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CN109096397B - A kind of anti-human CSF-1R monoclonal antibody and application - Google Patents

  • ️Tue Apr 16 2019

CN109096397B - A kind of anti-human CSF-1R monoclonal antibody and application - Google Patents

A kind of anti-human CSF-1R monoclonal antibody and application Download PDF

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Publication number
CN109096397B
CN109096397B CN201810788625.7A CN201810788625A CN109096397B CN 109096397 B CN109096397 B CN 109096397B CN 201810788625 A CN201810788625 A CN 201810788625A CN 109096397 B CN109096397 B CN 109096397B Authority
CN
China
Prior art keywords
antibody
seq
cdr
monoclonal antibody
ser
Prior art date
2018-07-18
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Active
Application number
CN201810788625.7A
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Chinese (zh)
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CN109096397A (en
Inventor
陈明久
谭巍
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Boo Letter Biotechnology (nanjing) Co Ltd
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Boo Letter Biotechnology (nanjing) Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
2018-07-18
Filing date
2018-07-18
Publication date
2019-04-16
2018-07-18 Application filed by Boo Letter Biotechnology (nanjing) Co Ltd filed Critical Boo Letter Biotechnology (nanjing) Co Ltd
2018-07-18 Priority to CN201810788625.7A priority Critical patent/CN109096397B/en
2018-12-28 Publication of CN109096397A publication Critical patent/CN109096397A/en
2019-04-16 Application granted granted Critical
2019-04-16 Publication of CN109096397B publication Critical patent/CN109096397B/en
Status Active legal-status Critical Current
2038-07-18 Anticipated expiration legal-status Critical

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    • 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
    • C07K16/2866—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against receptors for cytokines, lymphokines, interferons
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
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    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • C—CHEMISTRY; METALLURGY
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    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
    • C07K2317/565—Complementarity determining region [CDR]

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Abstract

The present invention relates to a kind of anti-human CSF-1R monoclonal antibody and applications, while providing coding nucleic acid molecule, expression vector, host cell and the method for expressing the antibody of the antibody.Additionally provide antibody mediated immunity coupling conjugate, bispecific molecule, embedding and antigen receptor, pharmaceutical composition and purposes including antibody of the present invention.Compared with the existing technology, the invention has the following advantages that the monoclonal antibody of energy specific recognition people CSF-1R of the invention, affinity of the antibody in conjunction with people CSF-1R are better than existing anti-human CSF-1R monoclonal antibody, sequence is novel.

Description

A kind of anti-human CSF-1R monoclonal antibody and application

Technical field

The present invention relates to a kind of high-affinity and with the monoclonal antibody or antibody piece of functional anti-human CSF1R Section.Invention also provides the coding nucleic acid molecule of the antibody, expression vector, host cells and for expressing the antibody Method.Additionally provide including antibody of the present invention antibody mediated immunity coupling conjugate, bispecific molecule, embedding and antigen receptor, Pharmaceutical composition and diagnostic and therapeutic method.

Background technique

Colony-stimulating factor 1 receptor (CSF-1R) belongs to the receptor tyrosine kinase family of type III, by proto-oncogene c- Fms coding, protein structure include kinase domain intracellular and the extracellular ligand knot by the similar structure composition of 5 immunoglobulins Close area.CS1R is expressed on mononuclear phagocytic cells surface, is played a crucial role to the survival of mononuclear phagocytic cells, proliferation, differentiation (Felix,et al.,(2015)Structure 23,1621-1631).And CSF1R is also high to express in kinds of tumor cells perhaps Surface.For example, CSF1R expression and tumor tissues size and low closely related (KLUGER, et al. (2004) Clinical of survival cancer research.vol.10,no.1,p.173-7；SCHOLL,et al.(1994)Journal of the National Cancer Institute.vol.86,no.2,p.120-6.).In oophoroma and carcinoma of endometrium, northern Hybridization analysis shows that most tumor tissues co-express CSF1 and CSF1R, and normal endometrial tissue CSF1R expression is very Weak (, et al. (1991) Cancer, vol.67, no.4, p.990-6).It is huge that CSF1R is also expressed in tumor infiltrating Phagocyte surface (CHAMBERS, et al. (1997) .Clinical Cancer Research.vol.3, no.6, p.999- 1007)。

After the extracellular region combination CSF-1 of CSF1R, cause CSF1R Receptor dimerization and its autophosphorylation intracellular, thus Originate intracellular signal transmitting.Abnormal receptor tyrosine kinase III signal transmitting causes a large amount of inflammation diseases and cancer to mention Show that RTK type III intracellular plays central role in congenital and the acquired immune response.For example, abnormal CSF1R signal transmitting Typically occur in a variety of human diseases pathological states of such as rheumatoid arthritis, atherosclerosis and tumour growth. (Chitu and Stanley,(2006),Curr.Opin.Immunol.18,39-48；Masteller and Wong, (2014),Drug Discov.Today,19,1212-1216；Pollard(2009),Nat.Rev.Immunol.9,259- 270；Stanley and Chitu,(2014),Perspect.Biol.6,a021857；Verstraete and Savvides, (2012),Nat.Rev.Cancer.12,753-766)。

CSF1R signal is also proved to play physiological action in bone remodeling.The animal of gene knockout CSF1 or CSF1R are usual Show as osteopetrotic phenotype.For a long time, CSF1R inhibitor is as a kind of cancer, diseases associated with inflammation or bone loss disorders Potential therapy is furtherd investigate.Pexidartinib, a kind of inhibitor of CSF1R are clinical in 3 phases for the treatment of giant cell tumor of tendon sheath Powerful curative effect is shown in test.Another CSF1R inhibitor, Cabiralizumab, a kind of target tumor correlation macrophage The monoclonal antibody of cell, the positive early studies in man for carrying out metastatic cancer of pancreas.Another kind is in the drug of clinic II phase JNJ-40346527, a kind of oral CSF1R inhibitor, the mechanism of action are the survival of inhibition macrophage, proliferation and differentiation, but right In the intractable active rheumatoid arthritis of disease repairing type antirheumatic drug (DMARD-refractory active Rheumatoid arthritis) treatment is to no effect.

Although CSF1R antibody has exploitation, disease as above for treatment has more high-affinity and other drugs pass The CSF1R inhibitor of keyness matter, especially monoclonal antibody need to be furtherd investigate exploitation.

Summary of the invention

In order to overcome drawbacks described above, the object of the present invention is to provide a kind of anti-human CSF-1R monoclonal antibody and applications, should Antibody has high-affinity and functionality, is better than existing anti-human CSF-1R monoclonal antibody.

In order to achieve the above object, the present invention provides a kind of anti-human CSF-1R monoclonal antibody, which is characterized in that the antibody Include: heavy chain and light chain；

The heavy chain and light chain includes variable region, which includes complementary determining region；

Complementary determining region CDR1, CDR2 and CDR3 of the heavy chain are indicated with CDR-H1, CDR-H2 and CDR-H3 respectively；

Complementary determining region CDR1, CDR2 and CDR3 of the light chain are indicated with CDR-L1, CDR-L2 and CDR-L3 respectively；

The amino acid sequence of the CDR-H1 is shown in SEQ ID NO:3；

The amino acid sequence of the CDR-H2 is shown in SEQ ID NO:4；

The amino acid sequence of the CDR-H3 is shown in SEQ ID NO:5；

The amino acid sequence of the CDR-L1 is shown in SEQ ID NO:6；

The amino acid sequence of the CDR-L2 is shown in SEQ ID NO:7；

The amino acid sequence of the CDR-L3 is shown in SEQ ID NO:8.

Heavy chain variable amino acid sequence is shown in SEQ ID NO:1；Chain variable region amino acid sequence is SEQ ID Shown in NO:2.

A kind of nucleic acid molecule, the nucleic acid molecule coding anti-human CSF-1R monoclonal antibody；

The sequence of the nucleic acid molecule is selected from SEQ ID NO:9 and/or SEQ ID NO:10；

The heavy chain variable region of the sequence SEQ ID NO:9 coding antibody；

The light chain variable region of the sequence SEQ ID NO:10 coding antibody.

A kind of expression vector, the expression vector contain the nucleic acid molecule.

A kind of host cell, the host cell contain the expression vector.

A kind of preparation method of anti-human CSF-1R monoclonal antibody, the preparation method comprise the following steps:

Step 1: the expression vector of nucleic acid molecule of the preparation containing the expression anti-human CSF-1R monoclonal antibody；

Step 2: transfecting eukaryotic host cell with the expression vector of step 1；

Step 3: the eukaryotic host cell that incubation step 2 transfects；

Step 4: isolating and purifying, obtain the antibody.

The invention further relates to the antibody mediated immunity coupling conjugates, double special for including anti-human CSF-1R monoclonal antibody above-mentioned Property molecule, embedding and antigen receptor or pharmaceutical composition.

The invention further relates to anti-human CSF-1R monoclonal antibodies to prepare anti-tumor drug, rheumatoid arthritis drug, move Application in pulse atherosclerosis drug or bone remodeling drug.

The heavy chain and light chain all further includes constant region, which is the constant region of human IgG, it is therefore preferable to IgG1's Constant region.

Compared with the existing technology, the invention has the following advantages that the monoclonal of energy specific recognition people CSF-1R of the invention Antibody, affinity of the antibody in conjunction with people CSF-1R are better than existing anti-human CSF-1R monoclonal antibody, and sequence is novel.

Specific embodiment

The following further describes the technical solution of the present invention with reference to embodiments.

One, the acquisition of antibody:

Embodiment 1 obtains the mouse monoclonal antibody of the anti-CSF1R of specificity by fusion hybridoma technology

1.1 animal immune

According to (E Harlow, D.Lane, Antibody:A Laboratory Manual, Cold Spring in document Harbor Laboratory Press, Cold Spring Harbor, N.Y., 1998) mouse is immunized in general method.It is immune It originally was recombined human CSF1R (amino acid section I l e20-Glu 512) albumen (Acro that C-terminal contains human IgG1's Fc label biosystems,Cat#CSR-H5258).Using recombined human CSF1R with hi s label albumen (Acro biosystems, Cat#CSR-H5228) the detection antigen as measurement serum titer and hybridoma screening.Briefly, suitable Fu Shi assistant is taken out Into 1.5ml EP pipe, oscillator is mixed for agent.Antigen protein solution is prepared with PBS.Amount mixes adjuvant as required and albumen is anti- Original solution mutually pushes away the solution that fully emulsified antigen forms stable Water-In-Oil by syringe, then carries out animal injection.According to blood Clear titration after first immunisation as a result, usually require to can be only achieved good immune effect after carrying out 2 to 3 booster immunizations. The high immune mouse row intraperitoneal injection of selection serum titer carries out cell fusion after exempting from eventually.

1.2 hybridoma fusions and screening

Before cell fusion, culture murine myeloma cell (SP2/0-Ag14, ATCC#CRL-1581) is in logarithmic growth Phase.It puts to death immunized mice gnotobasis and takes spleen, PEGylated fusion spleen bone-marrow-derived lymphocyte and SP2/0 are used according to method in document Myeloma cell (E Harlow, D.Lane, Antibody:A Laboratory Manual, (Cold Spring Harbor Laboratory Press,Cold Spring Harbor,N.Y.,1998)；Kohler G,and Milstein C," Continuous cultures of fused cell secreting antibody of predefined specificity,"Nature,256:495-497(1975)).Fused 96 porocyte culture plates of plating cells, usual 7 arrive The Growth of Hybridoma Cell that survival can be observed after 10 days under microscope comes out.Plating cells after two weeks, are collected in each hole culture Clearly, hybridoma screening is carried out with ELISA method employment CSF1R-his proteantigen.It is summarized as follows, with the people of 60ul 2ug/ml The PBS solution coated elisa plate of CSF1R-his antigen, 4 degree (" degree " in the present invention refers to degree Celsius) overnight.Then PBST board-washing After 4 times, the PBST solution for 5% skimmed milk power that 200 holes μ l/ are added is placed in 37 degree and closes 2 hours.60 μ l/ are added in board-washing again The hybridoma supematant in hole, 37 degree are incubated for 40 minutes, then board-washing 4 times.Diluted horseradish peroxidase is added with 100 holes μ l/ The sheep anti-Mouse secondary antibody (Jackson Immuno research, cat#115-036-071) of label, 37 degree are incubated for 40 minutes, and Board-washing 4 times afterwards, pat dry.The TMB chromogenic substrate in 100 holes μ l/ is added, color development at room temperature 5 to 15 minutes, then uses the sulfuric acid solution of 1M It terminates, measures the light absorption value in each hole of 450 nanometers.Choose the positive hybridoma holes cell of ELISA colour developing, is transferred to 24 orifice plates In, continue to cultivate.And the second wheel secondary screening is carried out by ELISA method, it filters out specific recognition CSF1R antigen and can block The hybridoma that CSF1R/CSF1 is combined (the results are shown in Table 1, wherein 1G7 is the hybridoma that the present invention obtains, which expresses this hair Bright obtained anti-human CSF-1R monoclonal antibody), it is subcloned by limiting dilution assay, obtains desired monoclonal cell strain.And Afterwards by these monoclonal antibodies of a small amount of Expression products of free serum culture, antibody purification carries out the Function Appraising analysis of next step.

The ELISA of 1 CSF1R Mouse Hybridoma Cells supernatant of table tests and assesses

Two, ira vitro analytical methods:

Embodiment 2 is used to measure the ira vitro analytical methods of CSF1R monoclonal antibody functional activity

The 2.1 binding ability 1xPBS based on capture ELSIA measurement antibody prepare special two of goat anti-mouse igg Fcr Anti- (Jackson Immuno Research, #115-006-071), makes its final concentration of 2 μ g/ml, with 100 μ l/ hole liquid feedings in 96 hole elisa Plates, 4 degree of coatings are overnight.Next day adds after PBS solution (i.e. 1xPBST) board-washing 4 times containing 0.05% polysorbas20 The PBST solution for entering 5% skimmed milk power in 200 holes μ l/ is placed in 37 degree and closes 2 hours.The dilute of 100 holes μ l/ is added in board-washing again After releasing antibody-solutions or hybridoma supematant, 37 degree are incubated for 40 minutes, then board-washing 4 times.The 60nM prepared is added with 100 holes μ l/ Biotin labeling people CSF1R Fc protein solution (in the PBST of 2.5% skimmed milk power), 37 degree are incubated for 40 minutes, then board-washing 4 times.Streptavidin (the Jackson Immuno of the diluted horseradish peroxidase-labeled of 1:10000 is added with 100 holes μ l/ Research, #016-030-084), 37 degree are incubated for 40 minutes, and then board-washing 4 times, pat dry.The ELISA for adding 100 holes μ l/ is aobvious Color substrate TMB, color development at room temperature 5 to 15 minutes, then uses the sulfuric acid solution color development stopping of 1M, measures the suction in each hole of 450 nanometers Light value.

The binding ability of 2.2 flow cytometries assessment antibody combination cell film surface CSF1R antigen is collected raw in logarithm Long-term film surface is overexpressed the 293F cell line of people CSF1R, (contains 2% tire ox with FACS buffer solution after washing cell 2 times with PBS The PBS solution of serum) cell is resuspended.Density is adjusted, is plated in 96 hole U bottom plates with 2x105 cells/well, 300g is centrifuged 5 points Clock, incline supernatant, adds the CSF1R antibody-solutions of gradient dilution and is placed on and is incubated for 40 minutes on ice.It washes cell 2 times, adds Add sheep anti-Mouse secondary antibody (the Jackson Immunoresearch, Cat#115-116- of 100 hole μ L/ phycoerythrin fluorescent markers 072,1:1000 dilution), 4 degree are protected from light incubation after forty minutes, wash cell 3 times, then every hole adds the FACS buffer solution weight of 100 μ L It is outstanding, blow upper machine testing after even cell.The fluorescence intensity of every hole cell is measured using BD company Canto II model flow cytometer. Data processing is carried out using Graphpad prism software, show that the EC50 concentration value of antibody combination cell (reaches the antibody Corresponding antibody concentration value when maximum fluorescence binding signal 50%).

2.3 competitive ELISA

2.3.1 ligand receptor, which combines, blocks ELISA

The blocking ability that CSF1R/CSF1 is combined by competitive ELISA method assessment CSF1R antibody.It is summarized as follows, uses 1xPBS prepares the CSF1-his albumen (BSI, cat#BS-TA1601154-96) of people, makes its final concentration of 2 μ g/ml, with 100 μ The hole l/ liquid feeding is in 96 hole elisa Plates, and 4 degree of coatings are overnight.Next day, with PBS solution (i.e. PBST) board-washing of the polysorbas20 containing 0.05% After 4 times, the PBST solution for 5% skimmed milk power that 200 holes μ l/ are added is placed in 37 degree and closes 2 hours.Board-washing 4 times again.

CSF1R antibody or control antibodies gradient dilution in people's CSF1R FC protein solution containing biotin labeling, Rear room temperature is prepared to incubate in advance 40 minutes.Then the solution of the antibody and CSF1R Fc biotin that have been incubated for is added to 100 holes μ l/ It has been coated on the plate of CSF1-his, 37 degree are incubated for board-washing 4 times again after forty minutes.Horseradish peroxide then is added with 100 holes μ l/ The Streptavidin of compound enzyme label, 37 degree of incubation board-washing 4 times after forty minutes pat dry.Add the TMB colour developing and 50 in 100 holes μ l/ The 1M sulfuric acid in the hole μ l/ terminates reaction, measures the absorption value of 450 nanometers.It is carried out at data using Graphpad prism software Reason obtains the IC50 concentration value that antibody blocking CSF1R/CSF1 is combined.

2.3.2 reference antibody blocks ELISA

Pass through competitive ELISA method assessment CSF1R antibody blocking reference antibody/CSF1R antigen binding blocking ability.Letter State it is as follows, with 1xPBS prepare reference antibody (Cabiralizumab), make its final concentration of 1 μ g/ml, with 100 μ l/ hole liquid feedings in 96 hole elisa Plates, 4 degree of coatings are overnight.Next day is added after PBS solution (i.e. PBST) board-washing 4 times containing 0.05% polysorbas20 The PBST solution of 5% skimmed milk power in 200 holes μ l/ is placed in 37 degree and closes 2 hours, board-washing 4 times again.

CSF1R antibody or control antibodies gradient dilution in people's CSF1R FC protein solution containing biotin labeling In (10nM), prepares rear room temperature and incubate in advance 40 minutes.Then the solution for the antibody and CSF1R Fc biotin being incubated for 100 μ The hole l/ is added on the plate for being coated with reference antibody, and 37 degree are incubated for board-washing 4 times again after forty minutes.Then with the addition of 100 holes μ l/ The Streptavidin of horseradish peroxidase-labeled, 37 degree of incubation board-washing 4 times after forty minutes, pats dry.Add TMB colour developing and 1M sulphur Acid solution terminates reaction, measures the absorption value of 450 nanometers.Data processing is carried out using Graphpad prism software, is obtained The IC50 concentration value that antibody blocking reference antibody/CSF1R is combined.

The combination activity of the anti-CSF1R mouse monoclonal antibody of embodiment 3

According to analysis method described in embodiment 2, the combination Activity Summary such as the following table 2 for CSF1R antibody of testing and assessing.Wherein Benchmark (Cabiralizumab) is existing not commercialized anti-human CSF1R monoclonal antibody as control.From table 2 It is found that the combination activity of anti-human CSF-1R monoclonal antibody and people's CSF1R antigen of the invention is substantially better than Benchmark.

The combination activity of 2 CSF1R antibody of table

4 functional blockade of embodiment experiment (analysis method referring to 2.3), it is real to obtain the antibody functional based on ELISA Data are commented in test

Such as the following table 3, the functional evaluating result of anti-CSF1R mouse monoclonal antibody is summarized.

Table 3 purifies the functional assessment of CSF1R mouse monoclonal antibody

The competitive ELISA experiment of antibody on human CSF1/CSF1R shows that 1G7 antibody of the invention can specific blockage in table 3 CSF1R combines its ligand CSF1, and blocking ability is substantially better than Benchmark；Antibody is to benchmark/ simultaneously The competitive ELISA experiment of humanCSF1R shows that 1G7 antibody does not block BM combination people's CSF1R antigen, shows that 1G7 is combined anti- Former epitope is different from Benchmark antibody, is unique antigen binding epitope.

Embodiment 5DNA clone and sequencing, the variable region protein sequencing of anti-CSF1R mouse monoclonal antibody

Using Trizol reagent (Invitrogen, catalog#15596-018) from the mouse monoclonal cell strain of culture Middle extraction total serum IgE.Process is summarized as follows, the cell of 5x106 is collected by centrifugation into 1.5ml centrifuge tube, blots supernatant.Add 1ml Trizol reagent and blow and beat repeatedly and be placed at room temperature for 5 minutes afterwards for several times for lytic cell.And then, every pipe is added 0.2ml's Chloroformic solution, acutely concussion was placed at room temperature for 3 minutes after 15 seconds.Then, 4 degree of 12000g of centrifuge tube are centrifuged 10 minutes, take out centrifugation Pipe draws upper strata aqueous phase solution into new 1.5ml centrifuge tube, adds the isopropanol of 0.4ml for precipitating from water phase RNA.After mixing EP is managed and placed room temperature 10min manually, 4 degree of 12000g are centrifuged 10 minutes, abandon supernatant.The second of 1ml 75% is added Alcohol, 4 degree of 7500rpm are centrifuged 5min again, abandon supernatant.Tube bottom RNA precipitate after ten minutes, is added 30 and arrives 50ul's in drying at room temperature Sterile DEPC processing water dissolves RNA sample.

And then, selecting the reverse transcription cDNA kit (catalog#6110A) of Taraka becomes CDNA total serum IgE.It is real The system of testing is formulated as follows, and+8.5 μ l RNase-free water (total 14ul) of+0.5 μ l Oligo (dT) of total serum IgE of 5 μ l is first placed in 65 5min initial denaturation is spent, is then put 2 minutes on ice.Further it is added+0.5 μ l's of dNTP mixture of+1 μ l of 5x buffer of 4 μ l + 1 μ l reverse transcriptase (20.5ul system in total) of RNase inhibitor, mixes after preparing, and runs 40 degree 50 minutes using PCR instrument, and 70 10min is spent, cDNA synthesis is completed.

CDNA is further formulated as follows at 3 ' ends plus Poly G, reaction system: the ddH2O of+33.5 μ l of cDNA sample of 5 μ l Terminal deoxynucleotidyl transferase (the total volume of the dGTP+0.5 μ l of the CoCl2+1 μ l of+5 μ l of 10xTdT buffer of+5 μ l 50ul), it is mixed after preparing, runs 37 degree 30 minutes, 70 degree of 10min using PCR instrument, complete Poly G tailing.

Further, the gene magnification of antibody variable region is carried out using the cDNA of tailing as template.It can for amplification heavy chain of antibody Become region sequence, prepare PCR reaction system: the general 0.5 μ l+ of poly C primer (forward primer) of 5 μ l+ of 10x Taq enzyme buffer is small 0.5 μ l+dNTP of mouse IgG1 reverse primer, 11 μ l+ddH2O of μ l+Taq 1 μ l+cDNA of polymerase, 41 μ l.It is light for amplification antibody Chain variable region sequence prepares PCR reaction system: the general 0.5 μ l of poly C primer (forward primer) of 5 μ l+ of 10x Taq enzyme buffer 0.5 μ l+dNTP of+mouse IgG kappa reverse primer, 11 μ l+ddH2O of μ l+Taq polymerase 1ul+cDNA, 41 μ l.Antibody The temperature cycles of heavy chain and light chain variable region PCR amplification are following (wherein step 2 to 4 repeats 25 circulations):

95 DEG C of .5min. of 1- initial denaturation

2- is denaturalized 95 DEG C of .20sec.

56 DEG C of .20sec. of 3- annealing

4- extends 72 DEG C of .30sec.

5- saves 25 DEG C of .60min.

PCR product is analyzed through 1% agarose gel electrophoresis, cut out corresponding size DNA section band (the about 600bp of VH, Vkappa light chain about 500bp), the extracting of DNA is carried out with the gel DNA QIAquick Gel Extraction Kit (catalog#28704) of Qiagen.Letter State as follows: gel weighing adds the QG buffer of 3 times of gel volumes, is then incubated for 10 minutes until gel is completely dissolved for 50 degree.Add After the isopropanol mixing for entering 1 times of colloid product, sample moves to QIA purification column, is centrifuged 13000rpm 1 minute.The PE of 750ul is added Buffer is into column, and then 13000rpm is centrifuged 1 minute.And 13000rpm is centrifuged liquid residual in 1 minute removal column again.Add The water elution column for entering 30ul is centrifuged 1 minute, obtains the DNA sample of preparation, and the PCR product of purifying obtains the variable of antibody through sequencing Region sequence is as shown in table 4, and the amino acid full length sequence of CSF1R mouse monoclonal antibody is as shown in table 5, CSF1R mouse monoclonal The nucleotide sequence of antibody is as shown in table 6.

The variable region amino acid sequence and CDR region of 4 CSF1R mouse monoclonal antibody of table

The amino acid full length sequence of 5 CSF1R mouse monoclonal antibody of table

The DNA encoding sequence of 6 CSF1R mouse monoclonal antibody of table

In conclusion the monoclonal antibody of energy specific recognition people CSF-1R of the invention, the antibody is in conjunction with people CSF-1R Affinity it is strong, sequence is novel, and combines unique epitope.

It is discussed in detail although the contents of the present invention have passed through above preferred embodiment, but it should be appreciated that above-mentioned Description is not considered as limitation of the present invention.After those skilled in the art have read above content, for of the invention A variety of modifications and substitutions all will be apparent.Therefore, protection scope of the present invention should be limited to the appended claims.

Sequence table

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gtagacatca gcaaggatga tcccgaggtc cagttcagct ggtttgtaga tgatgtggag 480

gtgcacacag ctcagacgca accccgggag gagcagttca acagcacttt ccgctcagtc 540

agtgaacttc ccatcatgca ccaggactgg ctcaatggca aggagttcaa atgcagggtc 600

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Glu Val Ser Ser Val Phe Ile Phe Pro Pro Lys Pro Lys Asp Val Leu

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Claims (9)

1. a kind of anti-human CSF-1R monoclonal antibody, which is characterized in that the antibody includes: heavy chain and light chain；

The heavy chain and light chain includes variable region, which includes complementary determining region；

Complementary determining region CDR1, CDR2 and CDR3 of the heavy chain are indicated with CDR-H1, CDR-H2 and CDR-H3 respectively；

Complementary determining region CDR1, CDR2 and CDR3 of the light chain are indicated with CDR-L1, CDR-L2 and CDR-L3 respectively；

The amino acid sequence of the CDR-H1 is shown in SEQ ID NO:3；

The amino acid sequence of the CDR-H2 is shown in SEQ ID NO:4；

The amino acid sequence of the CDR-H3 is shown in SEQ ID NO:5；

The amino acid sequence of the CDR-L1 is shown in SEQ ID NO:6；

The amino acid sequence of the CDR-L2 is shown in SEQ ID NO:7；

The amino acid sequence of the CDR-L3 is shown in SEQ ID NO:8.

2. a kind of anti-human CSF-1R monoclonal antibody according to claim 1, which is characterized in that heavy chain variable amino acid Sequence is shown in SEQ ID NO:1；Chain variable region amino acid sequence is shown in SEQ ID NO:2.

3. a kind of nucleic acid molecule, which is characterized in that the nucleic acid molecule encodes anti-human CSF- as claimed in claim 1 or 2 1R monoclonal antibody；

The sequence of the nucleic acid molecule is selected from SEQ ID NO:9 and/or SEQ ID NO:10；

The heavy chain variable region of the sequence SEQ ID NO:9 coding antibody；

The light chain variable region of the sequence SEQ ID NO:10 coding antibody.

4. a kind of expression vector, which is characterized in that the expression vector contains nucleic acid molecule as claimed in claim 3.

5. a kind of host cell, which is characterized in that the host cell contains expression vector as claimed in claim 4.

6. a kind of preparation method of anti-human CSF-1R monoclonal antibody of any of claims 1 or 2, which is characterized in that the preparation Method comprises the following steps:

Step 1: table of the preparation containing the nucleic acid molecule for expressing anti-human CSF-1R monoclonal antibody of any of claims 1 or 2 Up to carrier；

Step 2: transfecting eukaryotic host cell with the expression vector of step 1；

Step 3: the eukaryotic host cell that incubation step 2 transfects；

Step 4: isolating and purifying, obtain the antibody.

7. the preparation method of anti-human CSF-1R monoclonal antibody according to claim 6, which is characterized in that the expression Carrier contains the nucleotide sequence selected from SEQ ID NO:9 and/or SEQ ID NO:10.

8. including antibody mediated immunity the coupling conjugate, bispecific of anti-human CSF-1R monoclonal antibody of any of claims 1 or 2 Molecule, embedding and antigen receptor or pharmaceutical composition.

9. anti-human CSF-1R monoclonal antibody of any of claims 1 or 2 is preparing anti-tumor drug, rheumatoid arthritis medicine Application in object, atherosclerosis drug or bone remodeling drug.

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