KR20170069452A - Z domain-calsequestrin fusion protein for antibody isolation and purification and method of isolating and purifying antibody using the same - Google Patents
Z domain-calsequestrin fusion protein for antibody isolation and purification and method of isolating and purifying antibody using the same Download PDFInfo
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- KR20170069452A KR20170069452A KR1020150176634A KR20150176634A KR20170069452A KR 20170069452 A KR20170069452 A KR 20170069452A KR 1020150176634 A KR1020150176634 A KR 1020150176634A KR 20150176634 A KR20150176634 A KR 20150176634A KR 20170069452 A KR20170069452 A KR 20170069452A
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
- C12N15/09—Recombinant DNA-technology
- C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
- C12N15/62—DNA sequences coding for fusion proteins
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
- C07K1/14—Extraction; Separation; Purification
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
- C07K1/14—Extraction; Separation; Purification
- C07K1/30—Extraction; Separation; Purification by precipitation
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K19/00—Hybrid peptides, i.e. peptides covalently bound to nucleic acids, or non-covalently bound protein-protein complexes
Abstract
The present invention relates to a Z-domain and a calcineurin fusion protein for the isolation and purification of an antibody, and a method for high-speed separation and purification of an antibody using the Z-domain and a calcineurin fusion protein. According to the present invention, the antibody can be purified to high purity and high quality without using an expensive protein A chromatography column generally used for antibody purification.
Description
The present invention relates to a Z-domain and a calcineurin fusion protein for the isolation and purification of an antibody, and a method for high-speed separation and purification of an antibody using the Z-domain and a calcineurin fusion protein. According to the present invention, the antibody can be purified to high purity and high quality without using an expensive protein A chromatography column generally used for antibody purification.
Purification methods for monoclonal antibodies typically comprise four basic steps. These steps include (1) separation of host cells from collection-fermenting culture; (2) separation of the antibody from the majority of the components in the capture-purified collection; (3) microfiltration - removal of residual host cell contaminants and aggregates; And (4) placing the formulation-antibody in a carrier suitable for maximum stability and storage time. However, these steps do not necessarily produce an antibody composition of sufficient purity to be used in a pharmaceutical context. Therefore, a method of generating and purifying a target antibody in a pure form from which impurities sufficient for pharmaceutical use has been removed is most important.
Protein A chromatography is widely used for the production of industrial antibodies because it allows almost complete purification from cell culture supernatants of antibodies, usually IgG, in a single step. However, the protein A chromatography column has a problem that the ligand of the column is leaked to some extent by repeated use. Such a protein A or protein A fragment has an affinity for IgG, and forms a complex with an antibody to contaminate the antibody, and it is also difficult to remove the antibody from the purified antibody. In particular, Protein A is a bacterial protein, and thus can induce unwanted immune responses, necessitating that it be removed from the purified antibody. Therefore, the purification process of the antibody using the protein A chromatography has a problem that the remaining amount of the protein A must be monitored and removed on a process-by-process basis.
Accordingly, the present inventors have made intensive efforts to develop a method for purifying an antibody to high purity and high quality without using an expensive protein A chromatography column generally used for antibody purification, and as a result, it has been found that the use of calsequestrin and calcium It has been confirmed that the coagulation reaction can replace the column chromatography process which is inconvenient, time-consuming and costly, and the present invention has been completed.
The object of the present invention is to provide a nucleic acid encoding a Z domain and a calcisquaredrin fusion protein (hereinafter referred to as "Z-calcis questin protein") for high-speed separation and high purity purification of an antibody. It is another object of the present invention to provide a method for high-speed separation and purification of an antibody using a nucleic acid encoding the Z-calcisquared protein.
According to an embodiment of the present invention,
Disclosed is a nucleic acid encoding a Z domain and a calc-querestrin fusion protein for high-speed separation and high-purity purification of antibodies. An example of a Z domain and a calcisquaredrin fusion protein according to the present invention is shown in FIG.
As used herein, the term "Z protein" is obtained from protein A of Staphylococcus aureus , which refers to a protein used for the defense against an antibody present in a host cell. The Z protein binds to the Fc region of an antibody in a host cell and is used as a self-defense mechanism to prevent phagocytosis by macrophages. A tandem repeat dimer produced by manipulating only the binding site of an antibody in a protein A is called a "Z domain ".
As used herein, the term "Fc region" refers to a portion of an antibody that interacts with a cell surface receptor, referred to as the Fc receptor, as the tail region of the antibody. In general, when a full-length antibody is cleaved with a papain, two parts of the Fab region and the Fc region are obtained. The Fc region of all antibodies in one class has nearly identical properties.
As used herein, the term " calsequestrin "is a calcium-binding protein of sarcoplasmic reticulum which, although higher in the endoplasmic reticulum than the cytoplasm, also binds to calcium after muscle contraction, Allows storage of calcium ions in the sister plasma. One calcium-quercetin molecule can bind calcium (eg, 40-50 calcium-binding sites per molecule of calc-quercetin), so calcium storage capacity is very good.
In the Z domain and the calcineurin fusion protein of the present invention, the Z domain may include Zn (where n is an integer of 1 or more) in which the Z domain is repeated. For example, the Z domain may be a Z domain, where the Z domain is in the form of two repeats. Also, the Z domain may be a ZZ domain in which the Z domain is repeated three times. According to one exemplary embodiment, the Z domain may be an amino acid sequence of SEQ ID NO: 1 or a ZZ domain comprising the nucleotide sequence of SEQ ID NO: 2.
In the Z domain and the calc-querestrin fusion protein of the present invention, the calciquestrin may include the amino acid sequence of SEQ ID NO: 3. More specifically, the calciquestrin may comprise the nucleotide sequence of SEQ ID NO: 4.
In the Z domain and the calc-querestrin fusion protein of the present invention, the Z domain and calciquestrin can be fused through a linker. The linker may comprise the amino acid sequence of SEQ ID NO: 5. More specifically, the linker may comprise the nucleotide sequence of SEQ ID NO: 6.
In the Z domain and the calc-quedelin fusion protein of the present invention, the Z-calcis questin protein may include the amino acid sequence of SEQ ID NO: 7. More specifically, the Z-calcis questin protein may comprise the nucleotide sequence of SEQ ID NO: 8.
In the Z domain and the calc-quedelin fusion protein of the present invention, the antibody may be an antibody, a fragment, a derivative or an analogue of an antibody comprising Fc or a fragment or derivative / analogue thereof capable of specifically binding to ZZ protein . Specifically, the antibody may be IgG.
According to another embodiment of the present invention,
A) preparing a recombinant vector comprising a Z domain and a nucleic acid encoding a calc-querestrin fusion protein ("Z-calcisquistin protein"
B) transforming the recombinant vector into a host cell to obtain a transformant;
C) expressing the Z-calciequestrin protein from the transformant; And
D) separating the Z-calciequestrin protein-bound antibody from the expressed transformant using calcium. The present invention also provides a method for high-speed separation and purification of an antibody. An example of a method for high-speed separation and high-purity purification of an antibody using Z domain-calcisquaredrin fusion protein according to the present invention is shown in FIG.
As used herein, the term "vector" means an expression vector capable of expressing a protein of interest in a suitable host cell, and a nucleic acid construct comprising an essential regulatory element operably linked to the expression of the nucleic acid insert. These vectors include plasmids (e.g., pSC101, ColE1, pBR322, pUC8 / 9, pHC79, pGEX series, pET series, pACYC184 and pUC19 etc.), phage ,? -charon,?? z1, M13, etc.) or a virus (e.g., SV40 or the like).
As used herein, the term "transformation" refers to the introduction of DNA into a host to allow DNA to replicate either as a chromosomal factor or by chromosome integration completion, introducing foreign DNA into cells, . ≪ / RTI > The transformation can be carried out by a CaCl 2 precipitation method, a Hanahan method which uses a reducing material such as DMSO (dimethyl sulfoxide) as a CaCl 2 method, an electroporation method, a calcium phosphate precipitation method, a protoplast fusion method, a silicon carbide fiber Agrobacterium-mediated transformation, transformation with PEG, dextran sulfate, lipofectamine, and drying / inhibition-mediated transformation methods, but are not limited thereto.
As used herein, the term "host cell" refers to a cell that is parasitized with another microorganism or gene to provide nutrients, wherein the vector is transformed into a host cell to have a variety of genetic or molecular effects in the host cell do. The host cell may be a bacterium belonging to the genus Escherichia such as E. coli ; Bacteria of the genus Bacillus such as Bacillus subtilis ; Pseudomonas Pseudomonas (Pseudomonas) in bacteria such putida); Lactobacillus such as Lactobacillus and Enterococcus; Saccharomyces S. cerevisiae ), skiing investigation, Schizosaccharomyces yeast such as pombe ; But are not limited to, animal cells and insect cells.
In the high-throughput and high-purity purification method of the antibody of the present invention, the Z domain may be a ZZ domain comprising the amino acid sequence of SEQ ID NO: 1. More specifically, the Z domain may be a ZZ domain comprising the nucleotide sequence of SEQ ID NO: 2.
In the high-throughput and high-purity purification method of the antibody of the present invention, the calciquestrin may include the amino acid sequence of SEQ ID NO: 3. More specifically, the calciquestrin may comprise the nucleotide sequence of SEQ ID NO: 4.
In the high-throughput and high-purity purification method of the antibody of the present invention, the Z domain and calciquestrin can be fused through a linker. The linker may comprise the amino acid sequence of SEQ ID NO: 5. More specifically, the linker may comprise the nucleotide sequence of SEQ ID NO: 6.
In the high-speed separation and high-purity purification of the antibody of the present invention, the Z-calcisquaredine protein may comprise the amino acid sequence of SEQ ID NO: 7. More specifically, the Z-calcis questin protein may comprise the nucleotide sequence of SEQ ID NO: 8.
In the high-throughput and high-purity purification method of the antibody of the present invention, the antibody is an antibody, fragment, derivative or analogue of an antibody comprising Fc or a fragment or derivative / analogue thereof capable of specifically binding to ZZ protein . Specifically, the antibody may be IgG.
In the high-speed separation and high-purity purification of the antibody of the present invention, the step (D) of separating the Z-calciequestrin protein-bound antibody using calcium is carried out by:
(d-1) precipitating an antibody bound to Z-calciquestrin protein using calcium; And
(d-2) removing the precipitate through centrifugation or filtration.
The Z domain and calciequestrin fusion protein according to the present invention can easily and rapidly separate and purify an antibody by using a precipitating reaction depending on calcium, and can detect a large amount of antibody at a high speed , Thereby reducing purification costs and preventing antibody degradation. In addition, it is economical to use the chelate to reuse the Z domain and the calcinequestrin fusion protein.
FIG. 1 shows an example of a Z domain-calciquestrin fusion protein according to one embodiment of the present invention.
FIG. 2 shows an example of a method for high-speed separation and high-purity purification of an antibody using Z domain-calcisquaredrin fusion protein according to another embodiment of the present invention.
Figure 3 shows the design of a calcisquaredlin-Z fusion protein according to Example 1 of the present invention.
Unless otherwise defined herein, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains in more detail, with reference to the accompanying drawings, I want to explain. It is to be understood, however, that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention.
Example One: Calcise Quest Lin - ZZ Production of fusion protein
The ZZ-domain consisting of the amino acid sequence of SEQ ID NO: 1 is placed at the N-terminus and the linker consisting of the amino acid sequence of SEQ ID NO: 5 is placed for the functional disruption of the ZZ-domain and the calicequestrin, The human myocardial calciquestrin was placed to prepare calciquestrin-ZZ fusion protein (Fig. 3).
Example 2: Calcise Quest Lin - ZZ The gene of the fusion protein Cloning
The gene of the calciquestrin-ZZ fusion protein synthesized in Example 1 was amplified by polymerase chain reaction (PCR) in order to clone the expression vector pET28b. For this purpose, a forward primer (AATAAAA CATATG GTAGACAACAAATTCAAC) and a reverse primer (ATT CTCGAG TTA ATCATCATCATCATCATCTTC) were designed (Bioneer). The PCR product was purified using a DNA purification kit (genol) and treated with NdeI and XhoI restriction enzymes (underlined in the above primers, NEB). The pET28b vector (Novagen) was also treated with NdeI and XhoI restriction enzymes. The DNA fragment cut with NdeI and XhoI and the pET28b vector were ligated at 16 ° C for 12 hours using Ligation (NEB). The ligation was carried out in E. coli DH5a, cultured in kanamycin-containing agar medium for one day, and the vector was extracted from the grown colonies for sequencing (bioneer).
Example 3: Calcise Quest Lin - ZZ Expression and purification of fusion proteins
The plasmid prepared in Example 2 was suspended in Escherichia coli coli ) strain BL21 (DE3) (Novagen, Northumberland, UK). Transformants were induced by treating the bacteria with 1 mM isopropyl [beta] -D-thiogalactopyranoside (IPTG) (Sigma, St. Louis, MO) for 6 hours at 37 ° C. The bacteria were then harvested and resuspended in lysis buffer (50 mM sodium phosphate, pH 8.0, 300 mM NaCl and 5 mM imidazole) and lysed by ultrasonic sonication. The lysate was centrifuged at 1,550 g for 1 hour at 4 < 0 > C. (Gravity-flow column; BioRad, Daejeon, Korea) packed with Ni-NTA affinity resin (Peptron, Daejeon, Korea) pre-equilibrated with lysis buffer (3 mL bed capacity per liter of culture) Hercules, Calif.). The column and matrix were washed by lysis buffer with 10 times the bead volume and then eluted with calciquestrin. The protein was further purified by gel filtration using a Superdex 200 column (Amersham PHarmacia, Bucks, UK) pre-equilibrated with phosphate buffered saline (PBS, pH 7.4).
The present invention has been described with reference to the preferred embodiments. It will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the spirit and scope of the invention as defined by the appended claims. Therefore, the disclosed embodiments should be considered in an illustrative rather than a restrictive sense. The scope of the present invention is defined by the appended claims rather than by the foregoing description, and all differences within the scope of equivalents thereof should be construed as being included in the present invention.
<110> Korea Institute of Ceramic Engineering and Technology <120> Z DOMAIN-CALSEQUESTRIN FUSION PROTEIN FOR ANTIBODY ISOLATION AND PURIFICATION AND METHOD OF ISOLATING AND PURIFYING ANTIBODY USING THE SAME <130> 2015-PP-32202 <160> 8 <170> Kopatentin 2.0 <210> 1 <211> 116 <212> PRT <213> Artificial Sequence <220> <223> ZZ DOMAIN <400> 1 Val Asp Asn Lys Phe Asn Lys Glu Gln Gln Asn Ala Phe Tyr Glu Ile 1 5 10 15 Leu His Leu Pro Asn Leu Asn Glu Glu Gln Arg Asn Ala Phe Ile Gln 20 25 30 Ser Leu Lys Asp Asp Ser Ser Gln Ser Ala Asn Leu Leu Ala Glu Ala 35 40 45 Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys Val Asp Asn Lys Phe Asn 50 55 60 Lys Glu Gln Gln Asn Ala Phe Tyr Glu Ile Leu His Leu Pro Asn Leu 65 70 75 80 Asn Glu Glu Gln Arg Asn Ala Phe Ile Gln Ser Leu Lys Asp Asp Pro 85 90 95 Ser Gln Ser Ala Asn Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala 100 105 110 Gln Ala Pro Lys 115 <210> 2 <211> 348 <212> DNA <213> Artificial Sequence <220> <223> ZZ DOMAIN <400> 2 gtagacaaca aattcaacaa agaacaacaa aacgcgttct atgagattct gcatctgccg 60 aacctgaacg aagaacagcg taacgcgttc attcagagcc tgaaagatga tccgagccag 120 tctgcgaacc tgctggcgga agcgaaaaaa ctgaacgatg cgcaggcccc gaaagtggat 180 aataagttta ataaggagca gcagaatgcc ttttacgaaa tccttcacct tccaaatctt 240 aatgaggagc agcgcaatgc ctttatccag agtcttaagg acgacccaag tcagagtgcc 300 aatcttcttg ccgaggccaa gaagcttaat gacgcccagg ctccaaag 348 <210> 3 <211> 364 <212> PRT <213> Artificial Sequence <220> <223> CALSEQUESTRIN <400> 3 Glu Glu Leu Asn Phe Pro Thr Tyr Asp Gly Lys Asp Arg Val Val 1 5 10 15 Ser Leu Ser Glu Lys Asn Phe Lys Gln Val Leu Lys Lys Tyr Asp Leu 20 25 30 Leu Cys Leu Tyr Tyr His Glu Pro Val Ser Ser Asp Lys Val Thr Pro 35 40 45 Lys Gln Phe Gln Leu Lys Glu Ile Val Leu Glu Leu Val Ala Gln Val 50 55 60 Leu Glu His Lys Ala Ile Gly Phe Val Met Val Asp Ala Lys Lys Glu 65 70 75 80 Ala Lys Leu Ala Lys Lys Leu Gly Phe Asp Glu Glu Gly Ser Leu Tyr 85 90 95 Ile Leu Lys Gly Asp Arg Thr Ile Glu Phe Asp Gly Glu Phe Ala Ala 100 105 110 Asp Val Leu Val Glu Phe Leu Asp Leu Ile Glu Asp Pro Val Glu 115 120 125 Ile Ile Ser Ser Lys Leu Glu Val Gln Ala Phe Glu Arg Ile Glu Asp 130 135 140 Tyr Ile Lys Leu Ile Gly Phe Phe Lys Ser Glu Asp Ser Glu Tyr Tyr 145 150 155 160 Lys Ala Phe Glu Glu Ala Ala Glu His Phe Gln Pro Tyr Ile Lys Phe 165 170 175 Phe Ala Thr Phe Asp Lys Gly Val Ala Lys Lys Leu Ser Leu Lys Met 180 185 190 Asn Glu Val Asp Phe Tyr Glu Pro Phe Met Asp Glu Pro Ile Ala Ile 195 200 205 Pro Asn Lys Pro Tyr Thr Glu Glu Glu Leu Val Glu Phe Val Lys Glu 210 215 220 His Gln Arg Pro Thr Leu Arg Arg Leu Arg Pro Glu Glu Met Phe Glu 225 230 235 240 Thr Trp Glu Asp Asp Leu Asn Gly Ile His Ile Val Ala Phe Ala Glu 245 250 255 Lys Ser Asp Pro Asp Gly Tyr Glu Phe Leu Glu Ile Leu Lys Gln Val 260 265 270 Ala Arg Asp Asn Thr Asp Asn Pro Asp Leu Ser Ile Leu Trp Ile Asp 275 280 285 Pro Asp Phe Pro Leu Leu Val Ala Tyr Trp Glu Lys Thr Phe Lys 290 295 300 Ile Asp Leu Phe Arg Pro Gln Ile Gly Val Val Asn Val Thr Asp Ala 305 310 315 320 Asp Ser Val Trp Met Glu Ile Pro Asp Asp Asp Asp Leu Pro Thr Ala 325 330 335 Glu Glu Leu Glu Asp Trp Ile Glu Asp Val Leu Ser Gly Lys Ile Asn 340 345 350 Thr Glu Asp Asp Asp Gp Asp Asp Asp Asp Asp Asp 355 360 <210> 4 <211> 30 <212> DNA <213> Artificial Sequence <220> <223> CALSEQUESTRIN <400> 4 ggtggcggag ggagcggtgg agggggtagt 30 <210> 5 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> LINKER <400> 5 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 1 5 10 <210> 6 <211> 30 <212> DNA <213> Unknown <220> <223> LINKER <400> 6 ggtggcggag ggagcggtgg agggggtagt 30 <210> 7 <211> 490 <212> PRT <213> Artificial Sequence <220> <223> ZZ DOMAIN-CALSEQUESTRIN <400> 7 Val Asp Asn Lys Phe Asn Lys Glu Gln Gln Asn Ala Phe Tyr Glu Ile 1 5 10 15 Leu His Leu Pro Asn Leu Asn Glu Glu Gln Arg Asn Ala Phe Ile Gln 20 25 30 Ser Leu Lys Asp Asp Ser Ser Gln Ser Ala Asn Leu Leu Ala Glu Ala 35 40 45 Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys Val Asp Asn Lys Phe Asn 50 55 60 Lys Glu Gln Gln Asn Ala Phe Tyr Glu Ile Leu His Leu Pro Asn Leu 65 70 75 80 Asn Glu Glu Gln Arg Asn Ala Phe Ile Gln Ser Leu Lys Asp Asp Pro 85 90 95 Ser Gln Ser Ala Asn Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala 100 105 110 Gln Ala Pro Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Glu 115 120 125 Gly Leu Asn Phe Pro Thr Tyr Asp Gly Lys Asp Arg Val Val Ser Leu 130 135 140 Ser Glu Lys Asn Phe Lys Gln Val Leu Lys Lys Tyr Asp Leu Leu Cys 145 150 155 160 Leu Tyr Tyr His Glu Pro Val Ser Ser Asp Lys Val Thr Pro Lys Gln 165 170 175 Phe Gln Leu Lys Glu Ile Val Leu Glu Leu Val Ala Gln Val Leu Glu 180 185 190 His Lys Ala Ile Gly Phe Val Met Val Asp Ala Lys Lys Glu Ala Lys 195 200 205 Leu Ala Lys Lys Leu Gly Phe Asp Glu Glu Gly Ser Leu Tyr Ile Leu 210 215 220 Lys Gly Asp Arg Thr Ile Glu Phe Asp Gly Glu Phe Ala Ala Asp Val 225 230 235 240 Leu Val Glu Phe Leu Leu Asp Leu Ile Glu Asp Pro Val Glu Ile Ile 245 250 255 Ser Ser Lys Leu Glu Val Gln Ala Phe Glu Arg Ile Glu Asp Tyr Ile 260 265 270 Lys Leu Ile Gly Phe Phe Lys Ser Glu Asp Ser Glu Tyr Tyr Lys Ala 275 280 285 Phe Glu Glu Ala Ala Glu His Phe Gln Pro Tyr Ile Lys Phe Phe Ala 290 295 300 Thr Phe Asp Lys Gly Val Ala Lys Lys Leu Ser Leu Lys Met Asn Glu 305 310 315 320 Val Asp Phe Tyr Glu Pro Phe Met Asp Glu Pro Ile Ala Ile Pro Asn 325 330 335 Lys Pro Tyr Thr Glu Glu Glu Leu Val Glu Phe Val Lys Glu His Gln 340 345 350 Arg Pro Thr Leu Arg Arg Leu Arg Pro Glu Glu Met Phe Glu Thr Trp 355 360 365 Glu Asp Asp Leu Asn Gly Ile His Ile Val Ala Phe Ala Glu Lys Ser 370 375 380 Asp Pro Asp Gly Tyr Glu Phe Leu Glu Ile Leu Lys Gln Val Ala Arg 385 390 395 400 Asp Asn Thr Asp Asn Pro Asp Leu Ser Ile Leu Trp Ile Asp Pro Asp 405 410 415 Asp Phe Pro Leu Leu Val Ala Tyr Trp Glu Lys Thr Phe Lys Ile Asp 420 425 430 Leu Phe Arg Pro Gln Ile Gly Val Val Asn Val Thr Asp Ala Asp Ser 435 440 445 Val Trp Met Glu Ile Pro Asp Asp Asp Asp Leu Pro Thr Ala Glu Glu 450 455 460 Leu Glu Asp Trp Ile Glu Asp Val Leu Ser Gly Lys Ile Asn Thr Glu 465 470 475 480 Asp Asp Asp Gp Asp Asp Asp Asp Asp Asp 485 490 <210> 8 <211> 1470 <212> DNA <213> Artificial Sequence <220> <223> ZZ DOMAIN <400> 8 gtagacaaca aattcaacaa agaacaacaa aacgcgttct atgagattct gcatctgccg 60 aacctgaacg aagaacagcg taacgcgttc attcagagcc tgaaagatga tccgagccag 120 tctgcgaacc tgctggcgga agcgaaaaaa ctgaacgatg cgcaggcccc gaaagtggat 180 aataagttta ataaggagca gcagaatgcc ttttacgaaa tccttcacct tccaaatctt 240 aatgaggagc agcgcaatgc ctttatccag agtcttaagg acgacccaag tcagagtgcc 300 aatcttcttg ccgaggccaa gaagcttaat gacgcccagg ctccaaaggg tggcggaggg 360 agcggtggag ggggtagtga agaggggctt aatttcccca catatgatgg gaaggaccga 420 gtggtaagtc tttccgagaa gaacttcaag caggttttaa agaaatatga cttgctttgc 480 ctctactacc atgagccggt gtcttcagat aaggtcacgc caaaacagtt ccaactgaaa 540 gaaatcgtgc ttgagcttgt ggcccaggtc cttgaacata aagctatagg ctttgtgatg 600 gtggatgcca agaaagaagc caagcttgcc aagaaactgg gttttgatga agaaggaagc 660 ctgtatattc ttaagggtga tcgcacaata gagtttgatg gcgagtttgc agctgatgtc 720 ttggtggagt tcctcttgga tctaattgaa gacccagtgg agatcatcag cagcaaactg 780 gaagtccaag ccttcgaacg cattgaagac tacatcaaac tcattggctt tttcaagagt 840 gaggactcag aatactacaa ggcttttgaa gaagcagctg aacacttcca gccttacatc 900 aaattctttg ccacctttga caaaggggtt gcaaagaaat tatctttgaa gatgaatgag 960 gtggcttct atgagccatt tatggatgag cccattgcca tccccaacaa accttacaca 1020 gaagaggagc tggtggagtt tgtgaaggaa caccaaagac ccactctacg tcgcctgcgc 1080 ccagaagaaa tgtttgaaac atgggaagat gatttgaatg ggatccacat tgtggccttt 1140 gcagagaaga gtgatccaga tggctacgaa ttcctggaga tcctgaaaca ggttgcccgg 1200 gacaatactg acaaccccga tctgagcatc ctgtggatcg acccggacga ctttcctctg 1260 ctcgttgcct actgggagaa gactttcaag attgacctat tcaggccaca gattggggtg 1320 gtgaatgtca cagatgctga cagtgtctgg atggagattc cagatgatga cgatcttcca 1380 actgctgagg agctggagga ctggattgag gatgtgcttt ctggaaagat aaacactgaa 1440 gatgatgatg aagatgatga tgatgatgat 1470
Claims (13)
Wherein the Z domain comprises Zn (wherein n is an integer of 1 or more) in which the Z domain is in a repeated form.
Wherein the Z domain is a ZZ domain comprising the amino acid sequence of SEQ ID NO: 1.
Wherein the calciquestrin comprises the amino acid sequence of SEQ ID NO: 3.
Wherein the Z domain and calciquestrin are fused via a linker comprising the amino acid sequence of SEQ ID NO: 5.
Wherein the Z domain and calciequestrin fusion protein comprises the amino acid sequence of SEQ ID NO: 7.
B) transforming the recombinant vector into a host cell to obtain a transformant;
C) expressing the Z-calciequestrin protein from the transformant; And
D) separating the Z-calcisquistrine protein-bound antibody from the expressed transformant using calcium.
Wherein the Z domain comprises Zn (wherein n is an integer of 1 or more) in which the Z domain is in a repeated form.
Wherein the Z domain is a ZZ domain comprising the nucleotide sequence of SEQ ID NO: 2.
Lt; RTI ID = 0.0 > 4, < / RTI > wherein the calciquestrin comprises the nucleotide sequence of SEQ ID NO: 4.
Wherein the Z domain and calciquestrin are fused through a linker comprising the nucleotide sequence of SEQ ID NO: 6.
Wherein the Z domain and the calciequestrin fusion protein comprise the nucleotide sequence of SEQ ID NO: 8.
The step (D) of separating the Z-calciequestrin protein-bound antibody using calcium may comprise:
(d-1) precipitating an antibody bound to Z-calciquestrin protein using calcium; And
(d-2) removing the precipitate by centrifugation or filtration.
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| WO2020204601A1 (en) * | 2019-04-05 | 2020-10-08 | 한국세라믹기술원 | Method for expressing and purifying protein by using csq-tag |
| KR20200117881A (en) * | 2019-04-05 | 2020-10-14 | 한국세라믹기술원 | Method of expressing and purifying protein using csq-tag |
| WO2021201405A1 (en) * | 2020-03-30 | 2021-10-07 | 한국세라믹기술원 | Fusion protein of z-domain and calsequestrin, having improved reactivity, stability, and antibody recovery, and method for isolation and purification of antibody using same |
| WO2022131788A1 (en) * | 2020-12-18 | 2022-06-23 | 한국세라믹기술원 | Immunoprecipitation method using antibody binding protein and calsequestrin fusion protein |
| WO2023158286A1 (en) * | 2022-02-21 | 2023-08-24 | 주식회사 툴바이오 | Calsequestrin-based metal ion reactive particle and uses thereof |
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|---|---|---|---|---|
| US20060141570A1 (en) | 2004-11-16 | 2006-06-29 | Wood David W | Intein-mediated protein purification using in vivo expression of an aggregator protein |
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| WO2020204601A1 (en) * | 2019-04-05 | 2020-10-08 | 한국세라믹기술원 | Method for expressing and purifying protein by using csq-tag |
| KR20200117881A (en) * | 2019-04-05 | 2020-10-14 | 한국세라믹기술원 | Method of expressing and purifying protein using csq-tag |
| CN114040923A (en) * | 2019-04-05 | 2022-02-11 | 韩国窑业技术院 | Expression and purification method of protein using calcemin tag |
| JP2022528132A (en) * | 2019-04-05 | 2022-06-08 | 韓國セラミック技術院 | Method for expressing and purifying protein using CSQ-tag |
| WO2021201405A1 (en) * | 2020-03-30 | 2021-10-07 | 한국세라믹기술원 | Fusion protein of z-domain and calsequestrin, having improved reactivity, stability, and antibody recovery, and method for isolation and purification of antibody using same |
| KR20220110048A (en) * | 2020-03-30 | 2022-08-05 | 한국세라믹기술원 | Z domain-calsequestrin fusion protein with improved reactivity, stability and antibody recovery and method of isolating and purifying antibody using the same |
| CN115427575A (en) * | 2020-03-30 | 2022-12-02 | 韩国窑业技术院 | Fusion protein of Z-domain and cryptocalcitonin having improved reactivity, stability and antibody recovery rate and method for separating and purifying antibody using the same |
| WO2022131788A1 (en) * | 2020-12-18 | 2022-06-23 | 한국세라믹기술원 | Immunoprecipitation method using antibody binding protein and calsequestrin fusion protein |
| KR20220087698A (en) * | 2020-12-18 | 2022-06-27 | 한국세라믹기술원 | Immunoprecipitation using antibody binding protein-calsequestrin fusion protein |
| WO2023158286A1 (en) * | 2022-02-21 | 2023-08-24 | 주식회사 툴바이오 | Calsequestrin-based metal ion reactive particle and uses thereof |
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