CN107880129A - A kind of recombinant antibodies and preparation method thereof - Google Patents
A kind of recombinant antibodies and preparation method thereof Download PDFInfo
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- CN107880129A CN107880129A CN201711460744.1A CN201711460744A CN107880129A CN 107880129 A CN107880129 A CN 107880129A CN 201711460744 A CN201711460744 A CN 201711460744A CN 107880129 A CN107880129 A CN 107880129A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
- C07K16/2887—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against CD20
-
- 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
- A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
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- 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
- C07K2317/73—Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
- C07K2317/92—Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
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- Genetics & Genomics (AREA)
- Medicinal Chemistry (AREA)
- Molecular Biology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Life Sciences & Earth Sciences (AREA)
- Peptides Or Proteins (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
The present invention relates to field of biological pharmacy, specifically discloses a kind of recombinant antibodies and preparation method thereof.Described recombinant antibodies, including two heavy chains and two light chains,（1）Weight chain variable district, include following heavy chain CDR amino acid sequence：SEQ ID NO：1, SEQ ID NO：2, SEQ ID NO：3；（2）Light chain variable district, include following light chain CDR amino acid sequence：SEQ ID NO：4, SEQ ID NO：5, SEQ ID NO：6.The recombinant antibodies are by including SEQ ID NO：7 and SEQ ID NO：Nucleotide sequence coded described in 8 forms.Described recombinant antibodies, can increasing with very effective suppression A431 and HUVEC tumour cells, the inhibiting rate to HUVEC tumour cells is nearly 4 times of Avastin, have highly significant inhibition.
Description
Technical field
The present invention relates to field of biological pharmacy, more particularly to a kind of recombinant antibodies and preparation method thereof.
Background technology
Recombinant monoclonal antibodies include the humanization and human antibody of traditional mouse monoclonal antibody.With gene
The continuous development of engineering and perfect, the research and development of recombinant antibodies medicine obtain swift and violent development, have there is individual reconstituted drug more than 100
Into different clinical investigation phases, it is mainly used in tumour, allergy, autoimmune disease, infection etc..
Recombinant monoclonal antibodies be applied to it is antitumor, therapeutic effect can be improved, and reduce the side effect for the treatment of.
In recent years, the major target class of oncotherapy is：VEGF, EGFR, HER2 etc., obtained not in the application of these clinical drugs
Wrong effect, but there is also one it is common the shortcomings that：Some patientss are also easy to produce drug resistance, and only some is benefited in other words, and
Effect is limited.The reason for producing this drug resistance is mainly that the KRAS genes in some patientss body are undergone mutation, the KRAS of mutation
Albumen makes GTPase be constantly in activated state, sustained activation MAPK signals.
Therefore, a kind of brand-new recombinant monoclonal antibodies are researched and developed, inhibiting cancer can efficiently grow, be born so as to reduce patient
Load, it is a urgent problem to be solved to reduce medical expense, therefore antibody drug needs to upgrade.The variable region of antibody is different, resists
The immunogenicity of body is different, can influence the tolerance speed and toxicity of antibody, can directly affect drug effect.High-affinity it is variable
Domain antibodies, it is possible to reduce medicine dosage, so as to reduce the demand of medication amount, to reduce cost of use.Due to tumour cell
With different epitopes and same antigen epitope with different adhesions, therefore, exploitation one kind and tumor-cell antigen
Epitope has the antibody of more high-affinity, it will help obtains the antineoplastic of very good therapeutic effect.
The content of the invention
The present invention is also easy to produce drug resistance and the limited technical problem of effect to solve current tumour medicine, there is provided Yi Zhongchong
Group antibody, described recombinant antibodies can significantly inhibit the growth of tumour, so as to reach more preferable antitumor effect.
Above-mentioned technical problem to be solved by this invention, is achieved by following technical solution：
A kind of recombinant antibodies, including two heavy chains and two light chains, weight chain variable district, include following heavy chain CDR amino acid sequences
Row：SEQ ID NO：1, SEQ ID NO：2, SEQ ID NO：3；Light chain variable district, contain following light chain CDR amino acid sequence：
SEQ ID NO：4, SEQ ID NO：5, SEQ ID NO：6.
Preferably, the heavy chain constant region of the heavy chain constant region sequence behaviour IgGl, the constant region of light chain of the antibody
Sequence is people κ antibody light chain constant regions sequence
A kind of nucleic acid, it includes nucleotide sequence of the coding according to antibody in claim 1, and described sequence heavy chain is：SEQ
ID NO：7, light chain is：SEQ ID NO：Shown in 8.
The preparation method of above-mentioned recombinant antibodies, it is by including SEQ ID NO：7；SEQ ID NO ：Nucleotides described in 8
Sequential coding forms.
Application of the above-mentioned recombinant antibodies in anti-tumor drug is prepared.
A kind of pharmaceutical composition, it contains above-mentioned recombinant antibodies.
Preferably, described pharmaceutical composition, also comprising pharmaceutically acceptable carrier.
Preferably, described medicine is cancer therapy drug.
Beneficial effect：
, can be with the increasing of very effective suppression A431 and HUVEC tumour cells the invention provides a kind of brand-new recombinant antibodies
Long, the inhibiting rate to HUVEC tumour cells is nearly 4 times of Avastin, has the inhibition of highly significant.
Brief description of the drawings
Fig. 1 recombinant antibodies antitumor properties figures
The nucleotide sequence of Fig. 2 recombinant antibodies weight chain variable districts and its amino acid sequence of deduction, line out complementation and determine below
Determine amino acid residue CDR-Hl (the SEQ ID NO in area：1), CDR-H2 (SEQ ID NO：And CDR-H3 (SEQ ID 2)
NO：3).
The nucleotide sequence of Fig. 3 recombinant antibodies light chain variable districts and its amino acid sequence of deduction, line out below mutually
Mend amino acid residue CDR-L1 (the SEQ ID NO for determining area：4), CDR-L2 (SEQ ID NO：And CDR-L3 (SEQ 5)
ID NO：6).
Embodiment
The experimental method of unreceipted actual conditions in the following example, generally according to normal condition.
The heavy chain constant region sequence of the recombinant antibodies of the present invention is human IgG l heavy chain constant region sequence.The light chain of the antibody
Constant-region sequences are peopleκ Antibody light chain constant region sequence.
As used herein, term " variable region " refers to the amino acid residue for being responsible for antigen binding in antibody.Variable region includes coming
From " complementary determining region " the i.e. amino acid residue of " CDR " and/or residue from " variable loop " (i.e. and weight chain variable district
Residue).
For the ease of preserving, can by by with require the antibody of purity and optional physiologically acceptable carrier,
Excipient or stabilizer mixing, are made lyophilized formulations or the Antybody therapy preparation of aqueous solution form.Acceptable carrier, figuration
Agent or stabilizer are nontoxic to recipient in dosage and concentration, and they include such as phosphate, citrate and other
The buffer solution of organic acid；Antioxidant including vitamin C and methionine；Preservative (such as chlorination octadecyl two
Methyl-benzyl ammonium, hexamethonium chloride, benzalkonium chloride, benzethonium chloride, phenol, butanol or benzylalcohol, p-hydroxybenzoic acid
Methyl esters or propyl ester, catechol, resorcinol, ring alcohol, 3- amylalcohols and m-cresol)；Low molecule amount（Less than about 10 residues）
Polypeptide；Protein, such as seralbumin, gelatin or immunoglobulin, hydrophilic polymer, such as polyvinylpyrrolidone；
Amino acid, such as glycine, glutamine, asparagine, histidine, arginine or lysine；Monose, disaccharides or other sugar,
Including glucose, mannose or dextrin；Chelating agent, such as EDTA；Sugar, such as sucrose, mannitol, trehalose or sorb
Sugar alcohol；Into salt counter ion, such as sodium；Metal complex（Such as Zn- protein complexs）And/or nonionic surfactant,
Such as tween, Pluronics or polyethylene glycol.
The preparation of the recombinant antibodies of embodiment 1
To express recombinant antibodies of the present invention, with reference to Wood et al., J Immunol.145:The method of 3011 (1990) etc.,
Chinese hamster ovary celI, specifically bind the monoclonal antibody of CD20 extracellular regions.Contain antibody gene with the molecular biology method structure of routine
Expression vector（OptiCHO antibody express system are purchased from invitrogen companies）.Host cell is CHO-
A kind of derived cell system of k1 cells (ATCC CCL61).High and stable yields cell line is built, step is as described below：Host cell
Suspension growth is in CD-CHO culture mediums（Gbico, CA）, the host cell in exponential phase is centrifuged, given birth to again in suspending
It is longer than fresh CD-CHO culture mediums, counts, adjustment cell density is until 1.43 × 108Individual/milliliter, take the 400 above-mentioned cells of μ l
Suspension adds electric shock cup, then adds the μ g of plasmid 20 linearized, and inhaling to beat with liquid-transfering gun makes cell be well mixed with plasmid.Will
Bio-rad electroporation parameter settings are：Electric capacity：980 μ Fd, voltage：300V, electric shock turn.The normal electric shock time is 16-19 millis
Second.Cell after electric shock is resuspended in immediately the CD-CHO culture mediums of 37 DEG C of preheatings, 96 orifice plates are sub-packed in per the μ l of hole 100,2-3 days
The screening and culturing medium (CD-CHO media+80 μM MSX) of equivalent is added afterwards.ELISA determines 96 orifice plate cells and supernatants and resisted
The expression of body.The higher clone of expression is transferred to 24 orifice plates from 96 orifice plates, cell growth is treated to certain amount, thin
Dysuria with lower abdominal colic enters 6 orifice plates, every hole 5ml culture mediums is contained 4 × 105 cells, determines the antibody production and yield of cell.Usual 25
Clone is transferred to shaking flask and does further evaluation.Last 7-8 expression quantity highest clone carries out subclone and further expression
Detection.Feed liquid is harvested, cell and culture medium is separated by low-speed centrifugal, centrifugation supernatant high speed centrifugation is further clarified.With
Albumin A affinity purification and ion-exchange purification.
The recombinant antibodies anti-tumor experiment of embodiment 2
From growth inhibitory effect of people's A431 tumour cells in nude mouse come the recombinant antibodies antitumous effect evaluated.Letter
Singly it is described as follows：A431 cells (ATCC, CRL-7907) are grown on containing 13% hyclone and add and have 3mM glutamine
DMEM culture mediums.Collect A431 cells and be resuspended in PBS, 100 μ l volumes is contained 4 × 108Cell, take the female naked of 5-6 week old
Mouse, the 100 above-mentioned cell suspensions of μ l are injected in its right armpit.When gross tumor volume reaches 80-150mm3 When start packet administration, every group 20
Only.The μ l of buffer solution administered volume 100, it is administered 8 times altogether once every three days, administering mode is intraperitoneal injection.Recombinant antibodies are by every
The dosage of kg body weight 5mg amount of antibody is administered 8 times altogether once every three days, and administering mode is intraperitoneal injection, and volume injected is every
Secondary 100 μ l.Every 2 days measure of gross tumor volume is once.After last time is administered and determines gross tumor volume size（Administration 24 days for the first time
Afterwards）, animal by immediately with it is painless till death, tumour is stripped and weighed.Under 5mg/kg dosage, recombinant antibodies significantly suppress
The growth of tumour cell, experimental result are shown in Fig. 1, the results showed that, recombinant antibodies have significant suppression A431 tumor cell proliferations
Effect.
The external inhibition of endothelial cell proliferation experiment of the recombinant antibodies of embodiment 3
Its antitumous effect is evaluated using the suppression of recombinant antibodies Human Umbilical Vein Endothelial Cells in vitro.Concrete operations are as follows：It is thin in endothelium
In born of the same parents' minimal medium (DMEM, Sigma), growth factor (BulletKit, Lonza) and (purchase of 12% hyclone are added
From Sigma), it is configured to Endothelial Cell Growth Medium.As Human umbilical vein endothelial cells (HUVEC, ATCC, Cat No：CRL-
1730) when growing into fine and close individual layer, with 5 × 104The density of cells/well is inoculated in 96 orifice plates, and analysis nutrient solution now is not
Add growth factor.Positive control antibodies are Avastin, and recombinant antibodies are added by certain dilution gradient, after being incubated 1h, add weight
Group antibody makes its final concentration of 10ng/mL.37 DEG C, after 5% CO2 incubators culture 4 days.10 μ L MTT are added in per hole
(Invitrogen) continue to cultivate 24h.In excitation wavelength 540nm and launch wavelength 620nm, cell is determined using ELIASA
Proliferative conditions.Each processing sets 3 repetitions, and each replication is twice.
As a result, under recombinant antibodies valid density, the propagation of antibody on human huve cell, which has, preferably to be suppressed to make
With positive control antibodies Avastin is in three dosage groups（20 μ g/mL, 10 μ g/mL, 5 μ g/mL）In to HUVEC cells propagation
Inhibiting rate is respectively 25.0%, 13.4% and 12.3%, and this experiment recombinant antibodies are in three dosage groups（20 μ g/mL, 10 μ g/mL,
5μg/mL）In to HUVEC cells propagation inhibiting rate be respectively 80.3%, 40.5% and 27.0%, illustrate recombinant antibodies than compare
The effect of antibody Avastin inhibition of endothelial cell proliferation is notable, and is in dose dependent.
In summary, recombinant antibodies of the invention have the immune efficacy suitable with Avastin antibody, and resist with people
Former binding affinity is higher, has higher specificity.
Sequence table
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<120>A kind of recombinant antibodies and preparation method thereof
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ggccagggac ggctatatga cgacggctat atcaaccccg aggagcaggt ccaggtcgtc 180
gacggctacc acggctggtt tgcttactgg ggacagggca ccctcgtgac agtgcgtctc 240
gctggtttgc ttactgggac agggcagacg gctaacagtg gcaccctcga cggctacgtc 300
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tcctgctcca tcgtcagccc caagtccgga tccctgggcc tcaagctgga gagcagggtg 180
cacagcaacg ctgctcatct ggctccggaa tactactgct cacacctaaa ggtgagtacc 240
tgccctccaa aagctcatct ggctggcctc aagcacctaa agcatctggc gctagcaggc 300
catctggctc cgtgccctcc aaaacaccta aagctg 336
Claims (8)
1. a kind of recombinant antibodies, including two heavy chain two light chains, it is characterised in that（1）Weight chain variable district, include following heavy chain
Cdr amino acid sequence：SEQ ID NO：1, SEQ ID NO：2, SEQ ID NO：3；（2）Light chain variable district, include following light chain
Cdr amino acid sequence：SEQ ID NO：4, SEQ ID NO：5, SEQ ID NO：6.
2. recombinant antibodies as claimed in claim 1, it is characterised in that the weight of the heavy chain constant region sequence behaviour IgGl
Chain constant region, the antibody light chain constant region are behavedκAntibody light chain constant region sequence.
3. a kind of nucleic acid, it includes coding according to antibody nucleotide sequences in claim 1, described sequence such as SEQ ID NO：
7；SEQ ID NO：Shown in 8.
4. the preparation method of the recombinant antibodies described in claim 1 or 2, it is characterised in that by including SEQ ID NO：7 and SEQ
ID NO：Nucleotide sequence coded described in 8 forms.
5. application of the recombinant antibodies described in claim 1 or 2 in anti-tumor drug is prepared.
6. a kind of pharmaceutical composition, it is characterised in that the composition is containing any one of with good grounds claims 1 to 3 claim
The recombinant antibodies.
7. pharmaceutical composition according to claim 6, it is characterised in that also comprising pharmaceutically acceptable carrier.
8. the pharmaceutical composition according to claim 6 or 7, it is characterised in that described medicine is cancer therapy drug.
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| CN201711460744.1A CN107880129B (en) | 2017-12-28 | 2017-12-28 | Recombinant antibody and preparation method thereof |
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| CN107880129B CN107880129B (en) | 2021-01-15 |
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20030105298A1 (en) * | 1998-06-16 | 2003-06-05 | Genentech, Inc. | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
| CN1910199A (en) * | 2003-12-05 | 2007-02-07 | 血管遗传瑞典股份公司 | Angiogenesis affecting polypeptides, proteins, and compositions, and methods of use |
| CN105330739A (en) * | 2014-08-12 | 2016-02-17 | 中美华世通生物医药科技（武汉）有限公司 | Human vascular endothelial growth factor specifically-binding antibody or antigen-binding fragment and application thereof |
| JP2017523176A (en) * | 2014-07-25 | 2017-08-17 | シトムクス セラピューティクス，インコーポレイティド | Anti-CD3 antibody, activatable anti-CD3 antibody, multispecific anti-CD3 antibody, multispecific activatable anti-CD3 antibody, and methods of use thereof |
-
2017
- 2017-12-28 CN CN201711460744.1A patent/CN107880129B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20030105298A1 (en) * | 1998-06-16 | 2003-06-05 | Genentech, Inc. | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
| CN1910199A (en) * | 2003-12-05 | 2007-02-07 | 血管遗传瑞典股份公司 | Angiogenesis affecting polypeptides, proteins, and compositions, and methods of use |
| JP2017523176A (en) * | 2014-07-25 | 2017-08-17 | シトムクス セラピューティクス，インコーポレイティド | Anti-CD3 antibody, activatable anti-CD3 antibody, multispecific anti-CD3 antibody, multispecific activatable anti-CD3 antibody, and methods of use thereof |
| CN105330739A (en) * | 2014-08-12 | 2016-02-17 | 中美华世通生物医药科技（武汉）有限公司 | Human vascular endothelial growth factor specifically-binding antibody or antigen-binding fragment and application thereof |
Non-Patent Citations (3)
| Title |
|---|
| CLIVE R. WOOD等: ""HIGH LEVEL SYNTHESIS OF IMMUNOGLOBULINS IN CHINESE HAMSTER OVARY CELLS"", 《THE JOURNAOLF IMMUNOLOGY》 * |
| MEHRDAD BEHMANESH等: ""Characterization of the Structure and Expression of Mouse Itpa Gene and its Related Sequences in the Mouse Genome"", 《DNA RESEARCH》 * |
| 徐多多等: ""重组人血管内皮生长因子（VEGF）单克隆抗体的制备"", 《东北师大学报（自然科学版）》 * |
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