CN108728463A - A kind of minicircle dna carrier and its preparation method and application of expression IgG antibody - Google Patents
A kind of minicircle dna carrier and its preparation method and application of expression IgG antibody Download PDFInfo
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- CN108728463A CN108728463A CN201710244846.3A CN201710244846A CN108728463A CN 108728463 A CN108728463 A CN 108728463A CN 201710244846 A CN201710244846 A CN 201710244846A CN 108728463 A CN108728463 A CN 108728463A
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Classifications
-
- 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
- C12N15/63—Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/08—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from viruses
- C07K16/10—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from viruses from RNA viruses
- C07K16/1036—Retroviridae, e.g. leukemia viruses
- C07K16/1045—Lentiviridae, e.g. HIV, FIV, SIV
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
- C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
- C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding
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- Engineering & Computer Science (AREA)
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- General Engineering & Computer Science (AREA)
- Virology (AREA)
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- General Health & Medical Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biotechnology (AREA)
- Molecular Biology (AREA)
- Wood Science & Technology (AREA)
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- Biomedical Technology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Physics & Mathematics (AREA)
- Medicinal Chemistry (AREA)
- Immunology (AREA)
- Plant Pathology (AREA)
- Oncology (AREA)
- Microbiology (AREA)
- Hematology (AREA)
- AIDS & HIV (AREA)
- Peptides Or Proteins (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
Abstract
This application involves a kind of minicircle dna carriers and its preparation method and application of expression IgG antibody.More particularly to a kind of minicircle dna carrier for the complete IgG antibody of expressive function in vivo.In the IgG antibody and human immunodeficiency virus (HIV), other pathogen antigens or cancer cell antigen.The minicircle dna carrier, IgG antibody can be used in preventing or treating the illnesss such as AIDS (or HIV infection), other pathogenic infections or cancer.
Description
Technical field
The invention belongs to biomedicine fields, are related to a kind of recombination carrier, and in particular to one kind is for table in vivo
Up to the minicircle dna carrier of fully functional IgG antibody.
Background technology
Monoclonal antibody drug from the last century 80's approval listing since, be transfused in vivo after combine, in and/or remove
Specific internal antigen, including cell factor, cell membrane surface receptors and pathogen antigen etc..Monoclonal antibody medicine is widely used in exempting from
The prevention and treatment of the diseases such as epidemic disease correlation, cancer and infectious disease, achieve extraordinary clinical effectiveness.
Lethal sexually transmitted disease caused by AIDS is mainly infected by human immunodeficiency virus (HIV), in the world
It has been widely current.The inverase clinically applied at present, is aided with highly active antiretroviral therapy, can be to a certain degree
The upper life span for extending HIV infection person and its quality of life of improvement.But since HIV vaccine progress is slow and resistance to
Pharmacological property problem is increasingly apparent, and it is still the task of top priority to research and develop novel inverase.
The present invention is endogenous using human or animal by the minicircle dna carrier to internal infusion gene order containing IgG antibody
Albumen synthesis mechanism directly produces antibody protein drug in vivo, achievees the effect that prevent and treat disease.With most phase of the invention
Close technical solution includes:With AAV (adeno-associated virus) carrier expression HIV neutralizing antibodies AAV-anti-HIV
(WO2012115980), or by cell culture technology in vitro expression and purification HIV and albumen or other IgG antibodies.
However, there are disadvantages, including with high costs, safety risks for existing AAV expression antibody technique.It specifically includes:
(a) packaging, purification process of AAV viral vectors are complicated, need a large amount of cell culture, take time and effort;(b) preservation of AAV viruses,
The processes such as transport need low temperature environment, cause cost increase inconvenient for use;(c) AAV virus coats are easy to evoke strong be immunized
Reaction, and the DNA sequence dna radom insertion carried in carrier is easy to cause gene mutation or even carcinogenic risk.
Likewise, passing through cell culture expression and purification HIV antibody or mainly cost the shortcomings that other IgG antibodies in vitro
It is high, it is inconvenient for use.It specifically includes:(a) antibody in vitro expression and purification complex process, it is costly;(b) albumen is preserved, is transported
Usually require low temperature environment, it is desirable that harsher;(c) antibody use need to be needed for a long time by vein or hypodermic injection, limited half-life
It uses, increases patient burden.
The present invention is directed to be expressed by building recombination carrier (especially minicircle dna), and using recombination carrier
HIV neutralizing antibodies (MC.anti-HIV), to play a dual role of to aids prevention and treatment.Meanwhile the present invention is to it
The prevention and treatment of its pathogenic infection, cancer, autoimmune disease or other illnesss provide feasibility and operable
Reference and technical teaching.
Invention content
The present invention relates to a kind of minicircle dna carriers (MC.IgG) for the complete IgG antibody of expressive function in vivo, use
In Binding in vivo, in and/or remove specific antigen and its associated cell or pathogen.
It is in the IgG antibody and anti-the present invention provides a kind of recombination carrier of the complete IgG antibody of expressive function
Original, the antigen are selected from human immunodeficiency virus (HIV) or other antigens, and other antigens are selected from other pathogen, cancer
Cell or in vivo other antigens.In in other respects, other antigens are further selected from and the relevant antigen of autoimmune disease.
In one embodiment, it is preferred to, the recombination carrier is selected from non-viral gene vector;It is furthermore preferred that
The recombination carrier is selected from minicircle dna carrier.
In one embodiment, the recombination carrier is recombinant expression carrier, selected from prokaryotic expression carrier or very
Nuclear expression carrier.It is preferred that carrier for expression of eukaryon, is more preferably used for the recombinant expression carrier of mammalian cell eukaryotic expression.
In one embodiment, the IgG antibody includes:Such as SEQ ID NO:The heavy chain of amino acid sequence shown in 1 can
Become area VH, and such as SEQ ID NO:The light chain variable region VL of amino acid sequence shown in 2.Preferably, the IgG antibody includes:Such as
SEQ ID NO:The heavy chain of amino acid sequence shown in 3, and such as SEQ ID NO:The light chain of amino acid sequence shown in 4.
In one embodiment, the heavy chain variable region VH that the IgG antibody includes has and SEQ ID NO:Sequence shown in 1
The row at least amino acid sequence with 90%, 95%, 98% or 99% homology, including light chain variable region VL have and SEQ
ID NO:At least amino acid sequence with 90%, 95%, 98% or 99% homology of sequence shown in 2.
In one embodiment, the heavy chain that the IgG antibody includes has and SEQ ID NO:Sequence shown in 3 at least has
Have the amino acid sequence of 90%, 95%, 98% or 99% homology, including light chain variable region VL have and SEQ ID NO:2
The shown sequence at least amino acid sequence with 90%, 95%, 98% or 99% homology.
The present invention provides a kind of recombination carrier of the complete IgG antibody of expressive function, the recombination carrier
Include the encoding gene of the IgG antibody.
In one embodiment, the nucleotide sequence of encoding gene such as SEQ ID described in the recombination carrier
NO:Shown in 3.
In one embodiment, encoding gene described in the recombination carrier has and SEQ ID NO:Shown in 3
The sequence at least nucleotide sequence with 90%, 95%, 98% or 99% homology.It is well known to those skilled in the art, do not changing
In the case of becoming encoded amino acid, the justice such as one or more of described coding gene sequence codon can carry out are replaced
It changes, such as one or several codons, such as 1,2,3,4,5,6,8,9,10,15,20,30,40,50 codon.
The present invention provides the IgG antibodies expressed by a kind of recombination carrier by before described in embodiment.It is excellent
Choosing, the recombination carrier is selected from non-viral gene vector;It is furthermore preferred that the recombination carrier is selected from minicircle dna
Carrier.
The present invention provides a kind of preparation methods of recombination carrier described in embodiment before, including walk as follows
Suddenly:
(1) sequence of the IgG antibody and its heavy chain variable region and light chain variable region that neutralize antigen is obtained;
(2) the recombination carrier of structure expression IgG antibody;
Optional, (3) identify the expression of IgG antibody in vivo and in vitro, and detect in corresponding antigen and/or clear
Except effect;
Wherein, the antigen is selected from human immunodeficiency virus (HIV) or other antigens, other antigens and other senses
The illnesss such as dye, cancer or autoimmune disease are related.
In one embodiment, in the step (1) of the preparation method, (a) obtains HIV from the prior art
The sequence of the heavy chain variable region and light chain variable region of neutralizing antibody or other IgG antibodies;Or (b) the separation HIV antibody positive is suffered from
HIV specificity neutralizing monoclonal antibody in person's serum or other IgG antibodies are then sequenced the variable region of the antibody.
The present invention provides a kind of host cells, including the recombination carrier described in embodiment before, or by it
The obtained recombination carrier of preparation method described in preceding embodiment.
In one embodiment, the host cell includes bacterial cell, yeast cell, mammalian cell or elder brother
Worm cell.
The present invention provides a kind of preparation method of IgG antibody described in embodiment before, specific steps include:
(1) the recombination carrier is built;
(2) by the recombination vector introduction host cell;
(3) under conditions suitable for the expression, host cell is cultivated, expression isolates and purifies, obtains the IgG antibody.
The present invention provides a kind of pharmaceutical compositions, including before recombination carrier described in embodiment or before
IgG antibody described in embodiment and pharmaceutically acceptable carrier.
In one embodiment, pharmaceutical preparation can be made in described pharmaceutical composition according to conventional methods.In production process,
It is preferred that recombination carrier or antibody are mixed with pharmaceutically acceptable carrier or diluted with carrier.When carrier is as diluent
When, can be solid, semisolid or liquid.Preparation is selected from tablet, pill, pulvis, capsule, elixir, suspension, emulsion, molten
The forms such as liquor, aerosol, capsule, injection solution.Suitable carrier, excipient or diluent include water, lactose, grape
Sugar, sucrose, sorbierite, mannitol, calcium silicates, cellulose, polyvinylpyrrolidone, methyl hydroxybenzoate, hydroxybenzoic acid
Propyl ester, talcum powder, magnesium stearate and mineral oil etc..Preparation can also include filler, anticoagulant, lubricant, wetting agent, tune
Taste agent, emulsifier, preservative etc..
The present invention provides recombination carrier described in embodiment before, the IgG antibody, the host is thin
Born of the same parents or the pharmaceutical composition are preparing the application in preventing or treating the drug of illness, and the illness is selected from AIDS, HIV
Infection, other pathogenic infections, cancer or Other diseases.In in other respects, the illness further includes autoimmune disease.
In one embodiment, the pathogenic infection includes virus, bacterium, fungi, parasite, mycoplasma or other
Infectious diseases caused by pathogen.Preferably, the virus infection includes hepatitis virus (hepatitis A, hepatitis B, hepatitis etc.), influenza
Virus infection caused by virus, Epstein-Barr virus, rhinovirus, adenovirus, coronavirus, rotavirus, herpesviral or other viruses
Property disease.Preferably, the bacterium infection includes Escherichia coli, micrococcus scarlatinae, diplococcus, streptococcus pneumonia, gold
Staphylococcus aureus, klebsiella pneumoniae, haemophilus influenzae, pseudomonas aeruginosa, comma bacillus, typhoid bacillus, pylorus
Bacterium caused by helicobacter, mycobacterium tuberculosis, clostridium tetani, yersinia pestis, Bacillus anthracis or other bacteriums
Infectious diseases.Preferably, the parasitic infection includes amoeba worm, roundworm, hookworm, tapeworm, blood fluke, toxoplasma, silk
Parasite infectivity disease caused by worm, plasmodium, acarid or other parasites.
In one embodiment, the cancer is selected from lung cancer, non-small cell lung cancer, the cancer of the esophagus, gastric cancer, liver cancer, gall-bladder
Cancer, cancer of pancreas, carcinoma of small intestine, colorectal cancer, kidney, carcinoma of urinary bladder, prostate cancer, oophoroma, cervix cancer, carcinoma of endometrium,
Head and neck cancer, nasopharyngeal carcinoma, hypopharyngeal cancer, cancer eye, osteocarcinoma, sarcoma, the cancer of the brain, glioma, astrocytoma, leukaemia, lymthoma,
Cutaneum carcinoma, melanoma or other cancers.
In one embodiment, the autoimmune disease include rheumatoid arthritis, it is systemic loupus erythematosus, hard
Skin disease, ulcerative colitis, multiple sclerosis or other.
The present invention provides a kind of recombination carriers for the complete IgG antibody of expressive function in vivo, especially
Minicircle dna carrier, has the advantage that:
(a) the minicircle dna carrier is utilized, ensures that the light chain of IgG antibody, heavy chain molar ratio are 1 in same expression cassette:
1, and ensure that finally formed antibody is consistent or similar in sequence and function to natural antibody.The company of IgG antibody light chain, heavy chain
Connect mode, light chain, heavy chain molar ratio 1:It, could the most effective antibody for being formed with biological function when 1.
(b) compared with prior art, especially AAV carriers express neutralizing antibody, cell culture technology vivoexpression antibody
Compare, safety of the invention is more preferable, and cost is cheaper, carrier and antibody it is more convenient to use.
Description of the drawings
Fig. 1:The structure chart of minicircle dna carrier anti-HIV IgG1 (3BNC117).
Specific implementation mode
Following experimental methods are conventional method unless otherwise instructed, used experiment material unless otherwise instructed,
It can easily be obtained from commercial company.
The structure of embodiment 1, AntiHIV1 RT activity IgG antibody (Anti-HIV IgG antibodies)
(a) Anti-HIV IgG antibodies are built, in the IgG antibody and human immunodeficiency virus (HIV).
(b) IgG antibody includes, such as SEQ ID NO:The heavy chain variable region VH of amino acid sequence shown in 1, and such as SEQ
ID NO:The light chain variable region VL of amino acid sequence shown in 2.
(c) the minicircle dna carrier of structure expression Anti-HIV IgG antibodies, includes the encoding gene of the IgG antibody;And
And also comprising suitable Expression element in minicircle dna carrier.
(d) include the expression cassette (shown in Figure 1) of Anti-HIV IgG antibodies, including following formula knot in minicircle dna carrier
Structure:
Kozak-SP-AA-HIV.VH-CH1-hinge-CH2-CH3-Furin-GSG-T2A-SP-AA-HIV.VL-
HIV.CL-His6
Wherein, Kozak is Kozak sequences, and SP is signal peptide (Signal Peptide);Hinge is antibody hinge region;
Furin is furin protease cleavages, 2A expression 2A self cleavages site.
SP can be Secrecon, and amino acid sequence is:MWWRLWWLLLLLLLLWPMVWA or other;Furin is sheared
The amino acid sequence in site is R-X- [R/K]-R (such as RRKR), and X refers to any amino acid;2A include E2A, F2A, P2A and
T2A etc., the wherein amino acid sequence of T2A are EGRGSLLTCGDVEENPGP.
The nucleotide sequence of above-mentioned expression cassette such as SEQ ID NO:Shown in 5.
The preparation of embodiment 2, the structure of minicircle dna carrier and micro-loop (MC)
(a) encoding gene of IgG antibody is synthesized.
(b) suitable site double digestion minicircle dna empty carrier pMC.BESPX is selected.
(c) seamless clones or conventional cloning methods (digestion-connection) is used to be inserted into the encoding gene of IgG antibody
In empty carrier pMC.BESPX after double digestion, it is built into IgG antibody minicircle dna carrier (pMC.IgG antibody).
(d) pMC.IgG antibody converts Escherichia coli E coli.ZYCY10P3S2T, is obtained by standard micro-loop preparation method micro-
Ring (MC.IgG antibody)
Wherein, minicircle dna empty carrier pMC.BESPX, engineering bacteria E coli.ZYCY10P3S2T and micro-loop preparation method
See document Nat Biotechnol.2010,28 (12):1287-9.
The expression and purifying of embodiment 3, Anti-HIV IgG antibodies
One, expression of the IgG antibody in 293T cells
Above-mentioned minicircle dna is transfected by 293T cells using superfect plasmid transfections kit (Invitrogen companies),
293T cell supernatants are collected respectively after being cultivated three days in serum free medium, and Anti-HIV is detected using Western Blot
The expression of IgG antibody albumen.
Two, IgG antibody purifies
293 cell culture supernatants are first subjected to low-temperature centrifugation or in-depth filtration, take supernatant, then using Protein A parents
And chromatographic purifying, albumen after purification use Western Blot qualitative detections, and it is dense using ELISA method quantitative detection of protein
Degree.Purified product is placed in -20 DEG C or less long-term preservations.
Without departing from the spirit of the invention, those skilled in the art combine known technology, can be done to the present invention
Go out many modifications, such modification also falls into the scope of the present invention.
Sequence table
SEQUENCE LISTING
<110>Shenzhen Xin Nuo micro-loops bio tech ltd
<120>A kind of minicircle dna carrier and its preparation method and application of expression IgG antibody
<130>
<160> 5
<170> PatentIn version 3.3
<210> 1
<211> 123
<212> PRT
<213>Artificial sequence
<400> 1
Gln Val Gln Leu Leu Gln Ser Gly Ala Ala Val Thr Lys Pro Gly Ala
1 5 10 15
Ser Val Arg Val Ser Cys Glu Ala Ser Gly Tyr Asn Ile Arg Asp Tyr
20 25 30
Phe Ile His Trp Trp Arg Gln Ala Pro Gly Gln Gly Leu Gln Trp Val
35 40 45
Gly Trp Ile Asn Pro Lys Thr Gly Gln Pro Asn Asn Pro Arg Gln Phe
50 55 60
Gln Gly Arg Val Ser Leu Thr Arg His Ala Ser Trp Asp Phe Asp Thr
65 70 75 80
Tyr Ser Phe Tyr Met Asp Leu Lys Ala Leu Arg Ser Asp Asp Thr Ala
85 90 95
Val Tyr Phe Cys Ala Arg Gln Arg Ser Asp Tyr Trp Asp Phe Asp Val
100 105 110
Trp Gly Ser Gly Thr Gln Val Thr Val Ser Ser
115 120
<210> 2
<211> 100
<212> PRT
<213>Artificial sequence
<400> 2
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Thr Val Thr Ile Thr Cys Gln Ala Asn Gly Tyr Leu Asn Trp Tyr
20 25 30
Gln Gln Arg Arg Gly Lys Ala Pro Lys Leu Leu Ile Tyr Asp Gly Ser
35 40 45
Lys Leu Glu Arg Gly Val Pro Ser Arg Phe Ser Gly Arg Arg Trp Gly
50 55 60
Gln Glu Tyr Asn Leu Thr Ile Asn Asn Leu Gln Pro Glu Asp Ile Ala
65 70 75 80
Thr Tyr Phe Cys Gln Val Tyr Glu Phe Val Val Pro Gly Thr Arg Leu
85 90 95
Asp Leu Lys Arg
100
<210> 3
<211> 457
<212> PRT
<213>Artificial sequence
<400> 3
Gln Val Gln Leu Leu Gln Ser Gly Ala Ala Val Thr Lys Pro Gly Ala
1 5 10 15
Ser Val Arg Val Ser Cys Glu Ala Ser Gly Tyr Asn Ile Arg Asp Tyr
20 25 30
Phe Ile His Trp Trp Arg Gln Ala Pro Gly Gln Gly Leu Gln Trp Val
35 40 45
Gly Trp Ile Asn Pro Lys Thr Gly Gln Pro Asn Asn Pro Arg Gln Phe
50 55 60
Gln Gly Arg Val Ser Leu Thr Arg His Ala Ser Trp Asp Phe Asp Thr
65 70 75 80
Tyr Ser Phe Tyr Met Asp Leu Lys Ala Leu Arg Ser Asp Asp Thr Ala
85 90 95
Val Tyr Phe Cys Ala Arg Gln Arg Ser Asp Tyr Trp Asp Phe Asp Val
100 105 110
Trp Gly Ser Gly Thr Gln Val Thr Val Ser Ser Ala Ser Thr Lys Gly
115 120 125
Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly
130 135 140
Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val
145 150 155 160
Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe
165 170 175
Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val
180 185 190
Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val
195 200 205
Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys
210 215 220
Ser Cys Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro
225 230 235 240
Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys
245 250 255
Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val
260 265 270
Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr
275 280 285
Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu
290 295 300
Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His
305 310 315 320
Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys
325 330 335
Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln
340 345 350
Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu
355 360 365
Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro
370 375 380
Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn
385 390 395 400
Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu
405 410 415
Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val
420 425 430
Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln
435 440 445
Lys Ser Leu Ser Leu Ser Pro Gly Lys
450 455
<210> 4
<211> 206
<212> PRT
<213>Artificial sequence
<400> 4
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Thr Val Thr Ile Thr Cys Gln Ala Asn Gly Tyr Leu Asn Trp Tyr
20 25 30
Gln Gln Arg Arg Gly Lys Ala Pro Lys Leu Leu Ile Tyr Asp Gly Ser
35 40 45
Lys Leu Glu Arg Gly Val Pro Ser Arg Phe Ser Gly Arg Arg Trp Gly
50 55 60
Gln Glu Tyr Asn Leu Thr Ile Asn Asn Leu Gln Pro Glu Asp Ile Ala
65 70 75 80
Thr Tyr Phe Cys Gln Val Tyr Glu Phe Val Val Pro Gly Thr Arg Leu
85 90 95
Asp Leu Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro
100 105 110
Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu
115 120 125
Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn
130 135 140
Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser
145 150 155 160
Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala
165 170 175
Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly
180 185 190
Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
195 200 205
<210> 5
<211> 2202
<212> DNA
<213>Artificial sequence
<400> 5
atgtggtggc gcctgtggtg gctgctgctg ctgctgctgc tgctgtggcc catggtgtgg 60
gccgccgccc aggtgcagct cctccagtca ggagcagcag tgaccaagcc aggagccagc 120
gtgagagtgt cttgcgaagc cagcggctac aacatcaggg actacttcat ccattggtgg 180
cggcaggctc caggacaggg actccagtgg gtcggttgga ttaaccccaa gaccggccag 240
cctaacaatc ccaggcagtt ccagggcagg gtgtctctga caaggcacgc ctcttgggac 300
ttcgacacct acagcttcta catggacctg aaggccctga ggagcgacga taccgccgtg 360
tacttttgcg ccaggcagcg gagcgactat tgggacttcg acgtctgggg aagcggaaca 420
caggtcacag tgtctagcgc cagcacaaag ggacctagcg tgttccctct ggccccttct 480
agcaagagca cctcaggagg aacagcagct ctgggttgcc tggtgaagga ctacttcccc 540
gagccagtga ccgtgtcttg gaatagcgga gccctgacca gcggagtgca cacatttcca 600
gccgtgctgc agtctagcgg cctgtatagc ctgagcagcg tggtgacagt gccttcttct 660
agcctgggca cccagaccta catctgcaac gtgaaccaca agcccagcaa caccaaggtg 720
gacaagaagg tggagcccaa gtcttgcccc aaatcttgtg acaaaactca cacatgccca 780
ccgtgcccag cacctgaact cctgggggga ccgtcagtct tcctcttccc cccaaaaccc 840
aaggacaccc tcatgatctc ccggacccct gaggtcacat gcgtggtggt ggacgtgagc 900
cacgaagacc ctgaggtcaa gttcaactgg tacgtggacg gcgtggaggt gcataatgcc 960
aagacaaagc cgcgggagga gcagtacaac agcacgtacc gtgtggtcag cgtcctcacc 1020
gtcctgcacc aggactggct gaatggcaag gagtacaagt gcaaggtctc caacaaagcc 1080
ctcccagccc ccatcgagaa aaccatctcc aaagccaaag ggcagccccg agaaccacag 1140
gtgtacaccc tgcccccatc ccgggatgag ctgaccaaga accaggtcag cctgacctgc 1200
ctggtcaaag gcttctatcc cagcgacatc gccgtggagt gggagagcaa tgggcagccg 1260
gagaacaact acaagaccac gcctcccgtg ctggactccg acggctcctt cttcctctac 1320
agcaagctca ccgtggacaa gagcaggtgg cagcagggga acgtcttctc atgctccgtg 1380
atgcatgagg ctctgcacaa ccactacacg cagaagagcc tctccctgtc tccgggtaaa 1440
cggagaaaga gaggcagcgg cgagggaaga ggatctctgc tgacatgcgg cgacgtggaa 1500
gagaatccag gacctatgtg gtggcgcctg tggtggctgc tgctgctgct gctgctgctg 1560
tggcccatgg tgtgggccgc cgccgatatc cagatgaccc agagccctag ctctctgagc 1620
gctagcgtgg gcgatacagt gaccatcact tgccaggcca acggctacct gaattggtac 1680
cagcagaggc ggggcaaggc tcctaagctg ctgatctacg acggctccaa gctggagagg 1740
ggcgtgccca gcagattcag cggaagacgc tggggccagg agtacaatct gaccatcaac 1800
aacctgcagc ccgaggacat cgccacctac ttttgccagg tgtacgagtt cgtggtgcca 1860
ggaaccaggc tggatctgaa gagaaccgtg gccgctccta gcgtgttcat cttccctccc 1920
agcgacgagc agctgaagtc aggaacagcc agcgtcgtgt gtctgctcaa caacttctac 1980
cccagggagg ccaaggtcca gtggaaagtg gacaacgccc tgcagagcgg aaactctcag 2040
gagagcgtga ccgagcagga cagcaaggac agcacctaca gcctgagcag cacactgacc 2100
ctgagcaagg ccgactacga gaagcacaag gtgtacgctt gcgaggtcac acaccaggga 2160
ctgtctagcc cagtgaccaa gagcttcaac cgaggcgagt gc 2202
Claims (10)
1. a kind of recombination carrier of the complete IgG antibody of expressive function, which is characterized in that in the IgG antibody and antigen,
The antigen is selected from human immunodeficiency virus (HIV) or other antigens, and other antigens are selected from other pathogen, cancer cell
Or internal other antigens;Preferably, the recombination carrier is selected from non-viral gene vector;It is furthermore preferred that the recombination base
Because carrier is selected from minicircle dna carrier.
2. recombination carrier as described in claim 1, which is characterized in that the IgG antibody includes, such as SEQ ID NO:1
The heavy chain variable region VH of shown amino acid sequence, and such as SEQ ID NO:The light chain variable region VL of amino acid sequence shown in 2.
3. recombination carrier as claimed in claim 1 or 2, which is characterized in that the recombination carrier includes the IgG
The encoding gene of antibody.
4. recombination carrier as claimed in claim 3, which is characterized in that the nucleotide sequence of the encoding gene such as SEQ
ID NO:Shown in 5.
5. the IgG antibody expressed by recombination carrier as described in any one of claim 1-4.
6. such as the preparation method of 1-4 any one of them recombination carriers in claim, which is characterized in that including walking as follows
Suddenly:
(1) sequence of the IgG antibody and its heavy chain variable region and light chain variable region that neutralize antigen is obtained;
(2) the recombination carrier of structure expression IgG antibody;
Optional, (3) identify the expression of IgG antibody in vivo and in vitro, and detect to be directed in corresponding antigen and/or remove and make
With;
Wherein, the antigen is selected from human immunodeficiency virus (HIV) or other antigens, and other antigens are selected from other cause of diseases
Body, cancer cell or internal other antigens.
7. preparation method as claimed in claim 6, which is characterized in that in the step (1), (a) is obtained from the prior art
Take the heavy chain variable region of HIV neutralizing antibodies or other IgG antibodies and the sequence of light chain variable region;Or (b) separation HIV antibody is positive
Property patients serum in HIV specificity neutralizing monoclonal antibody or other IgG antibodies, then to the variable region of the antibody survey
Sequence.
8. a kind of host cell, which is characterized in that comprising the recombination carrier as described in any one of claim 1-4, or
The obtained recombination carrier of preparation method as claimed in claims 6 or 7.
9. a kind of pharmaceutical composition, which is characterized in that comprising as described in any one of 1-4 recombination carrier or as right is wanted
Seek the IgG antibody and pharmaceutically acceptable carrier described in 5.
10. the recombination carrier as described in any one of claim 1-4, IgG antibody as claimed in claim 5 are such as weighed
Profit requires host cell described in 8 or pharmaceutical composition as claimed in claim 9 to prevent or the drug for the treatment of illness preparing
In application, the illness be selected from AIDS, HIV infection, other pathogenic infections, cancer, autoimmune disease or other
Illness.
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Cited By (1)
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CN110564751A (en) * | 2019-09-03 | 2019-12-13 | 深圳新诺微环生物科技有限公司 | Design and application of micro-ring DNA vaccine |
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