Dietary structure it is unreasonable
And ionising radiation toxin stimulation etc. leads to normal mammary epithelial canceration.
Currently, fat closely related with the morbidity of breast cancer caused by unreasonable and inherent cause of dietary structure etc..
Clinically, the incidence with clinical-grade and obesity of breast cancer are proportionate, and excess fat tissue is the proliferation of tumour cell
Energy is provided with migration, while adipose tissue is also that the transfer of tumour cell and chemotherapy exhaust protect place.
Adipose tissue serves not only as the storage of fat drips, the even more important secretory of body, is reported and breast cancer
Generation it is closely related.On the one hand, excess fat tissue leads to body glucose and insulin resistant, the grape of excessive level
Sugar provides sufficient energy and signal stimulus with the proliferation that insulin is tumour cell to shift.On the other hand, obesity leads to fat
Fat tissue is in hypoxia, inducing hypoxia inducible factor (HIF1 α), transforming growth factor-β (TGF-β), matrix metalloprotease
The expression of enzyme (MMPs) etc. further remolds tumor microenvironment and induces Tumor Angiongesis and transfer.In addition, fat usually companion
With the chronic inflammation of adipose tissue, the inflammatory factor of adipose tissue secretion, such as interleukin family, tumor necrosis factor α
(TNF α) etc. participates in moulding tumor microenvironment and promotes the generation and development of tumour.
Currently, the treatment mainly auxiliary surgical of breast cancer is with the means of chemicotherapy.Clinically, breast cancer according to estrogen by
Body (ER), progesterone receptor (PR), HER2 expressions are broadly divided into following four classes：Epithelium A types (Luminal
Subtype A, ER+/PR+, HER2-), epithelium Type B (Luminal subtype B, ER+/PR+, HER2+), HER2 mistakes
Expression type (HER2over-expression subtype, ER-, PR-, HER2+), three cloudy breast cancer (ER-, PR-, HER2-).
According to different molecular hypotype, be clinically aided with different Chemotherapeutic treatments, for example, for ER/PR positive patients give female by
Body/progesterone receptor targeting medicine treatment (tamoxifen), while blocking estrogen to synthesize using arimedex；For
The targeted drug He Saiding of HER2；Common chemotherapeutic drugs Cisplatin etc. is used for three negative patients.But clinically breast cancer is controlled
It treats often along with the recurrence of tumour and chemoresistance, especially adiposis patient, reality is difficult to by reducing lipopexia, resisting obesity
Now with keep and be difficult to achieve the effect that treat tumour.Therefore, the method for new safely and effectively inhibition breast cancer is found
Through becoming research hotspot.
Resistin protein (Resistin) is generated and is secreted by adipocyte in mouse, in human body mainly by fatty thin
Born of the same parents and mononuclear macrophage generate and secretion.Resistin be reported it is closely related with fat and type-II diabetes, clinically,
Resistin levels are proportionate with breast cancer patients grade malignancy in serum, and Resistin can promote in vitro culture breast cancer thin
The migration of born of the same parents, while experiment in vitro proves, Resistin promotes the proliferation of breast carcinoma stem cell and the chemotherapy of breast cancer is promoted to support
It is anti-.
Currently, for Resistin immune neutralizing antibody there has been no for experiments in vivo, and make it is difficult, it is of high cost.
We place hope on finds the preparation that the specific peptide fragments of Resistin are used to be immunized neutralizing antibody by bioinformatics means, big to advise
Mould prepares polyclonal antibody, designs mouse obese model, and carry out the verification of breast cancer treatment.
Invention content
For the above-mentioned problems in the prior art, in being immunized the present invention provides a kind of effective anti-mouse source phylaxin
And preparation method for antibody.
The preparation method includes choosing antigen polypeptide, selection immunization ways, antibody purification serum.A step of going forward side by side determines
Antibody concentration and antibody effects.
The antigen polypeptide is Resistin albumen specific polypeptides sections, and the Resistin albumen specific polypeptides section includes more
Peptide sequence EAIDKKIKQDF (mouse source Resistin full length sequences 30-40 amino acids from N-terminal).
The immunization ways be Resistin albumen specific polypeptides sections C-terminal by cysteine be coupled BSA resisted
Former polypeptide liquid, after mixing with Freund's complete adjuvant, toward 8 weeks macrandry new zealand rabbit left and right sides dorsal scs, subcutaneous abdomen,
Left and right hind leg muscle and left right rear leg popliteal nest lymph node totally 8 positions, inject above-mentioned antigen-adjuvant mixed liquor；Then the 2nd,
4,5,6,7 weeks, 8 weeks quick adjuvants of rabbit is uniformly mixed with antigen polypeptide liquid in advance, in above-mentioned 8 positions, inject above-mentioned antigen-
Quick adjuvant mixed liquor.
The antibody purification serum is to obtain antibody using the specific affinity purification of antigen-antibody.
On the other hand, the present invention provides anti-mouse source phylaxins, and application of the neutralizing antibody in treating tumor of breast is immunized,
The tumor of breast is fat induction, is played a role by in-situ injection.
New zealand rabbit is immunized as antigen using the polypeptide that sequence includes EAIDKKIKQDF in the present invention, passes through antigen-antibody
Affinity purification is purified from serum obtains the immune neutralizing antibody of anti-phylaxin, and neutralizing antibody is immunized in the anti-Resistin of gained can be significantly
Mitigate obesity mice tumor of breast weight and volume, reaches effective control and therapeutic effect.
Description of the drawings
The * occurred in attached drawing of the present invention indicates P<0.05, * * indicates P<0.01, * * * indicate P<0.001.
Fig. 1 show the monomer structure (a) of Resistin albumen, tripolymer (b), six dimeric structure figures (c) and
The full length sequence information (d) of Resistin.Wherein arrow is signified and red mark (1#) is used to prepare immune neutralization to be selected
Antibody peptide fragment.
Fig. 2 shows the immune flow chart that antibody is prepared by antigen injection new zealand rabbit.The past new zealand rabbit back at the 0th week
Subcutaneously, leg muscle is He popliteal nest lymph node injection Freund's complete adjuvant (Sigma-Aldrich companies) and antigen mixed liquor (1:1,
500μg).Then at the 2nd, 4,5,6,7 week, toward 8 weeks quick adjuvants of same injection location rabbit, (Beijing Bo Aolong immunological techniques were limited
Company) and antigen mixed liquor (1:1,250 μ g).Identification of the antibodies is carried out in the 8th week ear edge vein exploitating blood, it is total by neck at the 9th week
Artery acquires new zealand rabbit whole blood.
Fig. 3 shows that Western Blot verify new zealand rabbit serum in the 3T3-L1 adipocytes of differentiation and maturation
The recognition capability of Resistin.
Fig. 4 displays utilize the 1# polypeptide affinity purifications New Zealand figure serum moderate resistance Resistin antibody of coupling BSA, eluent
After elution after protein electrophorese, with antibody concentration in the eluent of coomassie brilliant blue staining measurement.
Fig. 5 ELISA experiments show identification of the purified antibodies for Resistin in 3T3-L1 adipocyte supernatants, sun
Property control use anti-Resistin antibody (PEPROTECH companies) for business, negative control is rabbit igg (scheme a).Figure b is shown will be pure
After antibody carries out gradient dilution after change, ELISA experiments are carried out, are detected for Resistin eggs in 3T3-L1 adipocyte supernatants
White and 1# polypeptides combination situation.
Fig. 6 shows the administration flow chart of mouse breast cancer under Resitin Antybody therapy obese models.Utilize 12 weeks drinks high in fat
After eating induction Female C57BL/6 mouse obesities, toward normal/the second mammary fat pad of obesity mice injection mouse source breast cancer cell line
E0771(5*105), neutralizing antibody then was immunized toward the anti-Resistin of mammary fat pad in-situ injection at the 1st, 4,8,12 day
The rabbit igg of (0.7mg/kg weight/time) or equivalent, while index of correlation is detected, mouse is slaughtered at the 13rd day, is counted.
Fig. 7 is normal/obesity mice whether giving anti-Resistin antibody in the case of, mouse chest offside mammary fat
The weight statistical chart (a) and visceral fat weight statistical chart (b) of pad.
Fig. 8 is normal/obesity mice giving anti-Resistin antibody or rabbit igg, mouse tumor volume it is daily
Measure figure.
Fig. 9 after the 13rd day slaughters mouse, measure normally with whether give anti-Resistin antibody under the conditions of obesity
Mouse mammary tumor weight chart (b), the audio-visual picture (a) with each grouping tumor size.
Specific implementation mode
Unless specifically stated otherwise, the new zealand rabbit in following embodiment used in injections of antigens is male, C57BL/6 is female greatly within 8 weeks
Mouse feeds high lipid food 12 weeks after birth 4th week, high lipid food fat ratio is 60%.
Unless specifically stated otherwise, reagent used in following embodiment and material are to analyze the reagent of pure rank, and can be from
The commercially available synthesis of regular channel or purchase, wherein 1# Purities needed for immune new zealand rabbit are>=95%.
Control group and anti-Resistin are immunized neutralizing antibody group and carry out statistical analysis, P by the present invention<0.05 i.e. expression group
Between difference have statistical significance.
The extensive preparation of neutralizing antibody is immunized in 1 Resistin of embodiment
In Mice Body, Resistin is mainly secreted by mature fat cell, and in vivo mainly with tripolymer and six
Dimer form exists.First, have using B cell antigen epi-position forecast analysis software analysis Resistin protein sequences and exempt from more by force
Then the stronger region of gained antigenicity is predicted using protein three-dimensional structure analysis software, according to egg in the region of epidemic focus
It is chosen the location of in white matter monomer and polymer 3D structures and is exposed to albumen 3D body structure surfaces and the stronger sequence of antigenicity
Row synthesis small peptide simultaneously carries out subsequent experimental assessment.
With 1# polypeptides (N-terminal α spirals, sequence EAIDKKIKQDF) as antigen, while passing through cysteine idol in its C-terminal
Join BSA, facilitates antigen presentation, enhancing immune.
According to the experimental program of figure two, at the 0th week in advance by 500 μ l of Freund's complete adjuvant (Sigma-Aldrich companies)
It mixes with 500 μ L of antigen polypeptide liquid (1 μ g/ μ L, be dissolved in physiological saline), and as on ice, is uniformly mixed with vacuum mixed instrument.It is past
8 weeks macrandry new zealand rabbit left and right sides dorsal scs, subcutaneous abdomen, left and right hind leg muscle and left right rear leg popliteal nest lymph node totally 8
Above-mentioned antigen-adjuvant mixed liquor is injected in a position, each to put about 120 μ L.Then at the 2nd, 4,5,6,7 week, in advance by rabbit 8 weeks
(1 μ g/ μ L, are dissolved in physiology salt to quick adjuvant (Beijing Bo Aolong Immune Technology Corp.) 250 μ L with 250 μ L of antigen polypeptide liquid
Water) quickly after mixing, in above-mentioned 8 positions, above-mentioned antigen-adjuvant mixed liquor is injected, it is each to put about 60 μ L.
8th week ear edge vein exploitating blood about 1ml in anticoagulant tube, be stored at room temperature after twenty minutes, in 4 DEG C of 3500 turns of centrifuges/
Minute centrifugation 15 minutes, Aspirate supernatant (serum), packing is stored in -20 degrees Celsius.Meanwhile with primary antibody dilution with 1:500
Dilution proportion new zealand rabbit serum, is tested using protein immunoblotting, verifies the antibody generated in serum for 3T3-L1 fat
In fat cell Resistin albumen identification (using 3T3-L1 precursors sample as negative control (not expressing Resistin), with
The Resistin antibody of PEPROTECH companies production is positive control).Experimental result is shown in the new zealand rabbit serum after being immunized
Resistin antibody is produced, the Resistin (Fig. 3) of identification overall length and secreted form that can be specific.
New zealand rabbit whole blood about 100mL is acquired by arteria carotis communis at the 9th week, after being stored at room temperature 2 hours, in 4 DEG C of centrifugations
3500 revs/min of machine centrifuges 30 minutes, Aspirate supernatant about 50ml (serum), freezes and is used in -80 degrees Celsius after liquid nitrogen flash freezer
Later purification experiment.
Purifying and the Activity determination of neutralizing antibody is immunized in 2 Resistin of embodiment
Neutralizing antibody is immunized in a large amount of pure anti-Resistin in order to obtain, we are solidifying using the agarose of antigen coupling
Glue carries out the purifying of Serum Antibody,
1. 1mg 1# polypeptide antigen-BSA fusion proteins are dissolved (coupling buffering overnight in coupling buffer at 4 DEG C
Formula of liquid：100mM NaHCO3, 500mMNaCl, adjust pH to 8.3).
2. under 4 DEG C of environment, 1ml cyanogen bromides (CNBr) are activated to activate in 1mM HCl solutions cold 20ml
Sepharose4B pearls 15 minutes.
3. cleaning pearl twice with 20ml 1mM HCl.
4. 4 DEG C of shaking tables of the sepharose 4B of activation and the 1# polypeptide antigen-BSA fusion proteins of dialysis are incubated overnight.
6. washing the Sepharose beads 2 times of albumen coupling with 15ml coupling buffers, supernatant is abandoned in centrifugation.
7. 5ml 0.1M Tris-HCl buffer solutions (pH8.0) are added to close the de- conjugation sites on bead, and at 4 DEG C
Under stand overnight.
8. next, being coupled Sepharose pearls by antigen protein to purify antiserum：
1) Sepharose pearls are washed 5 times with acid-base buffer first.(acid-base buffer formula：0.1M acetic acid/acetic acid
Sodium, pH4.0；0.1M Tris-HCl, 0.5M NaCl, pH8.0).
2) 4 DEG C of shaking tables overnight incubation (PBS buffer solution formulas of serum after 2 times are diluted by pearl and with PBS buffer solution：
10mM Na2HPO4, 1.8mM KH2PO4, 137mM NaCl, 2.7mM KCl, pH is to 7.4) for adjusting.
3) pearl and serum mixed liquor are flowed through into liquid by purification column collection, and will flow through liquid be stored in -20 degrees Celsius with
It is tested in ELISA.
4) pearl is washed 3 times with 10ml PBS buffer solution.
5) pillar is washed with 10ml 150mM NaCl-HCl (pH 5) solution.
6) 7ml elution buffer antibody elutions are used, 500 μ l be used in combination to be saturated in phosphate buffers and solution.(eluent is matched
Side：150mM NaCl, with salt acid for adjusting pH to 2.5；It is saturated phosphate-buffered formula of liquid：Na is added into PBS buffer solution2HPO4
Solid is until saturation).
7) antibody-solutions are packed as every pipe 1ml, in -80 DEG C of preservations.
Above-mentioned antibody-solutions are subjected to protein electrophorese and are quantified with coomassie brilliant blue staining.Antibody is dense in the eluent of survey
Spend about 150 μ g/ml (Fig. 4).
Next using the immune neutralizing antibody that is purified into of ELISA experiment detections whether can identify 1# antigen polypeptides and from
Resistin albumen under right state.
By 10ml maturation 3T3-L1 adipocyte cultures supernatant (DMEM culture medium of the mature fat cell without FBS
Supernatant is collected after culture 12h) 3000 revs/min of centrifugation 10min, then be placed in freeze drier with 0.22 μm of membrane filtration
It is dried to powder.Above-mentioned powder is dissolved into 2mg/ml (antigen coat formula of liquid with antigen coat liquid：Na2CO30.159g/
100ml, NaHCO30.293g/100ml) and 96 orifice plates of ELISA are coated with, are detected for ELISA.If Fig. 5 a are shown, 1:500
Dilution ratio under, the anti-Resistin antibody of purifying gained can identify Resistin albumen under natural conditions well, negative
Control is rabbit igg (with purifying gained antibody 1:It is consistent under 500 diluted concentrations), positive control is that business is anti-with anti-Resistin
Body (PEPROTECH companies, dilution ratio 1:2000).In addition, by ripe 3T3-L1 adipocyte cultures supernatant coating or 1#
Polypeptide segment antigen coat elisa plate, is detected under the conditions of gradient dilution, and the potency of the anti-Resistin antibody of purifying gained is real
It is as shown in Figure 5 b to test result, under the conditions of gradient dilution, antibody weakens the identification of two kinds of antigen in gradient, illustrates to purify institute
Obtain the specificity of antibody.
3 Resistin of embodiment is immunized neutralizing antibody and effectively treats tumor of breast hyperplasia caused by obesity
First, mouse obese model is built.The uniform female C57BL/6 mouse of size weight are selected, high fat diet is utilized
(60% lipid) feeds 12 weeks to mouse obesity after birth the 4th week.
Shown in planning by Fig. 6, at the 13rd week toward right side of mice the second mammary fat pad injection C57BL/6 mouse source
E0771 breast cancer cells 5*105A (cell is resuspended in 100 μ l PBS buffer solution), it is then past at the 1st, 4,8,12 day respectively
Be injected into the second mammary fat pad tumor tissues peripheral adipose tissue on the right side of normally/obesity mice 0.7mg/kg weight/time
The anti-Resistin antibody of purifying gained, control group are then dissolved in the rabbit igg of isometric equivalent in embodiment 2 slow through being saturated phosphate
In eluent after fliud flushing neutralization.
The 6th day after having injected breast cancer cell E0771, occur touching visible tumor of breast in mammary fat pad,
Using the major diameter (cm) and minor axis (cm) of tumour produced by every mouse of vernier caliper measurement, and tumour body is calculated using formula
Product.Gross tumor volume (cm3)=0.5* major diameter (cm) * minor axis (cm)2.From the 6th day, measured daily in the same time within continuous 8 days
The major diameter and minor axis of tumour, and the volume size of tumour is calculated, and do figure and compare.As shown in figure 8, fat (high fat diet) group is small
Mammary tumors volume is significantly greater than normal (normal diet) group mouse and injects anti-Resistin in addition, in fat group mouse
After immune neutralizing antibody, mouse mammary tumor volume is substantially reduced.
Further, mouse is slaughtered at the 13rd day, takes out mouse tumor tissue, visceral adipose tissue and left side mammary gland
Fat pad (tumour offside adipose tissue) is weighed, and is taken pictures, such as Fig. 9.Experimental result shows, fat group mouse mammary tumor weight
It is apparently higher than regular recombined small-mouse；After injecting the immune neutralizing antibody treatments of anti-Resistin, mouse mammary tumor volume is notable
It is reduced to normal group horizontal (Fig. 9), and the performance of the antitumor effect of the immune middle republicanism antibody of anti-Resistin is not relying on
In the reduction (Fig. 7) of adipose tissue mass, it is directly to tie to prompt anti-Resistin that the performance that neutralizing antibody acts in vivo is immunized
Resistin albumen is closed, and checks facilitation of the Resistin albumen for tumour growth.
Although the present invention has been described by way of example and in terms of the preferred embodiments, it is not limited to the present invention, any to be familiar with this skill
The people of art can do various change and modification, therefore the protection model of the present invention without departing from the spirit and scope of the present invention
Enclosing be subject to what claims were defined.
SEQUENCE LISTING
<110>Military medical research institute of PLA Academy of Military Sciences
<120>Neutralizing antibody and the application in treating breast cancer is immunized in a kind of anti-phylaxin
<160> 1
<170> PatentIn version 3.3
<210> 1
<211> 11
<212> PRT
<213>Mouse
<400> 1
Glu Ala Ile Asp Lys Lys Ile Lys Gln Asp Phe
1 5 10
Claims (10)
1. neutralizing antibody is immunized in a kind of anti-phylaxin, which is characterized in that antigen is Resistin albumen specific polypeptides sections, described
Resistin albumen specific polypeptides sections include amino acid sequence such as SEQ ID NO：Polypeptide shown in 1.
2. neutralizing antibody is immunized in a kind of anti-phylaxin according to claim 1, which is characterized in that the Resistin albumen
The amino acid sequence of specific polypeptides section such as SEQ ID NO：Shown in 1.
3. neutralizing antibody is immunized in a kind of anti-phylaxin according to claim 1 or 2, which is characterized in that be that rabbit source is polyclonal
Antibody, the rabbit include new zealand rabbit.
4. preparing the method that neutralizing antibody is immunized in any anti-phylaxin of claims 1 to 3, which is characterized in that including choosing
Antigen polypeptide, selection immunization ways, antibody purification serum.
5. according to the method described in claim 4, it is characterized in that, further including measuring antibody concentration and antibody effects.
6. according to the method described in claim 4, it is characterized in that, the immunization ways are in Resistin albumen specific polypeptides
The C-terminal coupling bovine serum albumin of section obtains antigen polypeptide liquid, after mixing with Freund's complete adjuvant, newly western toward 8 weeks macrandries
Blue rabbit left and right sides dorsal sc, subcutaneous abdomen, left and right hind leg muscle and left right rear leg popliteal nest lymph node totally 8 positions, in injection
State antigen-adjuvant mixed liquor；Then at the 2nd, 4,5,6,7 week, 8 weeks quick adjuvants of rabbit are mixed with antigen polypeptide liquid in advance
It is even, in above-mentioned 8 positions, inject above-mentioned antigen-quickly adjuvant mixed liquor.
7. method according to claim 4 or 5, which is characterized in that the antibody purification serum utilizes antigen-antibody
Specific affinity purification obtains antibody.
8. neutralizing antibody is immunized in preparing the drug for treating tumor of breast in any anti-phylaxin of claims 1 to 3
Application.
9. application according to claim 8, which is characterized in that the tumor of breast is fat induction.
10. neutralizing antibody is immunized in developing the drug for treating tumor of breast in any anti-phylaxin of claims 1 to 3
Application.
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| WO2023080695A1 (en) * | 2021-11-05 | 2023-05-11 | 서울대학교병원 | Resistin-specific antibody and use thereof |
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| MOTOHIRO MAEBUCHI等: "Low resistin levels in adipose tissues and serum in high-fat fed mice and genetically obese mice:development of an ELISA system for quantification of resistin", 《ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS》 * |
| 和倩倩 等: "抵抗素在胰岛素抵抗及肿瘤发生中的作用", 《肿瘤学杂志》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2023080695A1 (en) * | 2021-11-05 | 2023-05-11 | 서울대학교병원 | Resistin-specific antibody and use thereof |
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| Publication number | Publication date |
|---|---|
| CN108484768B (en) | 2021-03-30 |
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