CN106117354A - The full molecule IgG antibody of a kind of complete anti-CD47 in people source and application thereof - Google Patents
The full molecule IgG antibody of a kind of complete anti-CD47 in people source and application thereof Download PDFInfo
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- CN106117354A CN106117354A CN201610481322.1A CN201610481322A CN106117354A CN 106117354 A CN106117354 A CN 106117354A CN 201610481322 A CN201610481322 A CN 201610481322A CN 106117354 A CN106117354 A CN 106117354A
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- C07K16/30—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants from tumour cells
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- C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
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Abstract
The invention discloses the full molecule IgG antibody of a kind of complete anti-CD47 in people source, comprise variable region of light chain and variable region of heavy chain, the aminoacid sequence of described variable region of light chain is as shown in SEQ ID NO.3, or this sequence is added through one or more aminoacid, deletes, replaced, the conservative mutation modified and the conservative variant obtained；And the aminoacid sequence of described variable region of heavy chain is as shown in SEQ ID NO.4, or this sequence is added through one or more aminoacid, deletes, is replaced, the conservative mutation modified and the conservative variant obtained.The invention also discloses DNA molecular, expression vector, host cell and the application of above-mentioned full molecule IgG antibody.
Description
Technical field
The present invention relates to biological immune technical field, particularly relate to the full molecule IgG antibody of a kind of complete anti-CD47 in people source, also
Relate to DNA molecular, expression vector, host cell and the application of this full molecule IgG antibody.
Background technology
Macrophage removes pathogen and impaired or senile cell by phagocytosis from blood.Cell surface
CD47 can interact with the signal adjusting protein alpha (SIRP α) on macrophage, and then suppression swallows normal cell.
CD47 is a transmembrane glycoprotein expression widely, containing an immune protein spline structure territory and 5 cross-film districts, they constitutes
The part of SIRP α, combines SIRP α by the spline structure territory, variable region of NH2 end.SIRP α mainly expresses at myelocyte, bites including huge
Cell, granulocyte, medullary system dendritic cell, mastocyte, and their precursor, including hematopoietic stem cell.SIRP α can lead to
Crossing macrophage suppression host cell phagocytosis, SIRP α is by being combined formation one with the CD47 expressed on host target cells
Individual suppression signal, SHP-1 can play the effect of negativity regulation.Effect with CD47 suppression normal cell phagocytic function is consistent
Research shows, it is the stage temporary regulation before hematopoietic stem cell and blast cell thereof migrate, CD47 on these cells
Level determines the ability of phagocytosis.CD47 is the outer part of born of the same parents of Inhibitory receptor SIRP α in a word, and the two combination is suppressed by generation
Property signal reduce the phagocytic activity of macrophage, thus produce blastomogenic immunologic escape.
The monoclonal antibody technology of preparing of current domestic anti-CD47 is Mus source mostly, or carry out genetic engineering modified after carry out table
Reach, but expression is the highest or prepares loaded down with trivial details.This patent uses relatively advanced genetic engineering antibody expression system, and at table
Reach and be optimized in condition, it is thus achieved that the antibody that high specific and CD47 combine, cell experiment proves can in the presence of antibody
To promote the macrophage phagocytosis to blood tumor cell.
Summary of the invention
The technical problem existed based on background technology, the technical problem existed based on background technology, the purpose of the present invention exists
In the full molecule IgG antibody providing a kind of complete anti-CD47 in people source.
The purpose of the present invention is that again the DNA providing a kind of full molecule IgG antibody encoding the above-mentioned complete anti-CD47 in people source divides
Son.
The purpose of the present invention is again to provide a kind of containing the full molecule IgG antibody that can encode the above-mentioned complete anti-CD47 in people source
DNA molecular expression vector.
The purpose of the present invention is again to provide a kind of host cell converted by above-mentioned expression vector.
The present invention also aims to provide the application of the full molecule IgG antibody of the above-mentioned complete anti-CD47 in people source.
In order to realize the purpose of the present invention, inventor is studied by lot of experiments, including full people source Fab phage antibody library
Screening, the purification of anti-CD47 specific antibody, preparation, expression and the purification of anti-CD47 whole immunoglobulin IgG, anti-CD47 divides entirely
The specificity analysis of sub-IgG antibody, is finally obtained the full molecule IgG antibody of a kind of complete anti-CD47 in people source, comprises variable region of light chain
And variable region of heavy chain,
(1) aminoacid sequence of the variable region of light chain described in as shown in SEQ ID NO.3, or this sequence through one or
Multiple aminoacid add, delete, replace, the conservative mutation modified and the conservative variant obtained；
And the aminoacid sequence of the variable region of heavy chain described in (2) is as shown in SEQ ID NO.4, or this sequence is through one
Or multiple aminoacid adds, deletes, replaces, the conservative mutation modified and the conservative variant obtained.
Preferably, the aminoacid sequence of three antigen complementary region CDR of described variable region of light chain is SEQ ID NO.5,
Shown in SEQ ID NO.6 and SEQ ID NO.7；The aminoacid sequence of three antigen complementary region CDR of described variable region of heavy chain
Shown in SEQ ID NO.8, SEQ ID NO.9 and SEQ ID NO.10.
The full molecule IgG antibody of a kind of complete anti-CD47 in people source that the present invention also proposes, comprises constant region of light chain and heavy chain is permanent
Determining district, the aminoacid sequence of described constant region of light chain is shown in SEQ ID NO.11, the aminoacid of described CH
Sequence is shown in SEQ ID NO.12.
A kind of DNA molecular that the present invention also proposes, it encodes the heavy chain of above-mentioned full molecule IgG antibody or/and light chain.
Preferably, the nucleotide sequence of its encoded light chain variable region is shown in SEQID NO.1, the core of encoding heavy chain variable region
Acid sequence is shown in SEQ ID NO.2.
A kind of expression vector that the present invention also proposes, include above-mentioned DNA molecular and with this DNA molecular operability phase
Expression regulation sequence even.
A kind of host cell that the present invention also proposes, is converted by above-mentioned expression vector.
Preferably, the 293Freestyle cell that this host cell can be converted by above-mentioned expression vector.
The above-mentioned full molecule IgG antibody that the present invention also proposes is preparing diagnostic reagent or the treatment of the tumor relevant to CD47
Purposes in medicine.
The present invention has screened the people source Fab antibody to CD47 with high affinity by phage antibody library technique,
And obtain the described heavy chain of antibody excellent specific property of imparting and the aminoacid sequence of variable region of light chain and nucleotide sequence, and by institute
Heavy chain and the variable region of light chain of stating antibody are connected with the expression vector containing antibody constant region, are finally obtained and have special resisting
Former associativity and organ transplantation animal level have preferable immunologic rejection reaction.
The full molecule full people resource monoclonal that the invention provides a kind of anti-CD47 with high specific, good affinity resists
Body.Wide expression in the hematologic disease cell of CD47 derived from bone marrow, and do not express, therefore the present invention's is anti-
CD47 antibody can be applicable in the diagnosis of the tumor positive about CD47, treatment.The present invention is with CD47 as target molecule, in phage
Full molecule human antibody is prepared on the basis of Antibody library.The people source anti-cd 47 antibody of preparation is done Function Identification, display
This antibody can be specific binding with CD47, and In vitro cell experiment confirms that antibody can promote the macrophage blood to the CD47 positive
The phagocytosis of liquid tumor cell.
Compared with the monoclonal antibody of domestic existing anti-CD47 Mus source, prepared by the present invention is full humanized IgG antibody, and tests card
Bright have good specificity and can be remarkably reinforced the phagocyte phagocytosis to CD47 positive blood tumor cell.
The present inventor is by detecting the macrophage of derived from bone marrow to human promyelocytic leukemia in the presence of anti-cd 47 antibody
Cell HL-60 swallows experiment, and result proves that anti-cd 47 antibody can be remarkably reinforced the phagocytosis of macrophage.
Accompanying drawing explanation
Fig. 1 is the SDS-PAGE detection knot of the full molecule IgG antibody of the embodiment of the present invention 1 gained purification full people anti-CD47 in source
Really；Wherein 1 is Protein Marker product, and 2 is anti-cd 47 antibody, and 3 is anti-TLR4 antibody, and 4 is cells and supernatant, and 5 is stream
Wear；Visible use Pro.A column purification anti-cd 47 antibody purity is high.
Fig. 2 is the elisa testing result of the embodiment of the present invention 1 gained anti-cd 47 antibody, it is seen that anti-CD47
Antibody is stronger with the binding ability of CD47 albumen.
Fig. 3 is the immunoblotting qualification result of the embodiment of the present invention 1 gained anti-cd 47 antibody and CD47；Wherein 1 is anti-
The people in loop HL-60 that CD47 antibody is positive with CD47；2 is the rat marrow that anti-cd 47 antibody is negative with CD47
Oncocyte YB2/0；Visible antibody and CD47 albumen have specific binding capacity.
Fig. 4 is the affinity testing result of the embodiment of the present invention 1 gained anti-cd 47 antibody, and KD value is 3.362 × 10-10M。
Fig. 5 is the experimental result comparison diagram that the embodiment of the present invention 1 gained anti-cd 47 antibody promotes macrophage phagocytic effect.
Experimental result display anti-cd 47 antibody can make 80% phagocyte play phagocytosis.
Detailed description of the invention
Below, by specific embodiment, technical scheme is described in detail.
The preparation of the full molecule IgG antibody of the complete anti-CD47 in people source of embodiment 1
1) with CD47 antigen in the Fab phage library of people source through six enrichment isolation taking turns " absorption-eluting-amplification ", obtain
The Fab antibody of CD47 must be resisted, then obtained the variable region sequences of Fab antibody by PCR amplification order-checking.
2) according to the heavy and light chain variable region sequence of acquired antibody, primer is designed.
3) amplification anti-cd 47 antibody heavy chain, light chain.
With the people source Fab template of above-mentioned preparation, the upstream and downstream primer amplification with the above-mentioned heavy chain related to and light chain is complete respectively
Molecule human antibody heavy, light chain gene.
(1)PCR
Reaction system is as follows:
Reaction condition is as follows:
(2) 2% agarose gel electrophoresiies, observe purpose band under ultraviolet, cut glue and reclaim.
(3) glue reclaims kits target DNA fragment, deionized water eluting.
4) double digestion IgG expression plasmid
IgG expression plasmid pFUSE-CHIg-hG1, pFUSE-CLIg-hk (purchased from Invivogen company) comprise IgG1 type
The heavy chain in people source and light chain (Lambda) constant region alkali yl coding sequence.
(1) double digestion of pFUSE-CHIg-hG1, pFUSE-CLIg-hk template vector
Reaction system is as follows:
Reaction condition is: 37 DEG C of enzyme action are overnight.
(2) 1% agarose gel electrophoresiies, ultraviolet incision glue reclaims.
(3) glue reclaims kits target DNA fragment, deionized water eluting.
5) Infusion PCR recombinant expression plasmid
Reaction system is as follows:
Reaction condition is: hatch 15min for 50 DEG C.
Taking 5 μ L reactant liquor transformed competence colibacillus antibacterials, be laid on the flat board of corresponding resistant, next day chooses clone and send order-checking.To survey
The clone that sequence result is correct preserves strain amplification culture, extracts plasmid.
6) expression of anti-cd 47 antibody
(1) take the heavy chain plasmid after 50 μ g restructuring in the Opti-MEM culture medium of 1mL, take the light chain plasmids of 50 μ g in
In the Opti-MEM culture medium of 1mL, take the 293Fectin of 200 μ L in the Opti-MEM culture medium of 2.8mL, by above-mentioned three kinds
Mixed liquor room temperature stands 5min；
(2) then by after two plasmid mixed liquor mix homogeneously, after adding the Opti-MEM culture medium mix homogeneously of 500 μ L
It is directly added into the mixed liquor of transfection reagent 293Fectin, after mix homogeneously, stands 20min.Period processes 293F cell, by 293F
Use 293F Expression Medium resuspended after cell centrifugation, then count and calculate cell viability ratio with trypan blue, inhaling
Take 1 × 108Individual cell, in culture bottle, is 94mL with 293F Expression Medium constant volume；
(3) after 20min terminates, the complex of DNA, 293Fectin of 6mL is added in ready 293F cell；
(4) cell is placed in shaking table incubator cultivation, condition of culture 8%CO2,120rmp, 37 DEG C, collect thin after 6 days
Born of the same parents' supernatant.
7) purification of anti-cd 47 antibody
The cell conditioned medium membrane filtration of 0.22 μm that will collect, simultaneously by balance liquid and eluent filter membrane.Use AKATA
Purification instrument, according to the standard step purification of Protein A purification, with the speed loading of 1mL/min, is washed with the speed of 1.5mL/min
De-.
Result successful expression purification anti-cd 47 antibody.Purification anti-cd 47 antibody is carried out SDS-PAGE detection, its result
As shown in Figure 1.The antibody purity of purification is the highest as shown in Figure 1, and preferable by Pro.A column purification effect.
The functional activity of embodiment 2 anti-cd 47 antibody is identified
1) euzymelinked immunosorbent assay (ELISA)
It is coated ELISA96 orifice plate, every hole to 2 μ g/mL with being coated liquid (0.1M carbonate buffer solution, pH9.6) CD47 albumen
Adding 100 μ L, 4 DEG C overnight；PBST (PBS contains 0.5%Tween20) 5% skim milk-lavation buffer solution is closed, is hatched for 37 DEG C
2h；After PBST washs 5 times, each hole adds 100 μ LPA21 antibody (2 μ g/mL initial concentrations, 14 Concentraton gradient dilutions) 37
℃2h；Resist 100 μ L/ holes to join in hole with the goat-anti people two of 1:4000 dilution, hatch 1h for 37 DEG C；Peroxidase substrate develops the color
Liquid 100 μ L/ hole, room temperature uses 2M sulphuric acid stopped reaction, upper machine testing colorimetric employing dual wavelength 450nm/690nm after lower 10 minutes.
Shown in result such as Fig. 2 shows, as shown in Figure 2: anti-cd 47 antibody can play antigen antibody reaction with CD47 albumen.
2)Western blot
With do not express CD47 albumen rat myeloma cell YB2/0 as negative control, respectively by the morning of high expressed CD47
Myelocyte HL-60 and do not express the rat myeloma cell YB2/0 of CD47 albumen and carry out 10%SDS-PAGE electrophoresis and electricity turns
On nitrocellulose membrane, this film and 2 μ g/mL PA21 antibody at room temperature are hatched 1h, 1:4000 and dilutes HRP-goat anti-human igg (Beijing
Zhong Shan company) and ECL luminescence reagent box (Pierce company of the U.S.) be exposed to gel imaging system (Bio-Rad company).
Result is as shown in Figure 3: the CD47 albumen that anti-cd 47 antibody and HL-60 express has specific binding.
3) affinity detection
Isoelectric point, IP according to CD47 and optimize coupling bar according to the protocol of BiacoreX100control soft
Part, slope optimized choice sodium acetate is as coupling dilution buffer.After this buffer dilution CD47 diluted sample to 25 μ g/mL
It is coupled on CM5 chip.Preset the horizontal 1500RU of coupling.Then CD47 sample is diluted with the Running buffer of pH7.4, dilute
Release a series of concentration to 0nM, 5nM, 10nM 20nM, 40nM, 80nM.Arranging sample injection time is 180s, Dissociation time 10min, then
Raw buffer 50mMpH2.2Gly-HCl.Examination with computer is carried out according to the protocol of BiacoreX100control soft.
As shown in Figure 4, KD value is 3.362 × 10 to affinity testing result-10M。
4) anti-cd 47 antibody promotes the experiment of macrophage phagocytic effect
Respectively by the rat myeloma cell YB2/ of people in loop HL-60 and CD47 feminine gender positive for CD47
0 co-cultures (containing 10 μ g/mL's in culture medium with the ratio of 4:1 with the macrophage of bone marrow derived with after CFSE labelling
Anti-cd 47 antibody, matched group contains control antibodies simultaneously), count in every 100 phagocyte with fluorescence microscope after 2h
Phagocytotic cell number occurs, and experiment is in triplicate.
Result is as shown in Figure 5: in the presence of anti-cd 47 antibody, the phagocytosis of HL-60 cell is substantially increased by macrophage
By force, phagocyte percentage ratio reaches 80%, and remaining group has no obvious phagocytosis.
In above-mentioned literary composition, M is the implication of mol/L.
The above, the only present invention preferably detailed description of the invention, but protection scope of the present invention is not limited thereto,
Any those familiar with the art in the technical scope that the invention discloses, according to technical scheme and
Inventive concept equivalent or change in addition, all should contain within protection scope of the present invention.
Claims (8)
1. a full molecule IgG antibody of the complete anti-CD47 in people source, comprises variable region of light chain and variable region of heavy chain, it is characterised in that
(1) aminoacid sequence of the variable region of light chain described in is as shown in SEQ ID NO.3, or this sequence is through one or more
Aminoacid adds, delete, replace, the conservative mutation modified and the conservative variant obtained；
And the aminoacid sequence of the variable region of heavy chain described in (2) is as shown in SEQ ID NO.4, or this sequence is through one or many
Individual aminoacid adds, delete, replace, the conservative mutation modified and the conservative variant obtained.
The most full molecule IgG antibody, it is characterised in that three antigens of described variable region of light chain are mutual
The aminoacid sequence mending district CDR is SEQ ID NO.5, SEQ ID NO.6 and shown in SEQ ID NO.7；Described weight chain variable
The aminoacid sequence of three antigen complementary region CDR in district is SEQ ID NO.8, SEQ ID NO.9 and shown in SEQ ID NO.10.
3. a full molecule IgG antibody of the complete anti-CD47 in people source, comprises constant region of light chain and CH, it is characterised in that
The aminoacid sequence of described constant region of light chain is shown in SEQ ID NO.11, and the aminoacid sequence of described CH is
Shown in SEQ ID NO.12.
4. a DNA molecular, the heavy chain of full molecule IgG antibody described in its coding any one of claim 1-3 is or/and light chain.
DNA molecular the most according to claim 4, it is characterised in that the nucleotide sequence of its encoded light chain variable region is SEQID
Shown in NO.1, the nucleotide sequence of encoding heavy chain variable region is shown in SEQ ID NO.2.
6. an expression vector, includes the DNA molecular described in claim 4 and the table being operatively connected with this DNA molecular
Reach regulating and controlling sequence.
7. a host cell, is converted by the expression vector described in claim 6.
8. full molecule IgG antibody described in any one of claim 1-3 is being prepared the diagnostic reagent of the tumor relevant to CD47 or is being controlled
Treat the purposes in medicine.
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| WO2019042119A1 (en) * | 2017-09-01 | 2019-03-07 | 北京智仁美博生物科技有限公司 | Antibody against human cd47 and use thereof |
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| WO2019184912A1 (en) * | 2018-03-27 | 2019-10-03 | 信达生物制药(苏州)有限公司 | Anti-cd47 antibody and uses thereof |
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| WO2019042119A1 (en) * | 2017-09-01 | 2019-03-07 | 北京智仁美博生物科技有限公司 | Antibody against human cd47 and use thereof |
| WO2019179366A1 (en) * | 2018-03-20 | 2019-09-26 | Wuxi Biologics (Shanghai) Co. Ltd. | Novel anti-cd47 antibodies |
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| US11655296B2 (en) | 2018-03-27 | 2023-05-23 | Innovent Biologics (Suzhou) Co., Ltd. | Anti-CD47 antibody and use thereof |
| CN110615841B (en) * | 2018-06-20 | 2022-01-04 | 瑞阳(苏州)生物科技有限公司 | Anti-human CD47 monoclonal antibody and application thereof |
| CN110615841A (en) * | 2018-06-20 | 2019-12-27 | 瑞阳(苏州)生物科技有限公司 | Anti-human CD47 monoclonal antibody and application thereof |
| WO2020019135A1 (en) * | 2018-07-23 | 2020-01-30 | 中国科学院微生物研究所 | Anti-cd47 antibody and use thereof |
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| CN110872348B (en) * | 2018-09-03 | 2021-09-03 | 长春金赛药业有限责任公司 | Humanized anti-CD 47 monoclonal antibody and application thereof |
| CN113453719A (en) * | 2019-02-26 | 2021-09-28 | 信达生物制药(苏州)有限公司 | Formulations comprising anti-CD 47 antibodies, methods of making and uses thereof |
| WO2020173431A3 (en) * | 2019-02-26 | 2020-10-22 | 信达生物制药(苏州)有限公司 | Preparations containing anti-cd47 antibody, and preparation method and use therefor |
| WO2021204281A1 (en) * | 2020-04-10 | 2021-10-14 | Hutchison Medipharma Limited | Anti-cd47 antibody and uses thereof |
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