CN112553256A - IL-2 receptor compound and preparation method and application thereof - Google Patents
IL-2 receptor compound and preparation method and application thereof Download PDFInfo
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- CN112553256A CN112553256A CN202110190841.3A CN202110190841A CN112553256A CN 112553256 A CN112553256 A CN 112553256A CN 202110190841 A CN202110190841 A CN 202110190841A CN 112553256 A CN112553256 A CN 112553256A
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- Preparation Of Compounds By Using Micro-Organisms (AREA)
Abstract
The invention discloses an IL-2 receptor compound and a preparation method and application thereof. The IL-2 receptor complex is obtained by constructing the nucleic acid sequences of the encoding fusion protein I (SEQ ID NO:1 or 7) and the fusion protein II (SEQ ID NO:3 or 9) on the same eukaryotic expression vector or different eukaryotic expression vectors respectively, transfecting mammalian cells with the obtained recombinant expression vector, and separating and purifying the transfected mammalian cells from the cell culture supernatant. The invention utilizes the genetic engineering technology, directly obtains the IL-2 receptor alpha beta gamma heterotrimer protein through recombinant expression and one-step affinity chromatography purification, and does not need in vitro assembly; the heterotrimeric protein has high affinity activity with IL-2, and can be used for in vitro research of the interaction between IL-2 and an IL-2 receptor, preparation of antibodies by immune animals, in vitro screening of antibodies and the like.
Description
Technical Field
The invention relates to the field of genetic engineering, in particular to an IL-2 receptor compound and a preparation method and application thereof.
Background
Interleukin-2 (IL-2) is one of the first cytokines discovered, also known as T Cell Growth Factor (TCGF). In 1976 RobertGallo, a laboratory of NCI tumor cell biology, cultured bone marrow cells in medium conditioned with PHA-stimulated lymphocyte production, found survival in which 90% of T cells were maintained for up to 9 months. However, the fact that primary T cells cannot be cultured in vitro has been a bottleneck technical problem in the development of immunology. This substance that supports long-term growth of T cells is called T Cell Growth Factor (TCGF), also known as IL-2. IL-2 has important effects on T cell proliferation, development, differentiation and apoptosis.
The receptor Interleukin-2 receptor (IL-2R) for IL-2 comprises three subunits, alpha, beta and gamma. The three subunits can constitute receptors of different affinities, wherein alpha alone is a low affinity receptor and exists alone without participating in signal transduction, beta and gamma constitute receptors of intermediate affinity, downstream can signal through JAK, and in the case of alpha participation, affinity is enhanced to a high affinity receptor. After IL-2 is specifically combined with a receptor thereof, various ways such as Jak-STAT, MAPK, P13K and the like are started, apoptosis is inhibited, cell proliferation and differentiation are induced, and various biological effects are generated. Since the 90 s of the 20 th century, researchers began to achieve clinical therapeutic effects against tumors or autoimmune diseases by mutating the affinity of IL-2 and different receptor subunits or preparing antibodies against IL-2 receptors.
Although IL-2R α, β, and γ can form a receptor complex with high affinity for IL-2, the α subunit and the β and γ subunits do not form a receptor complex in direct contact. According to the structure, alpha is located on one side of IL-2, while beta and gamma form a "Y" shape, located on the other side of IL-2 (Xinquan Wang et al, 2005, science, 310(5751): 1159-63.). Thus, in the absence of IL-2, α, β and γ cannot directly form high affinity IL-2 receptor complexes. This also limits the use of antibody preparations and the like against IL-2R α β γ heterotrimers.
Disclosure of Invention
The invention aims to provide an IL-2 receptor complex (IL-2 receptor alpha beta gamma heterotrimer complex) and a preparation method and application thereof.
In order to achieve the object of the present invention, in a first aspect, the present invention provides an IL-2 receptor complex, which is obtained by constructing nucleic acid sequences encoding fusion protein I and fusion protein II into the same eukaryotic expression vector or separately onto different eukaryotic expression vectors, transfecting mammalian cells with the resulting recombinant expression vectors, and separating and purifying from the cell culture supernatant.
Wherein the fusion protein I is formed by connecting an IL-2R beta subunit or a variant thereof and a heterodimerization element 1 through a flexible linker;
the fusion protein II is formed by firstly connecting the IL-2R alpha subunit or the variant thereof with the IL-2R gamma subunit or the variant thereof through a flexible linker and then connecting the IL-2R alpha subunit or the variant thereof with the heterodimerization element 2 through the flexible linker;
optionally, the C-terminus of the fusion protein I, II contains a purification tag (such as an antibody Fc tag or other affinity tag);
wherein the heterodimerization element 1 is Fc-Knob, and the heterodimerization element 2 is Fc-Hole; or,
the heterodimerization element 1 is Fc-Hhole, and the heterodimerization element 2 is Fc-Knob; or,
the heterodimerization element 1 is a leucine zipper with a sequence shown as SEQ ID NO. 5, and the heterodimerization element 2 is a leucine zipper with a sequence shown as SEQ ID NO. 6; or,
the heterodimerization element 1 is a leucine zipper with a sequence shown as SEQ ID NO. 6, and the heterodimerization element 2 is a leucine zipper with a sequence shown as SEQ ID NO. 5.
The flexible linker is (G)nS)mWherein n is an integer between 1 and 6, and m is an integer between 2 and 8.
Preferably, the fusion protein I is formed by a first pass (G) between the IL-2R β subunit or variant thereof and the heterodimerization element 12S)3And connecting to form the product.
Preferably, the fusion protein II is first passed between the IL-2R α subunit or variant thereof and the IL-2R γ subunit or variant thereof (GS)1Is linked to and then passes between the heterodimerization element 2 (G)2S)3And connecting to form the product.
More preferably, the fusion protein I comprises or consists of the amino acid sequence:
i) 1 or 7 as shown in SEQ ID NO; or
ii) an amino acid sequence obtained by connecting a label at the N end and/or the C end of the i); or
iii) protein with same function obtained by substituting, deleting and/or adding one or more amino acids in the amino acid sequence of i) or ii).
More preferably, the fusion protein II comprises or consists of the amino acid sequence:
iv) an amino acid sequence as shown in SEQ ID NO 3 or 9; or
v) an amino acid sequence obtained by connecting a tag to the N terminal and/or the C terminal of iv); or
vi) the amino acid sequence of iv) or v) is substituted, deleted and/or added with one or more amino acids to obtain the protein with the same function.
In a second aspect, the invention provides a nucleic acid molecule encoding said IL-2 receptor complex.
In a third aspect, the present invention provides biological materials containing the above-described nucleic acid molecules, including but not limited to recombinant DNA, expression cassettes, transposons, plasmid vectors, viral vectors, engineered bacteria, or transgenic cell lines.
In a fourth aspect, the present invention provides a method of preparing an IL-2 receptor complex, comprising the steps of:
1) respectively constructing recombinant expression vectors of the fusion protein I and the fusion protein II;
2) co-transfecting the mammalian cells with the two recombinant expression vectors;
3) separating and purifying from cell culture supernatant to obtain IL-2 receptor complex.
In the present invention, the promoter of the recombinant expression vector may be selected from the group consisting of EF-1. alpha. (human electrophoresis factor-1. alpha.) promoter, hCMV (human cytokine virus) promoter, and SV40 (Simian vacuolating virus 40) late promoter.
Preferably, the starting vector of the recombinant expression vector is pcDNA3.1 (+).
In the present invention, the mammalian cell can be selected from Chinese hamster ovary Cells (CHO), mouse plasmacytoma cells (A non-Ig sectioning, non-light-synthesizing subclone of NS-1, NSO), baby hamster kidney cells (BHK), human embryonic kidney293 cells (human embryo Kidney293, HEK 293), and the like, preferably HEK293 cells.
In a specific embodiment of the invention, the constructed fusion protein I recombinant expression vector and the constructed fusion protein II recombinant expression vector are transfected into HEK293 cells according to the mass ratio of 1:1 by using a PEI transfection reagent to perform the recombinant expression of heterotrimers.
The invention designs and prepares stable IL-2 receptor alpha beta gamma heterotrimer protein by using a genetic engineering method. As shown in fig. 1: firstly, designing a beta subunit and a heterodimer element Fc-Knob into a polypeptide chain in series by a genetic engineering method to obtain a fusion protein I, designing an alpha subunit, a gamma subunit and a heterodimer element Fc-Hole into a polypeptide chain in series by a genetic engineering method to obtain a fusion protein II, then co-transfecting HEK293 cells with plasmids containing two fusion proteins, and utilizing the heterodimerization capability of the Fc-Knob and the Fc-Hole to obtain an IL-2 receptor alpha beta gamma heterotrimer compound.
In a fifth aspect, the invention provides the use of said IL-2 receptor complex or an IL-2 receptor complex prepared according to the above method in anti-IL-2R antibody screening (including non-disease diagnostic and therapeutic purposes).
By the technical scheme, the invention at least has the following advantages and beneficial effects:
the invention uses gene engineering technology to directly obtain IL-2 receptor alpha beta gamma heterotrimer protein through recombination expression without in vitro assembly.
And (II) a large amount of heterotrimeric protein with the SDS-PAGE electrophoretic purity of more than 98 percent and the HPLC purity of 90 percent can be obtained in a short time by using the HEK293 eukaryotic expression system, and the heterotrimeric protein has high affinity activity with IL-2.
And (III) the target protein expression and purification process is simple to operate and high in repeatability, and large-scale production and preparation can be realized.
Drawings
FIG. 1 is a schematic representation of the IL-2R α β γ heterotrimeric protein design in a preferred embodiment of the invention.
FIG. 2 is a map of expression vector pcDNA3.1.
FIG. 3 is an SDS-PAGE of IL-2R α β γ heterotrimeric protein in a preferred embodiment of the invention, wherein lane 1 is IL-2R α β γ heterotrimeric protein and lane 2 is protein Marker.
FIG. 4 is a diagram showing the HPLC detection results of IL-2R α β γ heterotrimeric protein in a preferred embodiment of the present invention.
FIG. 5 is a graph showing the results of detection of the binding activity of IL-2R α β γ heterotrimeric protein to interleukin-2 by ELISA in a preferred embodiment of the present invention.
FIG. 6 is a schematic diagram illustrating the principle of SPR technique in the preferred embodiment of the present invention.
FIG. 7A is a graph showing the results of detection of the binding affinity of IL-2R α β γ heterotrimeric complex protein to IL-2 using SPR techniques in a preferred embodiment of the invention.
FIG. 7B is a graph showing the results of detecting the binding affinity of IL-2R β γ to IL-2 using SPR techniques in accordance with a preferred embodiment of the present invention.
FIG. 7C is a graph showing the results of detecting the binding affinity of IL-2R α to IL-2 using SPR techniques in accordance with a preferred embodiment of the present invention.
FIG. 7D is a graph showing the results of detecting the binding affinity of IL-2R β to IL-2 using SPR techniques in accordance with a preferred embodiment of the present invention.
FIG. 7E is a graph showing the results of detecting the binding affinity of IL-2R γ to IL-2 using SPR techniques in accordance with a preferred embodiment of the present invention.
FIG. 8 is a schematic representation of the design of IL-2R α β γ heterotrimeric proteins in a preferred embodiment of the invention.
FIG. 9 is an SDS-PAGE of IL-2R α β γ heterotrimeric protein in a preferred embodiment of the invention, wherein lane 1 is IL-2R α β γ heterotrimeric protein and lane 2 is protein Marker.
FIG. 10 is a diagram showing the HPLC detection results of IL-2R α β γ heterotrimeric protein in a preferred embodiment of the present invention.
FIG. 11 is a graph showing the results of detecting the binding affinity of IL-2R α β γ heterotrimeric complex protein to IL-2 using SPR techniques in a preferred embodiment of the invention.
Detailed Description
The following examples are intended to illustrate the invention but are not intended to limit the scope of the invention. Unless otherwise indicated, the examples follow conventional experimental conditions, such as the Molecular Cloning handbook, Sambrook et al (Sambrook J & Russell DW, Molecular Cloning: a Laboratory Manual, 2001), or the conditions as recommended by the manufacturer's instructions.
EXAMPLE 1 construction of recombinant expression vectors
Construction of the fusion protein I recombinant expression vector pHEK-B1: a polynucleotide (the amino acid sequence of the encoded protein is shown as SEQ ID NO: 2) with the amino acid sequence shown as SEQ ID NO:1 is synthesized by Shanghai bioengineering company Limited, and a restriction enzyme BamH I restriction site and a Kozak sequence are added at the 5' end; the 3' end is added with a stop codon TAA and a restriction site of restriction enzyme XhoI. The synthesized product is subjected to double enzyme digestion by restriction enzymes BamH I and Xho I, then agarose gel electrophoresis is carried out, and the gel is cut to recover the target fragment. The target fragment is respectively connected with pcDNA3.1(+) (Invitrogen company, product number: V790-20) (figure 2) which is also subjected to double enzyme digestion by restriction enzymes BamH I and Xho I to construct a recombinant eukaryotic expression vector pHEK-B1, escherichia coli E.coli DH5 alpha is transformed, a single colony is selected for plasmid extraction after being cultured for 16h at 37 ℃, the extracted plasmid is subjected to double enzyme digestion by the restriction enzymes BamH I and Xho I and then subjected to agarose gel electrophoresis identification, a positive clone is sent to the Hai bioengineering Limited company for sequencing, the clone with correct sequencing is selected for amplified extraction of the plasmid, and the extracted plasmid is subjected to sterile filtration and is stored at-20 ℃ for later use.
Construction of fusion protein II recombinant expression vector pHEK-AG 1: a polynucleotide (the amino acid sequence of the encoded protein is shown as SEQ ID NO: 4) with an amino acid sequence shown as SEQ ID NO:3 is synthesized by Shanghai bioengineering company Limited, and a restriction enzyme BamH I restriction site and a Kozak sequence are added at the 5' end; the 3' end is added with a stop codon TAA and a restriction site of restriction enzyme XhoI. The synthesized product is subjected to double enzyme digestion by restriction enzymes BamH I and Xho I, then agarose gel electrophoresis is carried out, and the gel is cut to recover the target fragment. The target fragment is respectively connected with pcDNA3.1(+) (Invitrogen company, product number: V790-20) (figure 2) which is also subjected to double enzyme digestion by restriction enzymes BamH I and Xho I to construct a recombinant eukaryotic expression vector pHEK-B1, escherichia coli E.coli DH5 alpha is transformed, a single colony is selected for plasmid extraction after being cultured for 16h at 37 ℃, the extracted plasmid is subjected to double enzyme digestion by the restriction enzymes BamH I and Xho I and then subjected to agarose gel electrophoresis identification, a positive clone is sent to the Hai bioengineering Limited company for sequencing, the clone with correct sequencing is selected for amplified extraction of the plasmid, and the extracted plasmid is subjected to sterile filtration and is stored at-20 ℃ for later use.
EXAMPLE 2 transfection of HEK293 cells with recombinant expression vectors and expression of IL-2R α β γ heterotrimeric proteins
The constructed recombinant plasmids pHEK-B1 and pHEK-AG1 were transfected into HEK293 cells at a mass ratio of 1:1 by using PEI transfection reagent, and recombinant expression of heterotrimers was performed. HEK293 cells were plated at 1X 10 on the day before transfection6passage/mL, culture at 37 ℃. The cells were counted on the day of transfection and adjusted to a cell density of 1.8X 106-2.2×106The activity rate is more than 95 percent.
The amounts of the components in the transfection complex were calculated from the cell density: the corresponding relation between the plasmid dose and the number of cells is 1 × 106cells corresponds to 1 ug of plasmid, and the corresponding relation between the PEI dose and the plasmid dose is that the mass of PEI is 3 times of that of DNA.
Preparing a transfection complex according to the calculated component amount: 25ug of 200 ug/mL recombinant plasmid pHEK-B1 and 25ug of 200 ug/mL recombinant plasmid pHEK-AG1 were added to CD 293 TGE medium to 0.5mL (solution A), 150 ug of 1 mg/mL PEI transfection reagent was added to CD 293 TGE medium to 0.5mL (solution B), and after mixing, solution B was slowly added to solution A, and after mixing and standing at room temperature for 10-15 min, the transfection mixture was slowly added to 10 mL HEK293 cells. 37 ℃ and 5% CO2After culturing at 135 rpm for 96 hours, the supernatant was collected. The cell culture medium is CD 293 TGE medium (ACROYosylate)ms corporation, good number: CM-1156-11).
EXAMPLE 3 isolation and purification of IL-2R α β γ heterotrimeric protein
The heterotrimeric recombinant Protein prepared in example 2 was isolated and purified using Protein a affinity chromatography: the cell culture supernatant was collected by centrifugation at 1000g for 30 min at 4 ℃ and after filtration, the supernatant was bound to a Protein A column (St. Tokutaka bioengineering technology, Guangzhou, Ltd., cat # 17543803) equilibrated with a binding buffer (20 mM Tris-HCl, 150mM NaCl, pH 8.0), followed by elution of the target Protein with an elution buffer (100 mM glycine, 150mM NaCl, pH 3.5), followed by collection of a Protein eluate, neutralization with 1/40 volumes of a neutralization buffer (2M Tris-HCl, pH 8.0), and subjected to SDS-PAGE (FIG. 3) and HPLC analysis (FIG. 4). According to the result of SDS-PAGE, the two purified bands are respectively positioned near 66KDa and 116KDa, which accords with the theoretical molecular weight of the protein (I) and the protein (II), and the purity is up to more than 98%. According to HPLC analysis results, the purity of the heterotrimeric compound is as high as more than 90%.
Example 4 detection of the binding Activity of IL-2R α β γ heterotrimeric protein to IL-2
In this example, the binding activity of the IL-2R α β γ heterotrimer complex of the invention to IL-2 was tested by ELISA (enzyme-linked immunosorbent assay).
1. Coating: a96-well plate (Corning, cat # 42592) was coated with 0.1. mu.g/well (1. mu.g/ml, 100. mu.l/well) of IL-2 (Acrobiosystems, cat # IL 2-H4113) overnight (or 16H) at 4 ℃. IL-2 dilution with 15 mM Na coating buffer2CO3,35 mM NaHCO3,7.7 mM NaN3,pH9.6。
2. Washing: wells were washed 4 times with 300. mu.l of washing buffer (TBS, 0.05% Tween-20, pH7.4) per well. Note: thorough removal of the wash buffer is critical. After washing, the remaining solution was removed by suction and complete drying was ensured.
3. And (3) sealing: each well was blocked with 300. mu.l of blocking buffer (TBS, 0.05% Tween-20, 2% BSA, pH 7.4) for 1.5 h at 37 ℃.
4. Washing: and (5) repeating the step (2).
5. Adding a sample: mu.l 0.0976563-100 ng/ml IL-2R α β γ heterotrimer complex prepared in example 3 was added to each well and incubated for 1h at 37 ℃. The samples were diluted beforehand with a dilution buffer (TBS buffer containing 0.05% Tween-20 and 0.5% BSA, pH 7.4).
6. Washing: and (5) repeating the step (2).
7. Adding a detection antibody: mu.l of anti-human IgG antibody (Jackson, cat # 109. sup. 035. sup. quadrature. 098) was added to each well and incubated at 37 ℃ for 1 h. The antibody was diluted beforehand with a dilution buffer (TBS buffer containing 0.05% Tween-20 and 0.5% BSA, pH 7.4) at a ratio of 1: 20000;
8. washing: and (5) repeating the step (2).
9. Adding a substrate: to each well, 200. mu.l of substrate solution was added and incubated at 37 ℃ for 20 min. And (4) avoiding light. Preparing a substrate solution: in 10 ml of substrate solution (50 mM Na)2HPO4·12H2O, 25 mM citric acid, pH 5.5) with 8. mu.l of 3% H2O2And 100. mu.l of 10 mg/ml TMB (BBI Life sciences, cat # A600954).
10. And (3) terminating the reaction: 50. mu.l of 1M sulfuric acid was added to each well.
11. Reading OD value: OD was read at 450 nm and then OD450-ODBlankThe final OD value was obtained. Wherein ODBlankThe corresponding well is the assay result in step 5 with no sample added and only an equal volume of dilution buffer added, and serves as a blank control.
ELISA detection results are shown in FIG. 5, and the EC50 value of the IL-2R alpha beta gamma heterotrimer compound protein combined with IL-2 is 6.68ng/ml, which shows that the IL-2R alpha beta gamma heterotrimer compound protein has good combination activity with IL-2.
Example 5 binding affinity assay of IL-2R α β γ heterotrimeric protein to IL-2
In this example, the binding affinity of IL-2R α β γ heterotrimeric protein of the invention and other subunits of IL-2R to IL-2 was compared using SPR (Surface plasmon resonance) technology. Wherein the other subunits of IL-2R include IL-2R alpha (ACROYOSystems, Cat: ILA-H5251), IL-2R beta (ACROYOSystems, Cat: ILB-H5253), IL-2R gamma (ACROYOSystems, Cat: ILG-H5256), and IL-2R beta gamma (ACROYOSystems, Cat: ILG-H5254). The detection principle is shown in fig. 6:
1. fixing: an anti-Human IgG Fc Antibody, about 9000-14000RU, was immobilized using a CM5 chip (GE, cat # BR 100530) according to the instructions of the Human Antibody Capture Kit (GE, cat # BR-1008-39).
2. And (3) ligand capture: the ligand (IL-2R. alpha. beta.gamma. of the invention or other subunit of IL-2R as described above) was diluted to 10. mu.g/mL with running buffer (10 mM HEPES, 150mM NaCl, 3 mM EDTA, 0.005% Tween-20, pH 7.4) and then injected into the sample channel at a flow rate of 10. mu.l/min to achieve a capture level of about 800RU, with no need for a ligand capture step in the reference channel.
3. Combining: the analyte IL-2 protein (Acrobiosystems, cat # IL 2-H4113) was diluted to 9 concentrations (200, 100, 50, 25, 12.5, 6.25, 3.13, 1.56 and 0 nM) with the same running buffer (10 mM HEPES, 150mM NaCl, 3 mM EDTA, 0.005% Tween-20, pH 7.4). The IL-2 protein was set to inject into the reference and sample channels at a flow rate of 30. mu.l/min for a binding phase of 60 s or 120 s, and then dissociated for 90 s or 200 s. The binding and dissociation processes were all performed in running buffer. According to the analyte IL-2 concentration in ascending order repeat 8 cycles. The sensor chip surface should be completely regenerated using 3M magnesium chloride after each cycle according to the Human Antibody Capture Kit (GE Co., Ltd., cat # BR-1008-39) instructions.
4. Chip regeneration: the CM5 chip was regenerated according to the instructions of the Human Antibody Capture Kit (GE Co., Ltd., cat # BR-1008-39) by injecting 3M magnesium chloride at a flow rate of 20. mu.L/min into running buffer (10 mM HEPES, 150mM NaCl, 3 mM EDTA, 0.005% Tween-20, pH 7.4) for 30 seconds.
The results of the binding affinity of the IL-2R α β γ of the invention or other subunits of the IL-2R described above to IL-2 are shown in FIG. 7.
According to SPR detection results, the binding affinity of the IL-2R alpha beta gamma heterotrimeric complex protein and IL-2 is 0.041 nM (FIG. 7A), the binding affinity of IL-2R beta gamma, IL-2R alpha and IL-2R beta and IL-2 is 0.123 nM (FIG. 7B), 10.1 nM (FIG. 7C) and 337 nM (FIG. 7D), respectively, and the binding affinity of IL-2R gamma and IL-2 is less than 5RU, the linearity is poor, and almost no binding can be considered under the same conditions (FIG. 7E).
The above results indicate that the IL-2R α β γ protein of the present invention is a stable IL-2 heterotrimeric receptor protein, and that the IL-2R α β γ protein has the highest binding affinity for IL-2 compared to other subunits of IL-2R.
Example 6 preparation of IL-2R α β γ heterotrimeric proteins
In this example, heterodimeric element 1 is leucine zipper 1 (SEQ ID NO: 5) and heterodimeric element 2 is leucine zipper 2 (SEQ ID NO: 6). Wherein, leucine zipper 1 and isoleucine zipper 2 are used in pair. The IL-2R beta subunit or the variant thereof is connected with the leucine zipper 1 or the leucine zipper 2 through a flexible linker, and an antibody Fc tag or other affinity tags are added at the C terminal for protein purification; the IL-2R alpha subunit or the variant thereof is connected with the IL-2R gamma subunit or the variant thereof through a flexible linker, and then is connected with the leucine zipper 2 or the leucine zipper 1 through the flexible linker, and an antibody Fc tag or other tags are added at the C terminal for protein purification. This example selects an antibody Fc-tag.
The specific methods of recombinant expression vector construction, cell transfection, expression purification and binding affinity detection were the same as in examples 1, 2, 3 and 5, except that the protein sequence was different.
In this example, the protein sequences used were SEQ ID NO:7 (the corresponding nucleotide sequence was SEQ ID NO: 8) and SEQ ID NO:9 (the corresponding nucleotide sequence was SEQ ID NO: 10), plasmid constructions (pHEK-B2 and pHEK-AG 2) were respectively performed, and then expression purification of the protein was performed.
According to the SDS-PAGE result, the two bands of the IL-2R alpha beta gamma heterotrimeric protein obtained in the embodiment are respectively positioned near 68KDa and 120KDa, and accord with the theoretical molecular weight of the protein (I) and the theoretical molecular weight of the protein (II), and the purity is as high as more than 98%. According to HPLC analysis, the heterotrimeric complex was over 90% pure with a binding affinity of 0.024 nM to IL-2, similar to the heterotrimeric protein results prepared in example 3.
FIG. 8 is a schematic representation of the IL-2R α β γ heterotrimeric protein design in this example.
FIG. 9 is an SDS-PAGE of the IL-2R α β γ heterotrimeric protein of this example, wherein lane 1 is the IL-2R α β γ heterotrimeric protein and lane 2 is the protein Marker.
FIG. 10 is a graph showing the HPLC detection results of IL-2R α β γ heterotrimeric protein in this example.
FIG. 11 is a graph showing the results of the detection of the binding affinity of IL-2R α β γ heterotrimeric complex protein to IL-2 using SPR technique in this example.
Although the invention has been described in detail hereinabove with respect to a general description and specific embodiments thereof, it will be apparent to those skilled in the art that modifications or improvements may be made thereto based on the invention. Accordingly, such modifications and improvements are intended to be within the scope of the invention as claimed.
Sequence listing
<110> Beijing Baipusais Biotechnology Ltd
<120> IL-2 receptor complex, preparation method and application thereof
<130> KHP211110815.0YS
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Met Ala Ala Pro Ala Leu Ser Trp Arg Leu Pro Leu Leu Ile Leu Leu
1 5 10 15
Leu Pro Leu Ala Thr Ser Trp Ala Ser Ala Ala Val Asn Gly Thr Ser
20 25 30
Gln Phe Thr Cys Phe Tyr Asn Ser Arg Ala Asn Ile Ser Cys Val Trp
35 40 45
Ser Gln Asp Gly Ala Leu Gln Asp Thr Ser Cys Gln Val His Ala Trp
50 55 60
Pro Asp Arg Arg Arg Trp Asn Gln Thr Cys Glu Leu Leu Pro Val Ser
65 70 75 80
Gln Ala Ser Trp Ala Cys Asn Leu Ile Leu Gly Ala Pro Asp Ser Gln
85 90 95
Lys Leu Thr Thr Val Asp Ile Val Thr Leu Arg Val Leu Cys Arg Glu
100 105 110
Gly Val Arg Trp Arg Val Met Ala Ile Gln Asp Phe Lys Pro Phe Glu
115 120 125
Asn Leu Arg Leu Met Ala Pro Ile Ser Leu Gln Val Val His Val Glu
130 135 140
Thr His Arg Cys Asn Ile Ser Trp Glu Ile Ser Gln Ala Ser His Tyr
145 150 155 160
Phe Glu Arg His Leu Glu Phe Glu Ala Arg Thr Leu Ser Pro Gly His
165 170 175
Thr Trp Glu Glu Ala Pro Leu Leu Thr Leu Lys Gln Lys Gln Glu Trp
180 185 190
Ile Cys Leu Glu Thr Leu Thr Pro Asp Thr Gln Tyr Glu Phe Gln Val
195 200 205
Arg Val Lys Pro Leu Gln Gly Glu Phe Thr Thr Trp Ser Pro Trp Ser
210 215 220
Gln Pro Leu Ala Phe Arg Thr Lys Pro Ala Ala Leu Gly Lys Asp Gly
225 230 235 240
Gly Ser Gly Gly Ser Gly Gly Ser Pro Lys Ser Ser Asp Lys Thr His
245 250 255
Thr Ser Pro Pro Ser Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val
260 265 270
Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr
275 280 285
Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu
290 295 300
Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys
305 310 315 320
Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser
325 330 335
Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys
340 345 350
Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile
355 360 365
Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro
370 375 380
Pro Cys Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Trp Cys Leu
385 390 395 400
Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn
405 410 415
Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser
420 425 430
Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg
435 440 445
Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu
450 455 460
His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
465 470 475
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accagttggg ccagtgcagc agtgaacggc acaagccagt tcacctgttt ctacaacagt 120
agggcaaata tctcttgcgt atggtctcag gatggcgctc tgcaggatac ttcctgccag 180
gtgcacgcat ggccagaccg aaggagatgg aaccagacct gcgagttgct tcccgtttca 240
caagctagtt gggcttgtaa tctgatcctg ggggctcctg actcacaaaa actcaccaca 300
gttgatatcg taactctgag ggtcttgtgt agggagggag tgcgctggcg agtgatggct 360
atccaagact tcaagccatt cgaaaatctg cgcctgatgg cgccaatttc tctccaggtg 420
gtgcatgtag aaacccaccg gtgcaacatt tcctgggaga tctcccaggc aagccactat 480
tttgaaagac atcttgagtt tgaagctcga acgctgagtc cagggcacac ctgggaagag 540
gcaccacttc tgaccctgaa gcagaaacaa gagtggattt gtctggagac tttgacccca 600
gacactcagt acgagtttca ggtacgggtc aaaccccttc agggagagtt cactacatgg 660
agcccctgga gtcagcccct tgcctttcgc actaaacctg cagcgctggg gaaggatggc 720
ggatcaggag gaagcggagg aagtcctaaa tcctctgata agactcacac tagcccgcca 780
tctccagctc ctgaacttct gggcggacca agcgtatttc tgttcccccc aaaacctaag 840
gatactctga tgattagccg gactccagaa gtaacctgcg tcgtggtcga cgtgagccac 900
gaggaccctg aggttaaatt caattggtac gtcgatggcg tcgaagtcca taatgctaaa 960
acaaagccca gagaggaaca gtataattct acctatcggg ttgtatctgt cttgaccgta 1020
ctccatcagg actggctcaa tggaaaggag tataagtgca aggttagcaa caaggctctg 1080
cccgccccca ttgagaaaac catttccaag gccaagggac agcctaggga gccccaggta 1140
tatacactgc caccctgcag ggacgaattg accaagaacc aggtcagtct gtggtgcctg 1200
gtgaagggat tttaccccag cgatatagcc gttgaatggg agtcaaatgg ccagccggaa 1260
aataactata aaaccacccc tcccgttttg gactccgacg ggagcttctt cctttatagc 1320
aaactgactg tggacaaaag tcggtggcag cagggcaacg tgtttagctg ttccgtaatg 1380
cacgaagcat tgcacaatca ctacacccag aagtctctga gcttgagccc cggtaaa 1437
<210> 3
<211> 686
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<400> 3
Met Asp Ser Tyr Leu Leu Met Trp Gly Leu Leu Thr Phe Ile Met Val
1 5 10 15
Pro Gly Cys Gln Ala Glu Leu Cys Asp Asp Asp Pro Pro Glu Ile Pro
20 25 30
His Ala Thr Phe Lys Ala Met Ala Tyr Lys Glu Gly Thr Met Leu Asn
35 40 45
Cys Glu Cys Lys Arg Gly Phe Arg Arg Ile Lys Ser Gly Ser Leu Tyr
50 55 60
Met Leu Cys Thr Gly Asn Ser Ser His Ser Ser Trp Asp Asn Gln Cys
65 70 75 80
Gln Cys Thr Ser Ser Ala Thr Arg Asn Thr Thr Lys Gln Val Thr Pro
85 90 95
Gln Pro Glu Glu Gln Lys Glu Arg Lys Thr Thr Glu Met Gln Ser Pro
100 105 110
Met Gln Pro Val Asp Gln Ala Ser Leu Pro Gly His Cys Arg Glu Pro
115 120 125
Pro Pro Trp Glu Asn Glu Ala Thr Glu Arg Ile Tyr His Phe Val Val
130 135 140
Gly Gln Met Val Tyr Tyr Gln Cys Val Gln Gly Tyr Arg Ala Leu His
145 150 155 160
Arg Gly Pro Ala Glu Ser Val Cys Lys Met Thr His Gly Lys Thr Arg
165 170 175
Trp Thr Gln Pro Gln Leu Ile Cys Thr Gly Glu Met Glu Thr Ser Gln
180 185 190
Phe Pro Gly Glu Glu Lys Pro Gln Ala Ser Pro Glu Gly Arg Pro Glu
195 200 205
Ser Glu Thr Ser Gly Ser Leu Asn Thr Thr Ile Leu Thr Pro Asn Gly
210 215 220
Asn Glu Asp Thr Thr Ala Asp Phe Phe Leu Thr Thr Met Pro Thr Asp
225 230 235 240
Ser Leu Ser Val Ser Thr Leu Pro Leu Pro Glu Val Gln Cys Phe Val
245 250 255
Phe Asn Val Glu Tyr Met Asn Cys Thr Trp Asn Ser Ser Ser Glu Pro
260 265 270
Gln Pro Thr Asn Leu Thr Leu His Tyr Trp Tyr Lys Asn Ser Asp Asn
275 280 285
Asp Lys Val Gln Lys Cys Ser His Tyr Leu Phe Ser Glu Glu Ile Thr
290 295 300
Ser Gly Cys Gln Leu Gln Lys Lys Glu Ile His Leu Tyr Gln Thr Phe
305 310 315 320
Val Val Gln Leu Gln Asp Pro Arg Glu Pro Arg Arg Gln Ala Thr Gln
325 330 335
Met Leu Lys Leu Gln Asn Leu Val Ile Pro Trp Ala Pro Glu Asn Leu
340 345 350
Thr Leu His Lys Leu Ser Glu Ser Gln Leu Glu Leu Asn Trp Asn Asn
355 360 365
Arg Phe Leu Asn His Cys Leu Glu His Leu Val Gln Tyr Arg Thr Asp
370 375 380
Trp Asp His Ser Trp Thr Glu Gln Ser Val Asp Tyr Arg His Lys Phe
385 390 395 400
Ser Leu Pro Ser Val Asp Gly Gln Lys Arg Tyr Thr Phe Arg Val Arg
405 410 415
Ser Arg Phe Asn Pro Leu Cys Gly Ser Ala Gln His Trp Ser Glu Trp
420 425 430
Ser His Pro Ile His Trp Gly Ser Asn Thr Ser Lys Glu Asn Gly Gly
435 440 445
Ser Gly Gly Ser Gly Gly Ser Pro Lys Ser Ser Asp Lys Thr His Thr
450 455 460
Ser Pro Pro Ser Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe
465 470 475 480
Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro
485 490 495
Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val
500 505 510
Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr
515 520 525
Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val
530 535 540
Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys
545 550 555 560
Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser
565 570 575
Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Cys Thr Leu Pro Pro
580 585 590
Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Ser Cys Ala Val
595 600 605
Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly
610 615 620
Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp
625 630 635 640
Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val Asp Lys Ser Arg Trp
645 650 655
Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His
660 665 670
Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
675 680 685
<210> 4
<211> 2058
<212> DNA
<213> Artificial Sequence (Artificial Sequence)
<400> 4
atggacagct acttgctgat gtggggcctc ttgaccttca ttatggtacc cggatgtcag 60
gcagagctgt gtgacgatga cccaccagag atcccgcacg ccacattcaa agccatggcc 120
tataaagaag ggaccatgtt gaattgcgag tgtaagagag ggtttcggag aataaaaagt 180
ggaagcttgt acatgctgtg cactggcaac agctctcata gttcctggga taaccagtgt 240
cagtgcacga gtagcgctac cagaaacacg actaaacagg tgacacccca gcctgaggaa 300
cagaaggagc gcaagaccac ggaaatgcag agccccatgc agcctgtaga ccaggcctca 360
cttcctggac actgtaggga gcctcctcct tgggaaaacg aggctaccga gagaatctac 420
cactttgttg ttggccagat ggtgtactac cagtgcgtcc agggatacag agccttgcac 480
agagggcctg ccgaatccgt ttgtaagatg actcacggca agacgagatg gacccagcca 540
cagctgatct gcactggcga gatggagacc tcccagtttc cgggagagga aaaaccacag 600
gcctctcctg agggtcggcc tgaatccgaa acgtccggct cactcaatac cactatactg 660
actcctaacg gaaacgagga cactactgcc gattttttcc tgaccacaat gccaacagat 720
tctctctcag tgtctactct ccccctcccc gaggtgcagt gctttgtatt taacgtggaa 780
tacatgaatt gcacatggaa cagctcttcc gaaccccaac ctaccaacct gacattgcac 840
tactggtaca agaactccga caacgacaaa gtccagaagt gctcccatta cctctttagc 900
gaagaaatca cgtctggttg tcagctgcag aaaaaggaga tccatctgta tcagaccttc 960
gtggtccaac tccaggaccc aagagagcca agacgccagg ccacacaaat gctgaaattg 1020
cagaatctcg tgattccatg ggccccagaa aacctgaccc tccataagtt gagcgagagt 1080
cagctggagc ttaactggaa caaccggttt ctgaaccact gcttggagca cctcgtgcaa 1140
tacaggacag attgggacca cagttggaca gagcagagcg ttgattaccg gcacaagttt 1200
agccttccga gcgtggacgg gcagaagaga tatacattcc gcgtgcgctc cagattcaac 1260
ccattgtgcg ggagcgccca acattggtcc gagtggtccc accccattca ctggggcagc 1320
aacacatcta aagaaaatgg gggaagcgga ggttcaggag gatctcccaa aagtagcgat 1380
aaaactcata cttccccccc aagtcctgct cctgagctgc tcggaggacc ctctgtattc 1440
ctgtttccac caaagccgaa agacaccctg atgattagta gaacacccga ggtgacctgc 1500
gtggtcgtgg atgtgtcaca tgaagacccg gaggtgaaat tcaactggta tgtagacggg 1560
gtcgaagtac ataacgctaa aaccaagccg cgcgaggaac agtataatag cacgtatcgc 1620
gtggttagcg ttctgactgt actccatcag gattggctga atggaaagga atataagtgc 1680
aaggtgtcta ataaggctct gcccgctcca atcgagaaga ccatcagcaa agccaagggt 1740
caacccagag agccccaggt atgcactctg ccaccaagtc gagatgagct cactaagaac 1800
caggtttcac tgtcctgcgc cgtgaagggc ttttatccct ctgacatcgc cgttgagtgg 1860
gaatccaatg gacaacccga gaacaattat aagacgaccc cccctgtcct ggacagcgat 1920
ggttccttct ttctcgtttc caaactgacc gtggacaagt caagatggca gcagggaaac 1980
gtattctcat gcagtgtgat gcatgaagcc ttgcacaacc actacaccca gaagagtctg 2040
agcctttccc caggcaag 2058
<210> 5
<211> 40
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<400> 5
Leu Thr Asp Thr Leu Gln Ala Glu Thr Asp Gln Leu Glu Asp Glu Lys
1 5 10 15
Ser Ala Leu Gln Thr Glu Ile Ala Asn Leu Leu Lys Glu Lys Glu Lys
20 25 30
Leu Glu Phe Ile Leu Ala Ala His
35 40
<210> 6
<211> 40
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<400> 6
Arg Ile Ala Arg Leu Glu Glu Lys Val Lys Thr Leu Lys Ala Gln Asn
1 5 10 15
Ser Glu Leu Ala Ser Thr Ala Asn Met Leu Arg Glu Gln Val Ala Gln
20 25 30
Leu Lys Gln Lys Val Met Asn His
35 40
<210> 7
<211> 519
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<400> 7
Met Ala Ala Pro Ala Leu Ser Trp Arg Leu Pro Leu Leu Ile Leu Leu
1 5 10 15
Leu Pro Leu Ala Thr Ser Trp Ala Ser Ala Ala Val Asn Gly Thr Ser
20 25 30
Gln Phe Thr Cys Phe Tyr Asn Ser Arg Ala Asn Ile Ser Cys Val Trp
35 40 45
Ser Gln Asp Gly Ala Leu Gln Asp Thr Ser Cys Gln Val His Ala Trp
50 55 60
Pro Asp Arg Arg Arg Trp Asn Gln Thr Cys Glu Leu Leu Pro Val Ser
65 70 75 80
Gln Ala Ser Trp Ala Cys Asn Leu Ile Leu Gly Ala Pro Asp Ser Gln
85 90 95
Lys Leu Thr Thr Val Asp Ile Val Thr Leu Arg Val Leu Cys Arg Glu
100 105 110
Gly Val Arg Trp Arg Val Met Ala Ile Gln Asp Phe Lys Pro Phe Glu
115 120 125
Asn Leu Arg Leu Met Ala Pro Ile Ser Leu Gln Val Val His Val Glu
130 135 140
Thr His Arg Cys Asn Ile Ser Trp Glu Ile Ser Gln Ala Ser His Tyr
145 150 155 160
Phe Glu Arg His Leu Glu Phe Glu Ala Arg Thr Leu Ser Pro Gly His
165 170 175
Thr Trp Glu Glu Ala Pro Leu Leu Thr Leu Lys Gln Lys Gln Glu Trp
180 185 190
Ile Cys Leu Glu Thr Leu Thr Pro Asp Thr Gln Tyr Glu Phe Gln Val
195 200 205
Arg Val Lys Pro Leu Gln Gly Glu Phe Thr Thr Trp Ser Pro Trp Ser
210 215 220
Gln Pro Leu Ala Phe Arg Thr Lys Pro Ala Ala Leu Gly Lys Asp Gly
225 230 235 240
Gly Ser Gly Gly Ser Gly Gly Ser Leu Thr Asp Thr Leu Gln Ala Glu
245 250 255
Thr Asp Gln Leu Glu Asp Glu Lys Ser Ala Leu Gln Thr Glu Ile Ala
260 265 270
Asn Leu Leu Lys Glu Lys Glu Lys Leu Glu Phe Ile Leu Ala Ala His
275 280 285
Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro
290 295 300
Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
305 310 315 320
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
325 330 335
Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp
340 345 350
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr
355 360 365
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
370 375 380
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu
385 390 395 400
Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
405 410 415
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys
420 425 430
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
435 440 445
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
450 455 460
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
465 470 475 480
Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser
485 490 495
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
500 505 510
Leu Ser Leu Ser Pro Gly Lys
515
<210> 8
<211> 1537
<212> DNA
<213> Artificial Sequence (Artificial Sequence)
<400> 8
atggctgcac ctgcattgtc ttggagactg cccctgctga tattgctgct cccactggct 60
accagttggg ccagtgcagc agtgaacggc acaagccagt tcacctgttt ctacaacagt 120
agggcaaata tctcttgcgt atggtctcag gatggcgctc tgcaggatac ttcctgccag 180
gtgcacgcat ggccagaccg aaggagatgg aaccagacct gcgagttgct tcccgtttca 240
caagctagtt gggcttgtaa tctgatcctg ggggctcctg actcacaaaa actcaccaca 300
gttgatatcg taactctgag ggtcttgtgt agggagggag tgcgctggcg agtgatggct 360
atccaagact tcaagccatt cgaaaatctg cgcctgatgg cgccaatttc tctccaggtg 420
gtgcatgtag aaacccaccg gtgcaacatt tcctgggaga tctcccaggc aagccactat 480
tttgaaagac atcttgagtt tgaagctcga acgctgagtc cagggcacac ctgggaagag 540
gcaccacttc tgaccctgaa gcagaaacaa gagtggattt gtctggagac tttgacccca 600
gacactcagt acgagtttca ggtacgggtc aaaccccttc agggagagtt cactacatgg 660
agcccctgga gtcagcccct tgcctttcgc actaaacctg cagcgctggg gaaggatggc 720
ggatctgact gataccctgc aggcagaaac agatcagctg gaggatgaga aatctgccct 780
gcagacagaa attgccaacc ttttgaaaga gaaggagaaa cttgaattta tcctggctgc 840
tcaccctaag agctctgaca agacacatac ttgtccccct tgtcctgccc ctgagctgct 900
gggtgggccc tcagtattcc tctttccacc taaacctaaa gacacactta tgatttccag 960
gaccccagaa gtcacatgtg tagtggttga cgtgtcacac gaggatccag aggtgaagtt 1020
caactggtac gtggatggag tggaagttca taatgccaag actaagcccc gggaggagca 1080
gtataactcc acctatcggg tggtatcagt gctcacagtg cttcatcagg actggctcaa 1140
tgggaaggaa tataagtgca aggtgtcaaa caaagcgctg ccagccccaa tcgagaagac 1200
aattagtaag gccaagggtc agcccaggga gcctcaggtg tataccctcc cccctagccg 1260
cgatgagctg actaaaaatc aggtaagcct tacctgcctt gtcaaaggat tttaccctag 1320
tgacatcgcc gtggagtggg aatccaatgg gcagccggaa aacaattaca aaactactcc 1380
acccgtgctg gacagcgacg ggtctttttt tctttacagt aaactgaccg tcgacaaatc 1440
tcgatggcag caaggcaatg tgttcagctg ctcagtgatg cacgaagccc tccacaacca 1500
ctatacccag aaatcattga gtttgagtcc cggaaag 1537
<210> 9
<211> 726
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<400> 9
Met Asp Ser Tyr Leu Leu Met Trp Gly Leu Leu Thr Phe Ile Met Val
1 5 10 15
Pro Gly Cys Gln Ala Glu Leu Cys Asp Asp Asp Pro Pro Glu Ile Pro
20 25 30
His Ala Thr Phe Lys Ala Met Ala Tyr Lys Glu Gly Thr Met Leu Asn
35 40 45
Cys Glu Cys Lys Arg Gly Phe Arg Arg Ile Lys Ser Gly Ser Leu Tyr
50 55 60
Met Leu Cys Thr Gly Asn Ser Ser His Ser Ser Trp Asp Asn Gln Cys
65 70 75 80
Gln Cys Thr Ser Ser Ala Thr Arg Asn Thr Thr Lys Gln Val Thr Pro
85 90 95
Gln Pro Glu Glu Gln Lys Glu Arg Lys Thr Thr Glu Met Gln Ser Pro
100 105 110
Met Gln Pro Val Asp Gln Ala Ser Leu Pro Gly His Cys Arg Glu Pro
115 120 125
Pro Pro Trp Glu Asn Glu Ala Thr Glu Arg Ile Tyr His Phe Val Val
130 135 140
Gly Gln Met Val Tyr Tyr Gln Cys Val Gln Gly Tyr Arg Ala Leu His
145 150 155 160
Arg Gly Pro Ala Glu Ser Val Cys Lys Met Thr His Gly Lys Thr Arg
165 170 175
Trp Thr Gln Pro Gln Leu Ile Cys Thr Gly Glu Met Glu Thr Ser Gln
180 185 190
Phe Pro Gly Glu Glu Lys Pro Gln Ala Ser Pro Glu Gly Arg Pro Glu
195 200 205
Ser Glu Thr Ser Gly Ser Leu Asn Thr Thr Ile Leu Thr Pro Asn Gly
210 215 220
Asn Glu Asp Thr Thr Ala Asp Phe Phe Leu Thr Thr Met Pro Thr Asp
225 230 235 240
Ser Leu Ser Val Ser Thr Leu Pro Leu Pro Glu Val Gln Cys Phe Val
245 250 255
Phe Asn Val Glu Tyr Met Asn Cys Thr Trp Asn Ser Ser Ser Glu Pro
260 265 270
Gln Pro Thr Asn Leu Thr Leu His Tyr Trp Tyr Lys Asn Ser Asp Asn
275 280 285
Asp Lys Val Gln Lys Cys Ser His Tyr Leu Phe Ser Glu Glu Ile Thr
290 295 300
Ser Gly Cys Gln Leu Gln Lys Lys Glu Ile His Leu Tyr Gln Thr Phe
305 310 315 320
Val Val Gln Leu Gln Asp Pro Arg Glu Pro Arg Arg Gln Ala Thr Gln
325 330 335
Met Leu Lys Leu Gln Asn Leu Val Ile Pro Trp Ala Pro Glu Asn Leu
340 345 350
Thr Leu His Lys Leu Ser Glu Ser Gln Leu Glu Leu Asn Trp Asn Asn
355 360 365
Arg Phe Leu Asn His Cys Leu Glu His Leu Val Gln Tyr Arg Thr Asp
370 375 380
Trp Asp His Ser Trp Thr Glu Gln Ser Val Asp Tyr Arg His Lys Phe
385 390 395 400
Ser Leu Pro Ser Val Asp Gly Gln Lys Arg Tyr Thr Phe Arg Val Arg
405 410 415
Ser Arg Phe Asn Pro Leu Cys Gly Ser Ala Gln His Trp Ser Glu Trp
420 425 430
Ser His Pro Ile His Trp Gly Ser Asn Thr Ser Lys Glu Asn Gly Gly
435 440 445
Ser Gly Gly Ser Gly Gly Ser Arg Ile Ala Arg Leu Glu Glu Lys Val
450 455 460
Lys Thr Leu Lys Ala Gln Asn Ser Glu Leu Ala Ser Thr Ala Asn Met
465 470 475 480
Leu Arg Glu Gln Val Ala Gln Leu Lys Gln Lys Val Met Asn His Pro
485 490 495
Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu
500 505 510
Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp
515 520 525
Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp
530 535 540
Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly
545 550 555 560
Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn
565 570 575
Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp
580 585 590
Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro
595 600 605
Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu
610 615 620
Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn
625 630 635 640
Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile
645 650 655
Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr
660 665 670
Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys
675 680 685
Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys
690 695 700
Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu
705 710 715 720
Ser Leu Ser Pro Gly Lys
725
<210> 10
<211> 2178
<212> DNA
<213> Artificial Sequence (Artificial Sequence)
<400> 10
atggacagct acttgctgat gtggggcctc ttgaccttca ttatggtacc cggatgtcag 60
gcagagctgt gtgacgatga cccaccagag atcccgcacg ccacattcaa agccatggcc 120
tataaagaag ggaccatgtt gaattgcgag tgtaagagag ggtttcggag aataaaaagt 180
ggaagcttgt acatgctgtg cactggcaac agctctcata gttcctggga taaccagtgt 240
cagtgcacga gtagcgctac cagaaacacg actaaacagg tgacacccca gcctgaggaa 300
cagaaggagc gcaagaccac ggaaatgcag agccccatgc agcctgtaga ccaggcctca 360
cttcctggac actgtaggga gcctcctcct tgggaaaacg aggctaccga gagaatctac 420
cactttgttg ttggccagat ggtgtactac cagtgcgtcc agggatacag agccttgcac 480
agagggcctg ccgaatccgt ttgtaagatg actcacggca agacgagatg gacccagcca 540
cagctgatct gcactggcga gatggagacc tcccagtttc cgggagagga aaaaccacag 600
gcctctcctg agggtcggcc tgaatccgaa acgtccggct cactcaatac cactatactg 660
actcctaacg gaaacgagga cactactgcc gattttttcc tgaccacaat gccaacagat 720
tctctctcag tgtctactct ccccctcccc gaggtgcagt gctttgtatt taacgtggaa 780
tacatgaatt gcacatggaa cagctcttcc gaaccccaac ctaccaacct gacattgcac 840
tactggtaca agaactccga caacgacaaa gtccagaagt gctcccatta cctctttagc 900
gaagaaatca cgtctggttg tcagctgcag aaaaaggaga tccatctgta tcagaccttc 960
gtggtccaac tccaggaccc aagagagcca agacgccagg ccacacaaat gctgaaattg 1020
cagaatctcg tgattccatg ggccccagaa aacctgaccc tccataagtt gagcgagagt 1080
cagctggagc ttaactggaa caaccggttt ctgaaccact gcttggagca cctcgtgcaa 1140
tacaggacag attgggacca cagttggaca gagcagagcg ttgattaccg gcacaagttt 1200
agccttccga gcgtggacgg gcagaagaga tatacattcc gcgtgcgctc cagattcaac 1260
ccattgtgcg ggagcgccca acattggtcc gagtggtccc accccattca ctggggcagc 1320
aacacatcta aagaaaatgg gggaagcgga ggttcaggag gatctaggat cgctaggctg 1380
gaggaaaagg tgaagaccct gaaagcacag aatagtgaac tcgcctctac agcgaacatg 1440
ctgcgcgaac aggtggccca gctcaagcag aaggtgatga atcaccctaa gagctctgac 1500
aagacacata cttgtccccc ttgtcctgcc cctgagctgc tgggtgggcc ctcagtattc 1560
ctctttccac ctaaacctaa agacacactt atgatttcca ggaccccaga agtcacatgt 1620
gtagtggttg acgtgtcaca cgaggatcca gaggtgaagt tcaactggta cgtggatgga 1680
gtggaagttc ataatgccaa gactaagccc cgggaggagc agtataactc cacctatcgg 1740
gtggtatcag tgctcacagt gcttcatcag gactggctca atgggaagga atataagtgc 1800
aaggtgtcaa acaaagcgct gccagcccca atcgagaaga caattagtaa ggccaagggt 1860
cagcccaggg agcctcaggt gtataccctc ccccctagcc gcgatgagct gactaaaaat 1920
caggtaagcc ttacctgcct tgtcaaagga ttttacccta gtgacatcgc cgtggagtgg 1980
gaatccaatg ggcagccgga aaacaattac aaaactactc cacccgtgct ggacagcgac 2040
gggtcttttt ttctttacag taaactgacc gtcgacaaat ctcgatggca gcaaggcaat 2100
gtgttcagct gctcagtgat gcacgaagcc ctccacaacc actataccca gaaatcattg 2160
agtttgagtc ccggaaag 2178
Claims (10)
- An IL-2 receptor complex, characterized in that it is obtained by constructing nucleic acid sequences encoding fusion protein I and fusion protein II on the same eukaryotic expression vector or on different eukaryotic expression vectors, transfecting mammalian cells with the obtained recombinant expression vector, and separating and purifying from the cell culture supernatant;the fusion protein I is formed by connecting an IL-2R beta subunit or a variant thereof and a heterodimerization element 1 through a flexible linker;the fusion protein II is formed by firstly connecting the IL-2R alpha subunit or the variant thereof with the IL-2R gamma subunit or the variant thereof through a flexible linker and then connecting the IL-2R alpha subunit or the variant thereof with the heterodimerization element 2 through the flexible linker;wherein the C ends of the fusion protein I and the fusion protein II contain purification labels;the heterodimerization element 1 is Fc-Knob, and the heterodimerization element 2 is Fc-Hole; or,the heterodimerization element 1 is Fc-Hole, and the heterodimerization element 2 is Fc-Knob; or,the heterodimerization element 1 is a leucine zipper with a sequence shown as SEQ ID NO. 5, and the heterodimerization element 2 is a leucine zipper with a sequence shown as SEQ ID NO. 6; or,the heterodimerization element 1 is a leucine zipper with a sequence shown as SEQ ID NO. 6, and the heterodimerization element 2 is a leucine zipper with a sequence shown as SEQ ID NO. 5.
- 2. The IL-2 receptor complex of claim 1, wherein the flexible linker is (G)nS)mWherein n is an integer between 1 and 6, and m is an integer between 2 and 8.
- 3. The IL-2 receptor complex according to claim 2, wherein the fusion protein I is formed by the passage between the IL-2R β subunit or variant thereof and the heterodimerization element 1 (G)2S)3Are connected to form the product; and/orThe fusion protein II is prepared by first passing (GS) the IL-2R alpha subunit or the variant thereof and the IL-2R gamma subunit or the variant thereof1Is linked to and then passes between the heterodimerization element 2 (G)2S)3And connecting to form the product.
- 4. The IL-2 receptor complex according to claim 1, wherein the fusion protein I comprises or consists of the amino acid sequence:i) 1 or 7 as shown in SEQ ID NO; orii) an amino acid sequence obtained by connecting a label at the N end and/or the C end of the i); oriii) proteins with the same function obtained by substituting, deleting and/or adding one or more amino acids in the amino acid sequences of i) or ii); and/orThe fusion protein II comprises or consists of the amino acid sequence as follows:iv) an amino acid sequence as shown in SEQ ID NO 3 or 9; orv) an amino acid sequence obtained by connecting a tag to the N terminal and/or the C terminal of iv); orvi) the amino acid sequence of iv) or v) is substituted, deleted and/or added with one or more amino acids to obtain the protein with the same function.
- 5. A nucleic acid molecule encoding the IL-2 receptor complex according to any one of claims 1 to 4.
- 6. A biological material comprising a nucleic acid molecule according to claim 5, wherein the biological material is a recombinant DNA, an expression cassette, a transposon, a plasmid vector, a viral vector, an engineered bacterium or a transgenic cell line.
- A method of preparing an IL-2 receptor complex, comprising the steps of:1) respectively constructing recombinant expression vectors of the fusion protein I and the fusion protein II;2) co-transfecting the mammalian cells with the two recombinant expression vectors;3) separating and purifying from cell culture supernatant to obtain IL-2 receptor compound;wherein the fusion protein I and the fusion protein II are the same as the fusion protein I and the fusion protein II in the IL-2 receptor complex according to any one of claims 1 to 4.
- 8. The method according to claim 7, wherein the promoter of the recombinant expression vector is selected from the group consisting of EF-1 alpha promoter, hCMV promoter, SV40 late promoter; and/orThe starting vector of the recombinant expression vector is pcDNA3.1 (+).
- 9. The method according to claim 7 or 8, wherein the mammalian cell is selected from the group consisting of HEK293, CHO, NSO, BHK.
- 10. Use of the IL-2 receptor complex according to any one of claims 1-4 or the IL-2 receptor complex prepared according to the method of any one of claims 7-9 in anti-IL-2R antibody screening for non-disease diagnostic and therapeutic purposes.
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