CN106117354B - Whole-molecule IgG antibody of fully human anti-CD 47 and application thereof - Google Patents
Whole-molecule IgG antibody of fully human anti-CD 47 and application thereof Download PDFInfo
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- 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
- C07K16/30—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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- C07K2317/50—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
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- C07K2317/92—Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
Abstract
The invention discloses a fully human anti-CD 47 whole-molecule IgG antibody, which comprises a light chain variable region and a heavy chain variable region, wherein the amino acid sequence of the light chain variable region is shown as SEQ ID NO.3, or a conservative variant obtained by conservative mutation of the sequence through one or more amino acid additions, deletions, substitutions and modifications; and the amino acid sequence of the heavy chain variable region is shown as SEQ ID NO.4, or conservative variant obtained by conservative mutation of the sequence through one or more amino acid additions, deletions, substitutions and modifications. The invention also discloses a DNA molecule, an expression vector, a host cell and application of the whole IgG antibody.
Description
Technical Field
The invention relates to the technical field of biological immunity, in particular to a fully human anti-CD 47 full molecular IgG antibody, and also relates to a DNA molecule, an expression vector, a host cell and application of the fully human anti-CD 47 full molecular IgG antibody.
Background
Macrophages clear pathogens and damaged or senescent cells from the blood by phagocytosis. CD47 on the cell surface can interact with signal-regulatory protein alpha (SIRPa) on macrophages, thereby inhibiting phagocytosis of normal cells. CD47 is a broad transmembrane glycoprotein expression containing an immunoprotein-like domain and 5 transmembrane domains that form a ligand for SIRP α and bind SIRP α via the NH 2-terminal variable region-like domain. Sirpa is expressed primarily in myeloid cells, including macrophages, granulocytes, myeloid dendritic cells, mast cells, and their precursors, including hematopoietic stem cells. SIRP alpha can inhibit host cell phagocytosis by macrophages, and SHP-1 can play a role in negative regulation by binding to CD47 expressed on the target cell of the host to form an inhibitory signal. Studies consistent with the role of CD47 in inhibiting phagocytic function of normal cells indicate that it is transiently regulated at a stage prior to migration of hematopoietic stem cells and their mother cells, where the level of CD47 determines the capacity for phagocytosis. In conclusion, CD47 is an extracellular ligand of the inhibitory receptor SIRP alpha, and the combination of the two reduces the phagocytic activity of macrophages by generating inhibitory signals, thereby generating immune escape of tumors.
At present, most of domestic monoclonal antibody preparation technologies for resisting CD47 are mouse sources or are expressed after genetic engineering modification, but the expression quantity is not high or the preparation is complicated. The patent adopts a relatively advanced gene engineering antibody expression system, optimizes the expression conditions, obtains an antibody combined with high specificity and CD47, and cell experiments prove that the phagocytosis of macrophages on blood tumor cells can be promoted in the presence of the antibody.
Disclosure of Invention
Based on the technical problems in the prior art and the technical problems in the prior art, the invention aims to provide a fully human anti-CD 47 full molecular IgG antibody.
The present invention also provides a DNA molecule encoding the fully human anti-CD 47 IgG antibody.
The present invention also provides a DNA molecule expression vector containing a whole IgG antibody encoding the fully human anti-CD 47.
It is another object of the present invention to provide a host cell transformed with the above-described expression vector.
The invention also aims to provide application of the fully human anti-CD 47 full molecular IgG antibody.
In order to achieve the object of the present invention, the inventors finally obtained a fully human anti-CD 47 whole IgG antibody comprising a light chain variable region and a heavy chain variable region by a number of experimental studies including screening of a fully human Fab phage antibody library, purification of an anti-CD 47 specific antibody, preparation, expression and purification of an anti-CD 47 whole IgG, and characterization of an anti-CD 47 whole IgG,
(1) the amino acid sequence of the light chain variable region is shown as SEQ ID NO.3, or conservative variant obtained by conservative mutation of the sequence through one or more amino acid additions, deletions, substitutions and modifications;
and the amino acid sequence of the heavy chain variable region in (2) is shown as SEQ ID NO.4, or conservative variant obtained by conservative mutation of the sequence through one or more amino acid addition, deletion, substitution and modification.
Preferably, the amino acid sequences of the three antigen complementary region CDRs of the light chain variable region are shown as SEQ ID NO.5, SEQ ID NO.6 and SEQ ID NO. 7; the amino acid sequences of three antigen complementary region CDRs of the heavy chain variable region are shown as SEQ ID NO.8, SEQ ID NO.9 and SEQ ID NO. 10.
The invention also provides a fully human anti-CD 47 full molecular IgG antibody, which comprises a light chain constant region and a heavy chain constant region, wherein the amino acid sequence of the light chain constant region is shown in SEQ ID NO.11, and the amino acid sequence of the heavy chain constant region is shown in SEQ ID NO. 12.
The invention also provides a DNA molecule which encodes the heavy chain or/and the light chain of the whole IgG antibody.
Preferably, the nucleic acid sequence encoding the light chain variable region is shown in SEQ ID NO.1, and the nucleic acid sequence encoding the heavy chain variable region is shown in SEQ ID NO. 2.
The invention also provides an expression vector, which comprises the DNA molecule and an expression regulation and control sequence operatively connected with the DNA molecule.
The invention also provides a host cell transformed by the expression vector.
Preferably, the host cell may be 293Freestyle cells transformed with the above-described expression vector.
The invention also provides application of the whole molecular IgG antibody in preparing a diagnostic reagent or a therapeutic drug for CD 47-related tumors.
The invention screens the humanized Fab antibody with high affinity to CD47 by phage antibody library technology, obtains the amino acid sequence and nucleotide sequence of the heavy chain and light chain variable region which endows the antibody with excellent characteristics, and connects the heavy chain and light chain variable region of the antibody with an expression vector containing an antibody constant region, finally obtains the specific antigen binding property and has better anti-rejection reaction at the level of organ transplantation animals.
The invention provides a full-molecule fully human monoclonal antibody with high specificity and good affinity for CD 47. CD47 is widely expressed in blood disease cells derived from bone marrow, but not in normal tissues, and therefore the anti-CD 47 antibody of the present invention can be used for diagnosis and treatment of CD 47-positive tumors. The invention takes CD47 as a target molecule and prepares a full-molecular humanized antibody on the basis of a phage antibody library technology. The work of the prepared humanized anti-CD 47 antibody can be identified, the antibody can be shown to be specifically combined with CD47, and in vitro cell experiments prove that the antibody can promote the phagocytosis of macrophages on CD47 positive blood tumor cells.
Compared with the existing anti-CD 47 murine monoclonal antibody in China, the fully human IgG antibody prepared by the invention has good specificity and can obviously enhance the phagocytosis of phagocyte on CD47 positive blood tumor cells.
The inventor tests the phagocytosis of human promyelocytic leukemia cell HL-60 by detecting macrophage derived from bone marrow in the presence of anti-CD 47 antibody, and the result proves that the anti-CD 47 antibody can obviously enhance the phagocytosis of the macrophage.
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FIG. 1 shows the SDS-PAGE detection result of the purified fully human anti-CD 47 whole IgG antibody obtained in example 1 of the present invention; wherein 1 is a protein molecular weight standard, 2 is an anti-CD 47 antibody, 3 is an anti-TLR 4 antibody, 4 is cell culture supernatant, and 5 is flow-through; the anti-CD 47 antibody purified using the pro.a column was found to be of high purity.
FIG. 2 shows the result of ELISA detection of the anti-CD 47 antibody obtained in example 1, which shows that the anti-CD 47 antibody has strong binding ability to CD47 protein.
FIG. 3 shows the result of immunoblot identification of the anti-CD 47 antibody and CD47 obtained in example 1 of the present invention; wherein 1 is human promyelocytic leukemia cell HL-60 positive for anti-CD 47 antibody and CD 47; 2 is anti-CD 47 antibody and CD47 negative rat myeloma cell YB 2/0; the antibody can be seen to have specific binding ability with CD47 protein.
FIG. 4 shows the result of affinity assay of the anti-CD 47 antibody obtained in example 1 of the present invention, with KD value of 3.362X 10-10M。
FIG. 5 is a graph comparing the results of the experiment in which the anti-CD 47 antibody of example 1 of the present invention promotes macrophage phagocytosis. The experimental results show that the anti-CD 47 antibody can enable 80% of phagocytes to play phagocytosis.
Detailed Description
The technical solution of the present invention will be described in detail below with reference to specific examples.
EXAMPLE 1 preparation of Whole IgG antibody against CD47, which is fully human
1) The CD47 antigen is used for enrichment screening of six rounds of adsorption-elution-amplification in a humanized Fab phage library to obtain a Fab antibody of anti-CD 47, and then the variable region sequence of the Fab antibody is obtained by PCR amplification sequencing.
2) Based on the variable region sequence of the heavy and light chains of the obtained antibody, primers were designed.
3) The heavy chain and the light chain of the anti-CD 47 antibody are amplified.
And amplifying the heavy chain and light chain genes of the full-molecular human antibody by using the prepared human Fab template and the related upstream and downstream primers of the heavy chain and the light chain respectively.
(1)PCR
The reaction system is as follows:
the reaction conditions were as follows:
(2) performing 2% agarose gel electrophoresis, observing a target band under ultraviolet, cutting the gel and recovering.
(3) And purifying the target DNA fragment by using the gel recovery kit, and eluting by using deionized water.
4) Double restriction enzyme IgG expression plasmid
The IgG expression plasmids pFUSE-CHIg-hG1, pFUSE-CLIg-hk (available from Invivogen) contained base coding sequences for the heavy and light chain (Lambda) constant regions of human origin, IgG 1.
(1) Double enzyme digestion of pFUSE-CHIg-hG1 and pFUSE-CLIg-hk template vectors
The reaction system is as follows:
the reaction conditions are as follows: the cleavage was carried out overnight at 37 ℃.
(2) Electrophoresis was performed on 1% agarose gel, and the gel was recovered by cutting under ultraviolet.
(3) And purifying the target DNA fragment by using the gel recovery kit, and eluting by using deionized water.
5) Infusion PCR recombinant expression plasmid
The reaction system is as follows:
the reaction conditions are as follows: incubate at 50 ℃ for 15 min.
5 mul of reaction solution was taken to transform competent bacteria, spread on the corresponding resistant plates, and the next day clones were picked for sequencing. And cloning and preserving strains with correct sequencing results, carrying out amplification culture, and extracting plasmids.
6) Expression of anti-CD 47 antibody
(1) 50 μ g of the recombinant heavy chain plasmid was placed in 1mL of Opti-MEM medium, 50 μ g of the light chain plasmid was placed in 1mL of Opti-MEM medium, 200 μ L of 293Fectin was placed in 2.8mL of Opti-MEM medium, and the three mixtures were allowed to stand at room temperature for 5 min;
(2) then, after the two plasmid mixed solutions are uniformly mixed, 500 mu L of Opti-MEM culture medium is added and uniformly mixed, the mixed solution of the transfection reagent 293Fectin is directly added, and the mixture is uniformly mixed and then stands for 20 min. During the period, 293F cells were treated, the 293F cells were centrifuged and resuspended in 293F Expression Medium, then counted and the ratio of cell viability calculated with trypan blue, aspirated by 1X 108Placing the cells in a culture bottle, and fixing the volume to 94mL by using 293F Expression Medium;
(3) after 20min, adding 6mL of the compound of the DNA and the 293Fectin into the prepared 293F cells;
(4) the cells were cultured in a shaker incubator under 8% CO2, 120rmp, 37 ℃ for 6 days, and then cell supernatants were collected.
7) Purification of anti-CD 47 antibodies
The collected cell supernatant was filtered through a 0.22 μm filter while the balance and the eluate were filtered through a membrane. The Protein A was purified using an AKATA purifier according to standard procedures for Protein A purification, loading at 1mL/min, and eluting at 1.5 mL/min.
Results anti-CD 47 antibody was successfully expressed and purified. The purified anti-CD 47 antibody was subjected to SDS-PAGE, and the results are shown in FIG. 1. As can be seen from fig. 1, the purified antibody was high in purity and was purified by a pro.a column with a good effect.
Example 2 functional Activity identification of anti-CD 47 antibodies
1) Enzyme linked immunosorbent assay
Coating ELISA96 well plates with coating solution (0.1M carbonate buffer, pH9.6) CD47 protein to 2. mu.g/mL, adding 100. mu.L per well, and standing overnight at 4 ℃; PBST (PBS containing 0.5% Tween20) 5% skimmed milk-wash buffer blocked and incubated at 37 ℃ for 2 h; after 5 PBST washes, 100. mu.L PA21 antibody (2. mu.g/mL starting concentration, 14 concentration gradient dilutions) was added to each well for 2h at 37 ℃; mixing the raw materials in a ratio of 1: adding 100 mu L/hole of 4000 diluted goat anti-human secondary antibody into the hole, and incubating for 1h at 37 ℃; the peroxidase substrate color developing solution is 100 mu L/hole, the reaction is stopped by 2M sulfuric acid after 10 minutes at room temperature, and the double-wavelength 450nm/690nm is adopted for machine detection and color comparison.
The results are shown in FIG. 2, and it can be seen from FIG. 2 that: the anti-CD 47 antibody reacts with the CD47 protein as an antigen antibody.
2)Western blot
Taking rat myeloma cells YB2/0 not expressing CD47 protein as negative control, respectively carrying out 10% SDS-PAGE electrophoresis on promyelocytic HL-60 highly expressing CD47 and rat myeloma cells YB2/0 not expressing CD47 protein, transferring the electrophoresis to a nitrocellulose membrane, and incubating the membrane with 2 mu g/mL PA21 antibody for 1h at room temperature, 1: HRP-goat anti-human IgG (Beijing Cedar) and ECL luminescence kit (Pierce, USA) were exposed to a gel imaging system (Bio-Rad).
The results are shown in FIG. 3: the anti-CD 47 antibody specifically bound to HL-60-expressed CD47 protein.
3) Affinity assays
Sodium acetate was chosen as the coupling dilution buffer for slope optimization based on the isoelectric point of CD47 and protocol optimization according to BiacoreX100control soft. CD47 samples were diluted to 25. mu.g/mL with this buffer and coupled to CM5 chips. The preset coupling level was 1500 RU. The CD47 samples were then diluted with Running buffer at pH7.4 to a range of concentrations of 0nM, 5nM, 10nM 20nM, 40nM, 80 nM. Setting the sample injection time at 180s, dissociation time at 10min, and regenerating buffer solution with 50mM pH2.2Gly-HCl. The on-board test was performed according to the protocol of BiacoreX100control soft.
The results of the affinity assay are shown in FIG. 4, where the KD value is 3.362X 10-10M。
4) Experiment for anti-CD 47 antibody promoting macrophage phagocytosis
Human promyelocytic leukemia cells HL-60 positive for CD47 and rat myeloma cells YB2/0 negative for CD47, labeled with CFSE, were combined with mouse bone marrow-derived macrophages at a ratio of 4: 1 (10. mu.g/mL of anti-CD 47 antibody in the medium, and control antibody in the control group), and after 2h, the number of cells phagocytosed per 100 phagocytes was counted by fluorescence microscopy, and the experiment was repeated three times.
The results are shown in FIG. 5: in the presence of anti-CD 47 antibody, phagocytosis of HL-60 cells by macrophages is obviously enhanced, the percentage of phagocytic cells reaches 80%, and no obvious phagocytosis is found in the rest groups.
In the above, M is in the meaning of mol/L.
The above description is only for the preferred embodiment of the present invention, but the scope of the present invention is not limited thereto, and any person skilled in the art should be considered to be within the technical scope of the present invention, and the technical solutions and the inventive concepts thereof according to the present invention should be equivalent or changed within the scope of the present invention.
Claims (7)
1. A fully human anti-CD 47 whole IgG antibody comprising a light chain variable region and a heavy chain variable region,
(1) the amino acid sequence of the light chain variable region is shown as SEQ ID NO. 3;
and the amino acid sequence of the heavy chain variable region in (2) is shown in SEQ ID NO. 4;
the amino acid sequences of three antigen complementary region CDRs of the light chain variable region are shown as SEQ ID NO.5, SEQ ID NO.6 and SEQ ID NO. 7; the amino acid sequences of three antigen complementary region CDRs of the heavy chain variable region are shown as SEQ ID NO.8, SEQ ID NO.9 and SEQ ID NO. 10.
2. The fully human anti-CD 47 IgG antibody according to claim 1, comprising a light chain constant region and a heavy chain constant region, wherein said light chain constant region has the amino acid sequence shown in SEQ ID No.11 and said heavy chain constant region has the amino acid sequence shown in SEQ ID No. 12.
3. A DNA molecule encoding the whole IgG antibody according to claim 1 or 2.
4. The DNA molecule according to claim 3, wherein the nucleic acid sequence encoding the light chain variable region is represented by SEQ ID No.1 and the nucleic acid sequence encoding the heavy chain variable region is represented by SEQ ID No. 2.
5. An expression vector comprising the DNA molecule of claim 3 and an expression control sequence operably linked to the DNA molecule.
6. A host cell transformed with the expression vector of claim 5.
7. Use of the whole IgG antibody according to claim 1 or 2 for the preparation of a diagnostic agent or a therapeutic agent for CD 47-associated tumor.
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| TW201819413A (en) * | 2016-11-28 | 2018-06-01 | 大陸商江蘇恆瑞醫藥股份有限公司 | CD47 antibody, antigen-binding fragments and pharmaceutical use thereof |
| CN109096395B (en) * | 2017-06-20 | 2022-06-24 | 华兰生物工程股份有限公司 | Blocking type CD47 nano antibody and application thereof |
| CN109422811A (en) * | 2017-08-29 | 2019-03-05 | 信达生物制药(苏州)有限公司 | Anti-cd 47 antibody and application thereof |
| CN108503708B (en) * | 2017-09-01 | 2021-07-30 | 北京智仁美博生物科技有限公司 | Anti-human CD47 antibodies and uses thereof |
| WO2019179366A1 (en) * | 2018-03-20 | 2019-09-26 | Wuxi Biologics (Shanghai) Co. Ltd. | Novel anti-cd47 antibodies |
| CN110305212A (en) | 2018-03-27 | 2019-10-08 | 信达生物制药(苏州)有限公司 | Anti-cd 47 antibody and application 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 |
| 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 |
| 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 |
| CA3131307A1 (en) * | 2019-02-26 | 2020-09-03 | Innovent Biologics (Suzhou) Co., Ltd. | Formulation comprising anti-cd47 antibody, preparation method therefor and use thereof |
| AR121805A1 (en) * | 2020-04-10 | 2022-07-13 | Hutchison Medipharma Ltd | ANTI-CD47 ANTIBODY AND USES OF THE SAME |
| EP4217397A1 (en) * | 2020-09-28 | 2023-08-02 | Shanghai Henlius Biotech, Inc. | Anti-cd47 antibodies and methods of use |
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| CN101133083A (en) * | 2003-11-11 | 2008-02-27 | 中外制药株式会社 | Humanized anti-cd47 antibody |
| JP6166177B2 (en) * | 2010-05-14 | 2017-07-19 | ザ ボード オブ トラスティーズ オブ ザ レランド スタンフォード ジュニア ユニバーシティー | Humanized and chimeric monoclonal antibodies against CD47 |
| EA034778B1 (en) * | 2012-02-06 | 2020-03-19 | Инхибркс, Инк. | Cd47 antibodies and methods of use thereof |
| ES2786083T3 (en) * | 2012-12-12 | 2020-10-08 | Arch Oncology Inc | Therapeutic CD47 antibodies |
| ES2944477T3 (en) * | 2013-02-06 | 2023-06-21 | Inhibrx Inc | Non-Platelet Reducing and Non-Red Cell Reducing CD47 Antibodies and Methods of Using Them |
| CN104804093A (en) * | 2015-05-27 | 2015-07-29 | 江苏春申堂药业有限公司 | Single-domain antibody for CD47 |
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