CN109633165A - Application of the anti-HSPA4 autoantibody as breast cancer diagnosis or prognosis evaluation marker - Google Patents
Application of the anti-HSPA4 autoantibody as breast cancer diagnosis or prognosis evaluation marker Download PDFInfo
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- hspa4
- autoantibody
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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
- G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
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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
- G01N33/574—Immunoassay; Biospecific binding assay; Materials therefor for cancer
- G01N33/57484—Immunoassay; Biospecific binding assay; Materials therefor for cancer involving compounds serving as markers for tumor, cancer, neoplasia, e.g. cellular determinants, receptors, heat shock/stress proteins, A-protein, oligosaccharides, metabolites
Abstract
Application the present disclosure provides anti-HSPA4 autoantibody as breast cancer diagnosis or prognosis evaluation marker.Specifically, the present invention discloses the substance for being related to detecting heat resistanceheat resistant shock protein (HSPA4) autoantibody in preparation for the application in the product of breast cancer diagnosis or prognosis evaluation, application and relevant product and its application of the heat resistanceheat resistant shock protein HSPA4 autoantibody as breast cancer diagnosis or prognosis evaluation marker.Technology according to the present invention has good potential applicability in clinical practice in breast cancer area of medical diagnostics.
Description
Technical field
The present invention relates to biotechnologys and area of medical diagnostics, and in particular to serum heat resistanceheat resistant shock protein HSPA4 itself is anti-
Body is preparing the application in breast cancer diagnosis or Prognostic kit as diagnosis marker.
Background technique
As population increases, aging and socio-economic development, malignant tumour are increasingly becoming global Major health and ask
Topic all causes extreme influence to economical and social development, people's health.Therefore, the prevention with control of tumour have become the whole world and defend
The emphasis of biological and ecological methods to prevent plant disease, pests, and erosion control.The newest number issued according to oncology authoritative journal " Journal of Clinical Oncology " (CA Cancer J Clin)
According to the whole world in 2018 is estimated to increase by 18,100,000 cancer new cases, and 9,600,000 people are because of cancer mortality, and China's cancer illness rate is in state
It is located at medium level (Siegel RL etc., Cancer statistics, 2018.CA Cancer J on the upper side in border
Clin.2018；68(1):7-30.).
It is the highest malignant tumour of disease incidence in women by taking breast cancer as an example.In recent years, the hair of global women with breast cancer
Sick rate and the death rate are in the situation risen year by year, and account for female malignant morbidity, dead ratio also increased
(Picon-Ruiz M etc., Obesity and adverse breast cancer risk and outcome:
Mechanistic insights and strategies for intervention.Ca Cancer J Clin,2017,67
(5)).According to " Journal of Clinical Oncology " statistical result, breast cancer is the most common cancer types of women (24.2%), or female
The number one killer (15%) of property cancer patient.2014, national women with breast cancer new cases about 27.89 ten thousand accounted for women evil
Property tumor invasion 16.51%, occupy female malignant morbidity first place.Moreover, the Disease Spectrum of China's breast cancer is still
Be in a increasing trend year by year (Lee's he etc., Female Breast Cancer in China morbidity in 2014 and Study on mortality Chinese Journal of Oncology,
2018,40(3))。
Therefore, have for the early diagnosis of tumour and Index for diagnosis for the selection of Cancer Treatment Regimens and treatment curative effect
Important meaning.
Currently, diagnosing tumor mainly relies on iconography means (CT, MRI etc.) and serum mark analyte detection.However, for
For the cancer of many types, the diagnosis index and screening technology that have still lacked at present.Although the universal of Medical Imaging Technology mentions
The high ability of early detection tumour, however when Partial tumors patient makes a definite diagnosis has been terminal illness.Therefore, development is based on blood
The strategy of detection and Index for diagnosis has necessity.
Autoantibody refers to the antibody for autologous tissue, organ, cell and cell component, can be in normal human blood
There is the autoantibody of low titre, once autoantibody combination target antigen, causes the dysfunction of histoorgan, that is, induces and itself exempt from
Epidemic disease disease etc., such antibody be also referred to as pathologic antibody (.Cell such as Pagan J D, 2017；172(3):564-577).
Tumour is also because of the presence of specific antigen and associated antigen, and induction of antibodies generates, this is the antitumor important mechanisms of body,
It is also the current most important means of clinical tumor peripheral blood cell counts.
On the one hand, detect specific antigen autoantibody can indirect reaction tumor associated antigen presence.Studies have shown that swollen
Tumor antigen generate autoantibody be the better index of early diagnosis of tumor, and also can be used for the recurrence of tumour, curative effect monitoring and
Medication is with diagnosis etc..The detection for having more tumour autoantibody at present is used for the diagnosis of tumour, as pulmonary cancer diagnosis
The autoantibodies such as NY-SEO-1, p53, LAMR1；The autoantibodies such as p62, HCC1 for the diagnosing cancer of liver (.Mol such as Caron M
Cell Proteomics,2007,6(7):1115).However, the specificity for the autoantibody detection being currently known and sensitivity are not
It is high.Therefore, new tumour autoantibody is found, its variation tendency in tumor development, the diagnosis for tumour are detected
And Index for diagnosis has important value.
On the other hand, autoantibody existing for tumor patient also participates in during the occurrence and development of tumour.Clinical research
Show that there are the autoantibodies of high concentration in the Serum of Cancer Patients such as human milk gland, urogenital tract and incidence cancer, and with it is swollen
Tumor classification, transfer and low survival rate are close.Further study showed that antibody can activate the FcR γ receptor on myeloid cell to promote
Into the generation (Cancer such as Andreu P Cell2010,17 (2): 121-134.) of squamous cell carcinoma.Current research is further taken off
Shown the negative regulation function of thick liquid cell and antibody in tumour immunity: the Th2 type inflammatory reaction that human IgG 4 induces can antagonism it is anti-
The antineoplastic immune (the .J Clin Invest.2013,123 such as Karagiannis P (4): 1457-74.) that body mediates；Expression
Chemotherapy of tumors reaction that the inhibitive ability of immunity thick liquid cell of IgA inhibits T cell to rely on (.Nature such as Shalapour S 2015,
521(7550):94-98.).Therefore, it for the searching of tumor patient autoantibody and its target antigen, is not only advantageous to find disease
The important target of disease diagnosis, additionally aids the occurrence and development mechanism for illustrating disease, is prejudged in time to the prognosis of tumor patient,
Select suitable cancer immunotherapies.
Having the advantage that 1. extremely low tumour antigen i.e. as diagnosing tumor marker using autoantibody can induce certainly
Body antibody generates, therefore autoantibody can be also detected when tumour antigen expression is very low, has sensitive well
Degree；2. autoantibody can detect before clinical symptoms occurs in tumor patient, therefore can be used as early diagnosis tumor-marker
Object；3. autoantibody reaction and the canceration process of tumour cell are closely related, it also can be used for tumour progression and malignant turn
The assessment of change；4. the stability of autoantibody is good, the time being present in serum is longer, convenient for long-term storage and extensive sieve
It looks into.Therefore, patient tumors are reacted using the autoantibody that tumor inducing generates and machine progression of disease process occurs, just become and find
Important directions for early diagnosis of tumor and Index for diagnosis new target drone.
However, the searching for the target antigen that induction autoantibody generates is the difficult point of its research and application, because it is directly determined
The detection of autoantibody.The generation of autoantibody is easy to be influenced by body internal and external environment, especially inflammatory factor, from
And influence the specificity and sensitivity of detection.Moreover, there is also high-caliber antibody in itself in human peripheral.Therefore, it seeks
The autoantibody that the target antigen and its induction for finding tomour specific generate is applied to the detection of tumour to Guan Chong for autoantibody
It wants and the key points and difficulties of the area research.
Heat shock protein (heat shock protein, HSP) is the histone matter that cell is expressed under stress situation,
Can repair or degrade impaired protein, have chaperone activity, assist the correct folding of protein, protect cell adapted
The stimulation of external environment participates in during growth, metabolism and signal transduction of cell etc..According to its average molecular size, HSP
Six families, i.e. HSP27 family, HSP40 family, HSP60 family, HSP70 family, HSP90 family and other HSP families can be divided into
Race (HSP110 and GRP170) (Chatterjee S etc., Targeting Heat Shock Proteins in Cancer:A
Promising Therapeutic Approach.Int J Mol Sci.2017；18(9)).
Research finds that HSP is high in kinds of tumors tissue and expresses and played critical function, and HSP can be by promoting tumour
Cell Proliferation, invasion and inhibits apoptosis of tumor cells and promote the occurrence and development of tumour.For example, HSP70 participates in kinds of tumors
Occurrence and development, closely related (the Court K A of poor prognosis with the tumours such as cholangiocarcinoma, chondrosarcoma, melanoma, colon, bladder
Equal .HSP70inhibition synergistically enhances the effects of magnetic fluid
hyperthermia in ovarian cancer.Mol Cancer Ther.,2017,16(5).).HSP90 is in kinds of tumors
High expression in type, height expression is related with the prognosis mala of lung cancer, the cancer of the esophagus, bladder cancer, melanoma and leukaemia, at present
A variety of HSP90 inhibitor are applied to (Isaacs J S.Hsp90as a " Chaperone " of the in clinical tumor research
Epigenome:Insights and Opportunities for Cancer Therapy.Adv Cancer Res.,2016,
129:107-140.)。
However, HSP is as tumour antigen induction autoantibody generation participation tumor development process, there is not been reported.Mesh
Before, it there is no the research report in relation to anti-HSPA4 autoantibody for diagnosing tumor and Prognostic both at home and abroad.
And there is an urgent need in the art to search out to can be effectively used for that diagnosing tumor, cancer immunotherapies selection, tumor prognosis comments
The index estimated, and these are used for on the way.
Summary of the invention
The first purpose of the application is to search out itself that can be effectively used for breast cancer diagnosis and Prognostic
Antibody and its application.
In the first aspect of this paper, provides the substance for detecting anti-HSPA4 autoantibody and be used in preparation
Application in the product of object breast cancer diagnosis or prognosis evaluation.
In some embodiments of the application, it is described detection for suffer from or it is doubtful suffer from breast cancer or have suffer from mammary gland
Cancer risk once suffers from breast cancer but the mammal cured or the sample obtained from the mammal carry out.
In some embodiments, the mammal is selected from: primate, rodent, herding class lactation are dynamic
Object, mammalian pet etc., such as people, ape, orangutan, monkey, ox, sheep, horse, camel, pig, dog, cat, rabbit, mouse etc..
In some embodiments, the mammal used manner known in the art be accredited as suffer from breast cancer or
Breast cancer is cured.
In some embodiments of the application, the sample is selected from obtained from the mammal: blood sample, such as
Blood plasma, serum, whole blood；Tissue or cell sample, such as breast tissue or cell sample, cancerous tissue or cell sample, cancer beside organism
Or cell sample.
In some embodiments, the sample be fresh sample, freeze sample, (such as formalin is solid for fixed sample
Random sample product), embedded samples (such as paraffin-embedded sample).
In some embodiments of the application, the breast cancer is selected from following parting: invasive ductal carcinoma, non-wettability
Duct carcinoma；Alternatively, lumen A type, lumen Type B, lumen-HER2 type, HER2 overexpression type, basal cell template, the non-substrate of TNP-
Type；Alternatively, hormone receptor positive type, HER2/neu receptor positive type, three negative types.
It is described for detect the substance of anti-HSPA4 autoantibody to be to be used in some embodiments of the application
The substance of anti-HSPA4 autoantibody is detected on gene level and/or protein level；For example, the substance is for being selected from
Substance in the one or more detection techniques or method of the following group: immunohistochemical method is (such as immunofluorescence analysis, reversed enzyme-linked
Immuno absorbence, Colloidal Gold), western blot method, Northern blotting, PCR, biochip method.
In some embodiments of the application, the substance is selected from: confrontation HSPA4 autoantibody has the object of specificity
Matter, such as its antiantibody (preferably monoclonal antibody)；HSPA4 antigen or its have and anti-HSPA4 autoantibody binding specificity
Segment or the like, such as epitope, include the segment of its epitope or its analog；Anti- HSPA4 autoantibody is special
Anisotropic probe, genetic chip, PCR primer, gRNA etc..
In some embodiments, the substance has detectable marker, for example, the detectable mark selected from the group below
Remember object: radioactive isotope, fluorogen, chemiluminescent moiety, enzyme, zymolyte, enzyme cofactor, enzyme inhibitor, colloid color development mark
Note, dyestuff, metal ion or ligand (e.g., biotin or haptens).
In some embodiments, the substance is through immobilization, such as is fixed on solid-phase matrix.
In some embodiments, the solid-phase matrix is plane or curved surface solid-phase matrix.
In some embodiments, the solid-phase matrix includes the matrix that microwell plate, microsphere and perforated membrane are constituted.
In some embodiments of the application, compared with normal control values, the object or the sample obtained from the object
Anti- HSPA4 autoantibody improves in product, shows that the object is easy to or has occurred cancer metastasis, or show the object
Cancer prognosis is bad, or shows that the object has suffered from cancer.
In some embodiments, the level of anti-HSPA4 autoantibody be used for assess patient the disease-free survival time and/or
Overall survival.
In some embodiments, when the level of anti-HSPA4 autoantibody then indicates the disease-free survival of object higher than control
Between and/or Overall survival shorten.For example, the level of anti-HSPA4 autoantibody be higher than control when, indicate object without diease occurrence
Depositing the time can be for less than 40 month, such as less than 24 months, is less than 12 months, is less than 9.8 months, Overall survival can be few
It in 40 months, such as less than 24 months, is less than 12 months, is less than 9.8 months.
In some embodiments, when the level of anti-HSPA4 autoantibody then indicates the disease-free survival of object lower than control
Between and/or Overall survival it is long.For example, indicating the disease-free survival of object when the level of anti-HSPA4 autoantibody is lower than control
Time can be at least 40 months, for example, at least 50 months, at least 60 months, and Overall survival can be at least 40 months, such as
At least 50 months, at least 60 months.
In some embodiments, the normal control values, which are obtained from, does not suffer from the sample of breast cancer object, obtained from described right
As the sample of normal tissue, the anti-HSPA4 autoantibody of normal subjects.
In some embodiments, the normal control values are as follows: by the normal biological specimen of non-breast cancer (as being obtained from health
The sample of people or object normal tissue to be measured) in measure anti-HSPA4 autoantibody, by statistics determine group mark
Quasi- horizontal or normalised level.
In some embodiments of the application, the product is detection kit.
In some embodiments, the detection kit also includes one or more substances selected from the group below: container delays
Electuary, auxiliary agent, solvent, negative control object, positive control, operation instructions.
In one embodiment, the detection kit is based on reversed enzyme-linked immunosorbent assay detection biology
The kit of anti-HSPA4 autoantibody in sample.
In further aspect of the application, additionally provide for predicting Metastasis in Breast Cancer, pre- to breast cancer in object
The method of assessment or Diagnosis of Breast cancer afterwards, which comprises test object is anti-obtained from anti-HSPA4 in the sample of object itself
The horizontal step of body.
In some embodiments, compared with normal control, anti-HSPA4 in the object or sample obtained from the object
Autoantibody improves, and shows that the object is easy to or has occurred Metastasis in Breast Cancer, or shows that the breast cancer of the object is suffered from
Person's prognosis mala, or show that the object has suffered from cancer.
In some embodiments, each feature involved in the application method it is applied as described above defined in or illustrate.
In the another aspect of the application, additionally provide it is a kind of for breast cancer diagnosis or prognosis evaluation product (such as
Kit), it includes: for detecting the substance of anti-HSPA4 autoantibody；And it is optional for breast cancer diagnosis or
Other substances of prognosis evaluation, such as the detection substance of existing markers for breast cancer, such as detected for serology CA15-3, CEA,
The detection substance of (such as Ki-67, ER, PR, CerbB2) detects in pathological immune histochemistry.In some embodiments, the application
Each feature involved in product as defined in above or can illustrate.
In the another aspect of the application, additionally provide screening treatment breast cancer, alleviate or prevent Metastasis in Breast Cancer and/or
The method for improving the drug candidate of Prognosis in Breast Cancer, the method includes detecting the drug candidate to object or obtained from object
The influence of anti-HSPA4 autoantibody in sample, wherein after using the drug candidate, anti-HSPA4 autoantibody
Reduction then shows that the drug candidate has treatment breast cancer, alleviates or prevent Metastasis in Breast Cancer and/or improves Prognosis in Breast Cancer
Effect.
In some embodiments of the application, the detection of confrontation HSPA4 autoantibody is using as described herein
Product carries out.
In some embodiments, it is described reduce relative to be obtained from do not suffer from breast cancer object sample, be obtained from it is described right
As the sample of normal tissue, the anti-HSPA4 autoantibody of normal subjects.In some embodiments, described to reduce relatively
For normal control values, the normal control values are as follows: by the normal biological specimen of non-breast cancer (as being obtained from Healthy People or to be measured
The sample of object normal tissue) in measure anti-HSPA4 autoantibody molecular level, by statistics determine population norms water
Flat or normalised level.
In some embodiments, each feature involved in the application drug candidate screening technique is middle applied as described above is limited
Fixed or elaboration.
Those skilled in the art can carry out any combination without departing from this hair to technical solution above-mentioned and technical characteristic
Bright inventive concept and protection scope.Other aspects of the invention are due to this disclosure, to those skilled in the art
For be obvious.
Detailed description of the invention
The present invention will be further explained below with reference to the attached drawings, and wherein these displays are only for illustrating reality of the invention
Scheme is applied, rather than in order to limit to the scope of the present invention.
Fig. 1: the screening of the specific binding partner of breast cancer tumor-bearing mice autoantibodies:
A: normal and mice with tumor Serum Antibody (IgG1, IgG2a, IgG2b and IgG3) amount, P value use SPSS
Unpaired Student ' s t-tests in 17.0 is calculated；
(albumen NCL and ITGB3 are pair for the combination of B: immunoblotting (Western blot) detection serum antibody and HSPA4
According to).
The expression of people's target protein (HSPA4) in Fig. 2: SDS-PAGE analysis eluent:
Marker: molecular weight marker；Swimming lane 1: buffer control；Swimming lane 2: eluent 1；Swimming lane 3: eluent 2.
Fig. 3: serum heat resistanceheat resistant shock protein HSPA4 autoantibody and patient's disease-free survival time and Overall survival
Correlation:
A: serum heat resistanceheat resistant shock protein HSPA4 autoantibody and the Kaplan-Meier of patient's disease-free survival time are raw
Deposit curve；
B: the Kaplan-Meier of serum heat resistanceheat resistant shock protein HSPA4 autoantibody and patient's Overall survival is raw
Deposit curve.
Fig. 4: the correlation of serum heat resistanceheat resistant shock protein HSPA4 autoantibody and patient's lymphatic metastasis:
Normal serum (is donated blood, n=60) from normal person；Lymph Node-negative (LN-, n=52)；Lymph node positive (LN+, n
=56).P value is calculated using unpaired two-tailed Student ' the s t-tests in SPSS 17.0.
Specific embodiment
Present document relates to heat resistanceheat resistant shock protein HSPA4 autoantibodies as the molecules mark such as Prognosis in Breast Cancer, diagnosis, drug screening
Remember application and the Related product and application thereof of object.
Specifically, the present inventor applies proteomic techniques, identifies and resist present in patient with breast cancer's sample
HSPA4 autoantibody.It by purifying HSPA4 albumen, is analyzed, is detected anti-in serum using reversed enzyme linked immunosorbent assay (ELISA)
The expression of HSPA4 autoantibody, anti-HSPA4 autoantibody is significantly higher than just in blood serum of patients with human breast carcinoma as the result is shown
Ordinary person, and related to patient with breast cancer's lymphatic metastasis, height expression and total life span of patient be short, the significant phase of poor prognosis
It closes, can be used as independent Index for diagnosis factor.It is provided herein based on this with heat resistanceheat resistant shock protein HSPA4 autoantibody
For breast cancer diagnosis, prognosis evaluation, drug screening molecular marked compound, and provide corresponding product, there is certain clinic
With pharmacy application prospect.
All numberical ranges provided herein be intended to clearly include fall in all numerical value between endpoints of ranges and it
Between numberical range.The feature that the feature or embodiment that can be mentioned to the present invention are mentioned is combined.This specification is taken off
All features shown can be used in combination with any composition form, and each feature disclosed in specification any can provide phase
The alternative characteristics of same, impartial or similar purpose replace.Therefore except there is special instruction, revealed feature is only impartial or similar
The general example of feature.
As used herein, " containing ", " having " or " comprising " include "comprising", " mainly by ... constitute ", " substantially
By ... constitute " and " by ... constitute "；" mainly by ... constitute ", " substantially by ... constitute " and " by ... constitute "
Belong to the subordinate concept of " containing ", " having " or " comprising ".
Anti- HSPA4 autoantibody and its detection substance
As used herein, term " anti-HSPA4 autoantibody " with " protein of anti-HSPA4 autoantibody gene coding or
Polypeptide " is used interchangeably, and each means the protein encoded by anti-HSPA4 autoantibody gene or polypeptide, their conservative change
Different polypeptide or its homologous protein or polypeptide or its active fragment.
As used herein, it is related to the term " detection substance " of anti-HSPA4 autoantibody, " detection reagent " or " detection is anti-
The reagent of HSPA4 autoantibody molecule " or " reagent for detecting anti-HSPA4 autoantibodies amount " are used interchangeably, and are each meant
Specificity is directed to anti-HSPA4 autoantibody molecule, and can be used for directly or indirectly detecting depositing for anti-HSPA4 autoantibody molecule
And/or content substance.These detection substances can detect anti-HSPA4 autoantibody on gene level or protein level.
The detection substance of anti-HSPA4 autoantibody may include but be not limited to: confrontation HSPA4 autoantibody has specificity
Substance, such as its antiantibody (preferably monoclonal antibody)；HSPA4 antigen or its have with anti-HSPA4 autoantibody ining conjunction with specifically
The segment or the like of property, such as epitope, include the segment of its epitope or its analog；Anti- HSPA4 autoantibody
Probe, genetic chip, PCR primer, the gRNA etc. of specificity.
As used herein, term " autoantibody specificity binding partners ", which refers to, can specifically bind anti-HSPA4 antibody
Spouse's thing, such as HSPA4 (including its full length sequence) or its have with the segment of anti-HSPA4 autoantibody binding specificity or
Analog, such as epitope, include the segment of its epitope or its analog.
Specific binding partner for HSPA4 autoantibody used herein can use those skilled in the art
The gene engineering method synthesis known.It, can be according to needing to select protokaryon for example, the method using genetic engineering is synthesized
Expression system or eukaryotic expression system, prokaryotic expression system is mainly using escherichia expression system as representative, eukaryotic expression system
System is then using yeast, insect cell, mammalian expression systems as representative.
As used herein, term " HSPA4 antigen ", " HSPA4 albumen or polypeptide " and " protein of HSPA4 gene coding
Or polypeptide " be used interchangeably, each mean the protein encoded by HSPA4 gene or polypeptide, they conservative variation's polypeptides or
Its homologous protein or polypeptide or its active fragment.HSPA4 albumen is known in the art heat-shock protein family member, example
As the sequence of people HSPA4 can be as shown in Gene ID:3308；Mouse HSPA4 sequence can be as shown in Gene ID:15525.Due to anti-
The sequence of former HSPA4 is well known in the art, and those of ordinary skill in the art can prepare based on conventional means or pass through city
It sells and obtains the autoantibody that specificity is directed to HSPA4.
Also, for the ease of detection, detection reagent of the invention can also have detectable label, the detectable label packet
Include but be not limited to: radioactive isotope, fluorogen, chemiluminescent moiety, enzyme, zymolyte, enzyme cofactor, enzyme inhibitor, dyestuff,
Colloid chromogenic label, metal ion, ligand (e.g., biotin or haptens) etc..It can for example, can get by medical supply detection
The chemical group that substance quantifies optical signal, electric signal or emission signal accordingly is detected, because the quantifiable signal of acquisition is anti-with itself
The presence of body/content existence function relationship, to symbolize presence/content of autoantibody in sample.Enzyme label can be used peppery
Root peroxidase, alkaline phosphatase etc. and its substrate solution, detecting instrument is using visible light microplate reader etc..Fluorescent marker can
Each fluorochrome or time-resolved fluorescence dyestuff known using those skilled in the art, such as FITC, PE, Cy3, Cy5, rare earth gold
Belong to etc..Colloid gold label can be used in colloid chromogenic label, as a result can visually observe.
Detection reagent as described herein may be present in solution, be fixed on carrier (such as substrate, adsorbate) or with other
Mode conventional in the art exists, as long as the existing way is suitable for detecting HSPA4 autoantibody anti-in biological sample.
For example, can be deposited when detection reagent as described herein is nucleotide probe in the form of biochip (or " microarray ")
?.
In an embodiment of this paper, a kind of reagent for detecting anti-HSPA4 autoantibody in serum/plasma is provided
Box, main composition are solid-phase matrix, the specific binding partner of above-mentioned autoantibody, second of specific binding partner
With detectable group；Wherein, solid-phase matrix is in conjunction with specific binding partner, second of specific binding partner with can examine
Group is surveyed to combine.
In some embodiments, detection reagent as described herein can be through immobilization, such as is fixed on solid-phase matrix.It is suitable
For this paper solid-phase matrix can be plane or curved surface solid-phase matrix, including but not limited to: microwell plate, microsphere and perforated membrane structure
At matrix.Solid-phase matrix of the present invention is plane or curved surface solid-phase matrix.Common solid-phase matrix is the poly- of microwell plate
Styrene bottom surface, nitrocellulose, nylon membrane, the surface of pvdf membrane, the surface of glass matrix and various organic polymers or nothing
The surface etc. of machine microballoon, can be used as the solid-phase matrix of kit.The combination of specific binding partner and solid-phase matrix can pass through
A variety of combining forms such as physical absorption, Electrostatic Absorption or covalent bond, such combination/conjugation methods are those skilled in the art institutes
The application method known.
Breast cancer diagnosis and/or prognosis evaluation product
A kind of for breast cancer diagnosis and/or the product (such as kit) of prognosis evaluation, packet is provided herein
Contain: for detecting the substance (for example, as described in not yet) of anti-HSPA4 autoantibody；And it is optional for breast cancer
Other substances of diagnosis or prognosis evaluation, such as the detection substance of existing markers for breast cancer, such as serology CA15-3,
The detection substance of CEA detection, pathological immune histochemistry detection (such as Ki-67, ER, PR, CerbB2).
According to the needs of detection method used, anti-HSPA4 autoantibody detection substance appropriate may be selected, and be made into
Kit suitable for detection method used.Those of ordinary skill in the art can be according to physical condition and needing to detection mode and examination
Contained reagent is adjusted and changes in agent box.
A kind of detection kit has been also provided herein as a result, it includes: (i) detection is a effective amount of anti-for detecting
One or more reagents of HSPA4 autoantibody；(ii) optionally, one or more substances selected from the group below: container, use
Specification, positive control, negative control object, buffer, auxiliary agent or solvent, such as the solution for being suspended or fixing cell,
Detectable label or tag, the solution for making nucleic acid be easy to hybridize, for the solution of lytic cell, or for the molten of nucleic acid purification
Liquid.
In one example, it is suitable for detecting biological sample by reversed enzyme-linked immunosorbent assay there is provided herein one kind
In anti-HSPA4 autoantibody expression detection kit.The detection kit may include: coating buffer；Autoantibody is special
Specific binding partner, such as or its there is segment or the like with anti-HSPA4 autoantibody binding specificity, such as antigen
Epitope includes the segment of its epitope or its analog；Confining liquid；Secondary antibody, such as anti-human igg-HRP mark secondary antibody；Substrate
Buffer, such as DAB substrate buffer solution；Developing solution；And the optional container and operation instructions that mentioned reagent is housed.
Can also have the operation instructions of kit in the detection kit of this paper, how be described using kit
It is detected, and how Metastasis in Breast Cancer and prognosis situation to be judged using testing result, therapeutic scheme is selected
It selects.
Certainly, kit also may include clinically for the judgement of breast cancer development in object, the selection of therapeutic scheme and/
Or other reagents of prognosis evaluation, to assist or be verified the anti-obtained result of HSPA4 autoantibody of detection.This field is general
Logical technical staff carries out conventional selection according to specific needs.
Application and phase of the anti-HSPA4 autoantibody in Metastasis in Breast Cancer prediction, prognosis evaluation, diagnosis and drug screening
Answer check and evaluation method
According to content disclosed herein, the level of anti-HSPA4 autoantibody and the transfer of breast cancer, prognosis and examine
Break closely related, so as to be predicted as Metastasis in Breast Cancer, the index of prognosis evaluation and diagnosis.
As used herein, term " prognosis " refers to the possibility course of disease and final result of predictive disease comprising judges the spy of disease
Determine consequence (such as rehabilitation, certain symptom, sign and complication etc. are other abnormal to be appeared or disappeared and dead).Described herein
Prognosis mala includes but is not limited to: short survival, easy breast cancer shift, the increase of breast cancer quantity is fast, breast cancer becomes larger and adds
Fastly, TNM classification rising etc..After predicting patient's prognosis situation, in combination with controlling for the amount for reducing anti-HSPA4 autoantibody molecule
The prognosis for the treatment of method improvement patient.
In some aspects of the disclosure, when the level of anti-HSPA4 autoantibody be used to assess the disease-free survival of patient
Between and/or Overall survival.
In some embodiments, when the level of anti-HSPA4 autoantibody then indicates the disease-free survival of object higher than control
Between and/or Overall survival shorten.For example, the level of anti-HSPA4 autoantibody be higher than control when, indicate object without diease occurrence
Depositing the time can be for less than 40 month, such as less than 24 months, is less than 12 months, is less than 9.8 months, Overall survival can be few
It in 40 months, such as less than 24 months, is less than 12 months, is less than 9.8 months.
In some embodiments, when the level of anti-HSPA4 autoantibody then indicates the disease-free survival of object lower than control
Between and/or Overall survival it is long.For example, indicating the disease-free survival of object when the level of anti-HSPA4 autoantibody is lower than control
Time can be at least 40 months, for example, at least 50 months, at least 60 months, and Overall survival can be at least 40 months, such as
At least 50 months, at least 60 months.
In some embodiments, when the level of anti-HSPA4 autoantibody then indicates the disease-free survival of object higher than control
Between and/or Overall survival shorten risk improve.For example, being lower than the object compareed with the level of anti-HSPA4 autoantibody
It compares, the level of anti-HSPA4 autoantibody is higher than the disease-free survival time of the object of control and/or Overall survival shortens.
For example, the level of anti-HSPA4 autoantibody is higher than compared with the level of anti-HSPA4 autoantibody is lower than the subject population of control
The ratio that the disease-free survival time of the subject population of control and/or Overall survival shorten improves.
In general, following method, which can be used, carries out Metastasis in Breast Cancer prediction, prognosis evaluation and/or diagnosis: detecting object to be measured
Or the level obtained from HSPA4 autoantibody molecule anti-in the sample of the object, and the level is compared with control level；If than
The level of the anti-HSPA4 autoantibody molecule in object is higher than control level more as the result is shown, then prompts the object Yi Fasheng
Metastasis in Breast Cancer, prognosis mala have been inflicted with breast cancer.In some embodiments, the present processes also optionally include:
Sample to be tested is obtained from object；Contact sample to be tested with the reagent or kit for detecting anti-HSPA4 autoantibody.
As used herein, term " normal control " refers to the level of the anti-HSPA4 autoantibody molecule as reference, packet
Include but be not limited to: by same target non-breast cancer normal biological specimen (such as obtained from the object non-breast cancer cancer beside organism or
The sample of normal tissue) in the anti-HSPA4 autoantibody molecular level measured, the population norms that are determined by statistics it is horizontal,
Or normalised level.
The detection kit of the application (for example) can be used for diagnosing tumor by following steps and patient's prognosis is commented
Estimate: (a) obtaining sample to be tested from object；(b) sample to be tested is contacted with the detection reagent in detection kit of the present invention；(c)
The level of anti-HSPA4 autoantibody in the sample to be tested is detected, and the level is compared with control level；(d) according to detection
As a result diagnosing tumor and Prognostic are carried out: showing the anti-HSPA4 autoantibody in object tissue such as testing result
Level is higher than normal control values, then the object is prompted to suffer from possible breast cancer or metastases or patient's prognosis mala.
In addition, a kind of screening treatment breast cancer is also provided herein, alleviates or prevents Metastasis in Breast Cancer and/or improve mammary gland
The method of the drug candidate of cancer prognosis, the method includes testing the drug candidate to object or obtained from hot in the sample of object
The influence of the anti-HSPA4 autoantibody of shock protein, wherein after using the drug candidate, the anti-HSPA4 of heat shock protein
Autoantibody reduction shows that the drug candidate has treatment breast cancer, alleviates or prevent Metastasis in Breast Cancer and/or improvement
The effect of Prognosis in Breast Cancer.Each feature involved in the application drug candidate screening technique can be as defined herein or illustrate.
The product of the application can be can be used for screening or assessing treatment breast cancer by (for example) following steps, alleviate or prevent
Only Metastasis in Breast Cancer and/or improve Prognosis in Breast Cancer drug candidate:
(a) drug candidate is applied to object；
(b) drug candidate is detected to object or obtained from the influence of HSPA4 autoantibody anti-in the sample of object；
(c) judge whether the drug candidate has treatment breast cancer, alleviates or prevent breast cancer from turning according to testing result
The effect of Prognosis in Breast Cancer is moved and/or improves,
Wherein, after using the drug candidate, the anti-HSPA4 autoantibody reduction of heat shock protein shows the time
Drug is selected to have the effect for the treatment of breast cancer, alleviate or prevent Metastasis in Breast Cancer and/or improving Prognosis in Breast Cancer.
In addition, the application is by detecting anti-HSPA4 autoantibody to object breast cancer diagnosis and/or prognosis evaluation
In have the characteristics that highly sensitive, high accuracy, even better than existing regular breast cancer diagnosis and prognosis evaluation means.And
And the product and method of the application can also be diagnosed with existing regular breast cancer and prognosis evaluation means are used in combination, thus more
It is sensitive, more accurately to breast cancer carry out diagnosis and/or prognosis evaluation.This be used in combination can produce certain superposition or even add
Close effect.Existing regular breast cancer diagnosis and prognosis evaluation means include but is not limited to: serology CA15-3 and CEA detection,
Imaging diagnosis (such as molybdenum target), ultrasonic diagnosis, cytodiagnosis, pathological immune histochemistry detect (such as Ki-67, ER, PR,
CerbB2 etc.).
Embodiment
Present invention will be further explained below with reference to specific examples.It should be understood that these embodiments are merely to illustrate the present invention
Rather than it limits the scope of the invention.Those skilled in the art can make modification appropriate, variation to the present invention, these modifications
It is within the scope of the present invention with variation.
In the following examples, the experimental methods for specific conditions are not specified, the conventional method in this field can be used, such as join
Examine " Molecular Cloning:A Laboratory guide " (third edition, New York, CSH Press, New York:Cold Spring
Harbor Laboratory Press, 1989) or according to condition proposed by supplier.The sequencing approach of DNA is that this field is normal
The method of rule can also provide test by commercial company.
Unless otherwise stated, otherwise percentage and number are calculated by weight.Unless otherwise defined, as used herein all
Professional and scientific terms have the same meanings as commonly understood by one of ordinary skill in the art.In addition, any similar or equal to described content
Deng method and material can be applied to the method for the present invention.Preferred implement methods and materials described in the text only present a demonstration it
With.
Embodiment 1: the specific binding using protein spectrum technology screening breast cancer tumor-bearing mice autoantibodies is matched
Even body
Mouse mammary carcinoma cell line 4T1 is purchased from U.S. ATCC (+10% fetal calf serum of DMEM culture medium).The purchase of Balb/c mouse
From Shanghai western Poole-Bi Kai experimental animal Co., Ltd, raised in SPF grades of environment.
The foundation of mouse breast cancer model: 5 × 10 are injected under mouse (female, 8 week old) right lower abdomen mammary fat pad5
A/breast cancer cell line 4T1 cell, enzyme-linked immunization (ELISA) method detect antibody level in mice serum, observation mouse leaching
Fawn on transfer and tumour growth situation.
The purification of mice serum antibody: antibody purification kit (Melon Gel IgG Spin Purification is used
Kit, Pierce company, the U.S.) antibody purification from mice serum.Concrete operations carry out to specifications.
Protein spectrum detects specific binding partner after co-immunoprecipitation: collecting tumour cell 4T1, cell cracking is added
Buffer (contains protease inhibitors), takes supernatant after cracking.The serum antibody of purifying is added into cell pyrolysis liquid, 4 DEG C slowly
Rock overnight incubation.Pretreated protein A sepharose 4B is added in the cell pyrolysis liquid overnight with antibody incubation,
4 DEG C are slowly rocked incubation 2-4h.
After immune precipitation, sepharose 4B is centrifuged to tube bottom；Supernatant is carefully sucked, cleans fine jade with lysis buffer
Lipolysaccharide pearl 3-4 times；It is eventually adding SDS sample-loading buffer.Sample is sent to BeiJing HuaDa protein Research Center Co., Ltd and is done
Protein spectrum detection, screens specific binding partner.
As the result is shown: breast cancer tumor-bearing mice Serum Antibody amount is significantly higher than normal mouse (Figure 1A).To serum antibody
In conjunction with specific binding partner carry out protein spectrum detection, we screen tumour antigen HSPA4.We further utilize
Immunoblotting (western blot) method validation combination of serum antibody and HSPA4 (Figure 1B).
Result above prompt prompts the antibody can be with there are the antibody of target tumor antigen HSPA4 in tumor-bearing mice serum
Potential target as lesion detection.We further verify this discovery in clinical sample.
Embodiment 2: the expression and preparation of human specific binding partners (HSPA4)
The special of the above-mentioned autoantibody filtered out is synthesized using gene engineering method known to a person skilled in the art
Property binding partners (HSPA4).Because tumour antigen has different modifying, therefore the expression system of HSPA4 selects common human breast carcinoma
Cell line MBA-MD-231 (is purchased from U.S. ATCC), to obtain the antigen protein with immunogenicity.
1. cloned plasmids construct: using the method for being based on PAS (PCR-based Accurate Synthesis), design is complete
Long splicing primer (sequence of people HSPA4 is as shown in Gene ID:3308), is connected into expression vector pcDNA3.1；The recombination matter of acquisition
Grain is transferred to clone strain, and resistant panel selects positive colony.The small pumping of plasmid is carried out to positive colony, through double digestion and sequence verification
It is errorless；Positive colony plasmid is extracted, concentration is stand-by.
2. bed board after human breast cancer cell line MBA-MD-231:MBA-MD-231 cell culture is transfected, density to 40%~
60% transfection.Using transfection liquid of jetPRIME (being purchased from Polyplus company, the France) preparation containing above-mentioned plasmid, it is slowly added into training
It in nutrient solution, shakes up, 37 DEG C of incubators are set 6 hours, are changed to normal culture solution and are continued to cultivate.After 48 hour cells cover with, cell is extracted
Albumen.
3. the albumen column affinity purification of target protein: supernatant solution loading to Ni-IDA Binding-Buffer pre-equilibrates
Ni-IDA-Sepharose CL-6B affinity column.It is rinsed with cleaning solution.Destination protein is eluted with Elution-Buffer,
Collect efflux.The protein solution of above-mentioned collection is added in bag filter, using 20mMTris-HCl, 0.15M NaCl, pH8.0 into
Row dialysed overnight.
4. carrying out 12%SDS-PAGE detection and analysis, coomassie brilliant blue staining shows band.
The results show that analyzing through 12%SDS-PAGE, (about 110kDa) has single clear band at target stripe, it was demonstrated that
Target protein (HSPA4) is primarily present in eluent (Fig. 2).
Embodiment 3: the combination coating of specific binding partner and solid-phase matrix
The coating of microwell plate: matched with coating buffer (0.05mol/L carbonic acid buffer, pH9.6) dilution specific binding
Even body, packing to 96 hole elisa Plates, 4 DEG C overnight.Coating buffer is removed, is cleaned 2 times with PBS.Confining liquid (5% skimmed milk power-is added
PBS), room temperature 2-4 hours.Get rid of deblocking liquid, PBS cleaning.
Embodiment 4: the autoantibodies of enzyme labelling method detection targeting antigen HSPA4
100 μ L of patients serum or dilute serum is taken, addition has been coated in 96 orifice plates of specific binding partner, room temperature
It is incubated for 2 hours.PBST is cleaned 3 times.The limited public affairs of Beijing Zhong Shan Golden Bridge biotechnology (are purchased from using anti-human igg-HRP label secondary antibody
Department, article No. ZDR-5301), after PBST 1:1000 dilution, 96 orifice plates are added after incubation at room temperature 1 hour by every 100 μ L of hole and use
PBST is cleaned 3 times.100 μ L of TMB developing solution is added, 2M H is added in reaction after twenty minutes2SO4Terminate reaction.It is read in microplate reader
OD450。
Embodiment 5: the correlation of serum heat resistanceheat resistant shock protein HSPA4 autoantibody and patient's prognosis
Analyze serum heat resistanceheat resistant shock protein HSPA4 autoantibody and patient's disease-free survival time and Overall survival
Correlation.
108 Female breast cancer patients of 2011-2012 (coming from Tianjin tumour hospital) is chosen, patient does not connect before surgery
By chemotherapy and radiotherapy.All patients sign informed consent form.
Using the microwell plate being coated in embodiment 3, using the method for embodiment 4,108 breast cancer serums are detected
Heat resistanceheat resistant shock protein HSPA4 autoantibody analyzes the phase with patient with breast cancer's disease-free survival time and Overall survival
Guan Xing.P value uses the Chi-square tests in SPSS 17.0.
As a result, it has been found that: patient's (being higher than mean OD value, n=49) of the anti-HSPA4 autoantibody of serum high level compared to
Low-level patient (is lower than mean OD value, n=59), and disease-free survival time and Overall survival are shorter (Fig. 3 A and Fig. 3 B).
Should the result shows that: the anti-HSPA4 autoantibody of serum can be used as the evaluation index of patient with breast cancer's prognosis, water
Flat high instruction prognosis is poor.
Embodiment 6: the correlation of serum heat resistanceheat resistant shock protein HSPA4 autoantibody and patient's lymphatic metastasis.
Lymph node is the important indicator of the most common metastasis site of patient with breast cancer and Index for diagnosis, we analyze blood
The correlation of clear heat resistanceheat resistant shock protein HSPA4 autoantibody and patient's lymphatic metastasis.
60 normal serums are detected (from just using the method for embodiment 4 using the microwell plate being coated in embodiment 3
Ordinary person donates blood) and 108 breast cancer (52 Lymph Node-negatives (i.e. LN-) and 56 lymph node positives (i.e. LN+))) serum is anti-
Heat shock protein HSPA4 autoantibody analyzes the correlation with patient with breast cancer's lymphatic metastasis.
As a result, it has been found that: compared with normal person, two groups of blood serum of patients with human breast carcinoma heat resistanceheat resistant shock protein HSPA4 autoantibodies
Increased；Also, there is patients serum's heat resistanceheat resistant shock protein HSPA4 autoantibody of lymphatic metastasis than lymph node yin
Property patient significantly increases (Fig. 4).
The above results show: patients serum's heat resistanceheat resistant shock protein HSPA4 autoantibody is significantly higher than normal human serum
Level, and it is closely related with lymphatic metastasis, and its height expression is significant related to the poor prognosis of patient, which has prompted to suffer from
Person's serum heat resistanceheat resistant shock protein HSPA4 autoantibody can be used as breast cancer diagnosis or auxiliary diagnosis, prediction metastases or
The marker of Prognostic.
All references mentioned in the present invention is incorporated herein by reference, independent just as each document
It is incorporated as with reference to such.In addition, it should also be understood that, after reading the above teachings of the present invention, those skilled in the art can
To make various changes or modifications to the present invention, such equivalent forms equally fall within model defined by the application the appended claims
It encloses.
Claims (10)
1. production of the substance in preparation for object breast cancer diagnosis or prognosis evaluation for detecting anti-HSPA4 autoantibody
Application in product (such as kit).
2. application as described in claim 1, wherein the detection for suffer from or it is doubtful suffer from breast cancer or have suffer from mammary gland
Cancer risk once suffers from breast cancer but the mammal cured or the sample obtained from the mammal carry out.
3. application as claimed in claim 2, wherein the sample is selected from obtained from the mammal: blood sample, such as
Blood plasma, serum, whole blood；Tissue or cell sample, such as breast tissue or cell sample, cancerous tissue or cell sample, cancer beside organism
Or cell sample.
4. application as described in claim 1, wherein the breast cancer is selected from following parting: invasive ductal carcinoma, non-wettability
Duct carcinoma；Alternatively, lumen A type, lumen Type B, lumen-HER2 type, HER2 overexpression type, basal cell template, the non-substrate of TNP-
Type；Alternatively, hormone receptor positive type, HER2/neu receptor positive type, three negative types.
5. application as described in claim 1, wherein described for detecting the substance of anti-HSPA4 autoantibody is to be used for
The substance of anti-HSPA4 autoantibody is detected on gene level and/or protein level；For example, the substance is for being selected from
Substance in the one or more detection techniques or method of the following group: immunohistochemical method is (such as immunofluorescence analysis, reversed enzyme-linked
Immuno absorbence, Colloidal Gold), western blot method, Northern blotting, PCR, biochip method.
6. application as described in claim 1, wherein the substance is selected from: confrontation HSPA4 autoantibody has the object of specificity
Matter, such as its antiantibody (preferably monoclonal antibody)；HSPA4 antigen or its have and anti-HSPA4 autoantibody binding specificity
Segment or the like, such as epitope, include the segment of its epitope or its analog；Anti- HSPA4 autoantibody is special
Anisotropic probe, genetic chip, PCR primer, gRNA etc..
7. application as described in claim 1, wherein compared with normal control values, the object or the sample obtained from the object
Anti- HSPA4 autoantibody improves in product, shows that the object is easy to or has occurred cancer metastasis, or show the object
Cancer prognosis is bad, or shows that the object has suffered from cancer.
8. a kind of for breast cancer diagnosis or the product (such as kit) of prognosis evaluation, it includes: for detect anti-HSPA4 from
The substance of body antibody level；And optional other substances for being used for breast cancer diagnosis or prognosis evaluation, such as existing mammary gland
The detection substance of carcinoma marker, such as serology CA15-3, CEA detection, pathological immune histochemistry detection (such as Ki-67,
ER, PR, CerbB2) detection substance.
9. a kind of screening treatment breast cancer is alleviated or is prevented Metastasis in Breast Cancer and/or improves the drug candidate of Prognosis in Breast Cancer
Method, the method includes detecting the drug candidate to object or obtained from HSPA4 autoantibody anti-in the sample of object
Influence, wherein using after the drug candidate, anti-HSPA4 autoantibody reduction then shows the drug candidate tool
There is treatment breast cancer, alleviate or prevent Metastasis in Breast Cancer and/or improves the effect of Prognosis in Breast Cancer.
10. method as claimed in claim 9, wherein the detection of confrontation HSPA4 autoantibody uses such as claim 1-
Product mentioned in 8 carries out.
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