CN106046162B - Anti-human programmed death factor 1(PD-1) monoclonal antibody preparation and application - Google Patents
Anti-human programmed death factor 1(PD-1) monoclonal antibody preparation and application Download PDFInfo
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- 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
- C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
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Abstract
The invention discloses a kind of anti-human programmed death factor 1(PD-1) preparation of monoclonal antibody, variable region sequences and application.The present invention provides a kind of anti-human PD-1 protein monoclonal antibodies, including monoclonal antibody light chain and heavy chain variable region gene sequence.The 20th of the amino acid sequence of the heavy chain such as SEQ ID NO.3 is to shown in 134, and the 20th of the amino acid sequence of the light chain such as SEQ ID NO.4 is to shown in 131.A kind of monoclonal antibody 189-H-1 and its encoding gene that can block people's PD-1 function of new discovery of the present invention, monoclonal antibody 189-H-1 can be in conjunction with people's PD-1 antigentic specificity, medium effective concentration EC50 is 1.0667nM, it can inhibit signal with specific inhibition PD-1/PD-L, it therefore can be using monoclonal antibody 189-H-1 of the invention as the blocking agent of PD-1 access, to treat a kind of novel drugs as immunotherapy of tumors, chronic viral infection disease and autoimmune disease.
Description
Technical field
The present invention relates to the preparations and variable region sequence of biomedicine technical field more particularly to anti-human PD-1 monoclonal antibody
Column and application.
Background technique
PD-1 gene is to have 1 in discovery in 1992 and clone, extracellular region by Tasuku Honjo and its colleague earliest
The area GeIgVYang has 23% homology with CTLA-4, the I type cross-film of immunoglobulin superfamily being made of 288 amino acid
Glycoprotein is initially considered related to Apoptosis and is named as programmed death-1 (programmed death-1, PD-1).
(Ishida, Y. etc., Induced expression of PD-1, a novel member of the
Immunoglobulingene superfamily, upon programmed cell death.EMBO J, 1992,11:
3887).However the MYPPPY sequence that PD-1 albumen is combined due to a lack of mediation CD28/CTLA-4 with B7.1/B7.2, and
Mediate the FDPPPF sequence that combines with ICOS-L of ICOS, thus in structure with CD28, CTLA-4 and ICOS
There are notable differences.Therefore, the combination of PD-1 and ligand is very special, does not generate cross knot with other B7 family molecules
It closes.
There are two known ligand, PD-L1 (B7-H1, CD274) and PD-L2 (B7-DC, CD273) for PD-1 tool, they are
The member of the cell surface expression of B7 family.PD-1 be mainly expressed in CD4+T cell, CD8+T cell, NKT cell, B cell and
The onthe surface of monocytes of activation, mainly by the inducing expression of T cell receptor (TCR) or B-cell receptor (BCR) signal, TNF can increase
Expression (Francisco etc., The PD-1pathway in tolerance and of the strong PD-1 in these cell surfaces
Autoimmunity.Immunol Rev, 2010,236:219-242).This receptor and its ligand PD-L1 and PD-L2 are combined
(Okazaki etc., PD-1 and PD-1 ligands:from discovery to clinical
Application.International Immunology, 2007,19 (7): 813-824).Give PD-1 or PD-L1 antibody
It is interacted between PD-1/PD-L1 with blocking, then immunosupress or immune tolerance, extensive caused by can breaking or eliminate because of tumour
The ability of T lymphocyte identification and attack tumour target cell in complex, and then reach the good result of neoplasm growth and transfer
(HiranoF. etc., Blockade of B7-H1 and PD-1 by monoclonal antibodies potentiates
Cancer therapeutic immunity [J] Cancer Res, 2005,65 (3): 1089-1096.).
This material facts that PD-1 participates in negative regulation vivo immunization function are by TasukuHonjo and its colleague earliest
It is observed in research PD-1 knock out mice.They have found the mouse of PD-1 gene knockout in C57BL/6 genetic background
Under, lupoid acne glomerulonephritis and arthritis (Nishimura H etc., Developmentof lupus-like occurs
autoimmune diseases by disruption of the PD-1gene encoding an ITIM motif-
Carrying immunoreceptor.Immunity, 1999,11:141)；And under Balb/c genetic background, then generate high drop
Thus anti-cardiac muscular tissue's antibody of degree simultaneously causes serious autoimmune cardiomyopathy.
PD-1 and PD-L1 interaction has been obtained largely with the activation for adjusting control T cell in tumour and virus infection
Verifying.PD-L1 is expressed in kinds of tumor cells surface, these tumour cells include: lung cancer, liver cancer, oophoroma, cervical carcinoma, skin
Skin cancer, bladder cancer, colon cancer, breast cancer, glioma, kidney, gastric cancer, cancer of the esophagus, oral squamous cell carcinoma, head and neck cancer.
And the CD8+T cell of great expression PD-L1 is had also discovered on these cancer peripheries.Clinical statistics show that PD-L1 is thin in tumour
High expression level on born of the same parents is related to cancer patient's poor prognosis.Interaction between PD-1 and PD-L1 causes to penetrate into tumour
Lymphocyte reduce, T cell receptor mediate proliferation reduce and cancerous cells immune evasion (Dong H. etc., B7-
H1 pathway and its role in the evasion of tumor immunity . J Mol Med, 2003 ,
81: 281-7).Research is found by inhibiting the Local Phase interaction of PD-1 and PD-L1 that immunosupress can be reversed, and works as PD-
There is cumulative effects (Brown JA etc., Blockade of programmed when the interaction of 1 and PD-L2 is also blocked
death-1 ligands on dendritic cells enhances T cell activation and cytokine
production. J Immunol. 2003;170:1257-1266).
In conclusion inhibiting signal that can make the responsiveness cell to disable in body by specific inhibition PD-1/PD-L
Restore biological function, promotes the activation and proliferation of tumour and virus-specific CD8+T cell and the secretion of cell factor, enhancing
Lymphocyte improves immunity of organisms to the lethality of the virus of tumour antigen, exotic invasive etc., remove in time tumour cell and
Virus.Therefore, PD-1/PD-L is expected to effective target molecule as immunotherapy of tumors, is also the infection of HIV chronic diseases poison
Property disease and autoimmune disease treatment provide a new strategy.
Summary of the invention
The purpose of the present invention is to provide the antibody for having very high-affinity to hPD-1 (people PD-1), Antibody Designation 2-
189-H-1.Antibodies block hPD-1 receptor in conjunction with its ligand B7-H1, can be applied to treat it is antitumor, anti-infective and
In the therapeutic agents such as autoimmune disease.
The present invention provides 1 plant and stablizes the hybridoma cell strain of expression antibody protein, and is deposited in Wuhan University's Chinese Typical Representative
Culture collection.In the school for No. 299 Wuhan Universitys of Wuhan City, Hubei Province Wuchang District Bayi Road, Wuhan is big for depositary institution address
Learn collection.The deposit date is on September 28th, 2015, deposit number was CCTCC C2015160.Classification naming is cell.
The present invention provides a kind of isolated DNA molecule, encodes the heavy chain and/or light chain of the anti-hPD-1 human antibody
Variable region or full length amino acid.
The nucleic acid sequence of antibody heavy chain variable region is nucleotide sequence shown in the 58th to 402 of SEQ ID NO:1
；The nucleic acid sequence of its antibody's light chain variable region is nucleotide sequence shown in the 58th to 393 of SEQ ID NO:2.
The amino acid sequence of antibody heavy chain variable region is SEQ ID NO:3 or its conservative series of variation；Its antibody is light
The amino acid sequence of chain variable region is SEQID NO:4 or its conservative series of variation.
SEQ ID NO.1 and 2 the 1st to 57 bit base sequences be encoded signal peptide sequence nucleotide sequence.
SEQ ID NO.3 and 4 the 1st to 19 amino acids sequences be signal peptide sequence.
The anti-hPD-1 monoclonal antibody can be the full length sequence of antibody, be also possible to the piece of anti-PD-1 antibody
Section, above-mentioned albumen and antibody include: recombinant protein, recombinant antibodies, ScFv antibody, humanized antibody, chimeric antibody, bispecific
Antibody, single domain antibody and ADC coupled antibody and albumen.
The antibody can also further provide for the derivative of the anti-hPD-1 antibody, and the derivative is anti-for hPD-1
The segment of body, antibody/antibody fragment-factor fusion protein, antibody/antibody fragment-chemical coupling thing.
1 kind of the new discovery of the present invention monoclonal antibody 2-189-H-1 for having to hPD-1 a significant high-affinity.This Dan Ke
Grand antibody can not only be in conjunction with hPD-1 antigentic specificity, and medium effective concentration is close with referring to condition, and can block hPD-1
With the ability of its ligand binding.
The present invention obtains the gene order of purpose antibody from monoclonal cell strain, can be used to construct carrier for expression of eukaryon,
The activity that antibody can be rebuild after expression obtains anti-hPD-1 monoclonal antibody.
Anti- hPD-1 monoclonal antibody of the present invention can be used to prepare it is antitumor (lung cancer including high expression hPD-1,
Liver cancer, breast cancer, squamous cell carcinoma, oophoroma, colorectal cancer, gastric cancer, gastrointestinal stromal tumor, bladder cancer, thyroid cancer, black
Plain tumor, neck cancer, prostate cancer) drug, anti-infective (infectious diseases includes disease caused by the virus infections such as HIV, HBV, HCV)
Drug and for prepare autoimmune disease (including systemic loupus erythematosus, rheumatoid arthritis, systemic vasculitis,
Psoriasis, multiple sclerosis, ulcerative colitis) treatment drug, preparation method is to be with anti-PD-1 monoclonal antibody
Main component, in addition acceptable auxiliary material and/or additive in pharmaceutics are prepared into pharmaceutically acceptable by frozen dried
Medicament.
The advantage of the invention is that the antibody has very high affinity to hPD-1.The high efficient expression in zooblast can be used
In industrialized production.It is demonstrated experimentally that anti-hPD-1 monoclonal antibody blocks hPD-1 receptor of the invention and its ligand B7-H1 are tied
It closes.
So the treatment of antibodies on tumor of the present invention, infectious diseases and autoimmune disease has widely
Application prospect.
Detailed description of the invention
Fig. 1 is the affinity capacity experimental of anti-PD-1 antibody.
Fig. 2 is the blocking test of anti-PD-1 antibody.
Specific embodiment
Illustrate that embodiments of the present invention, protection scope of the present invention are not limited to down below by way of specific specific example
State specific specific embodiment.
Embodiment 1.
The stabilization film expression of hPD-1.
The cell strain of cell membrane surface expression hPD-1 albumen buys encoding human PD-1 overall length as immunogene in order to obtain
CDNA clone (Sino Biological Inc. HG10377-CF, Genbank accession number NM- of open reading frame
005018.2), direct it and be inserted into pCDNA3.1(+) in (invitrogen company) carrier, it is sequenced and determines that hPD-1 gene is compiled
After code frame is correct.By plasmid electrotransformation into CHO-DG44 cell, pressurization screening, clone obtains stablizing the CHO- of expression hPD-1
DG44 cell.It is named as hPD-1/DG44.
Embodiment 2.
Animal immune.
5 6-8 week old A/J mouse are selected, carry out 5 immune, each immunization intervals 14 days altogether.10 are immunized every time7It is a
HPD-1/DG44 cell, subcutaneous and abdominal cavity multiple spot are immune.First immunisation is mixed using isometric Freund's complete adjuvant and cell suspension
It closes, is immunized for remaining 4 times as incomplete Freund's adjuvant and cell suspension mixing.
The configuration of cell culture medium.
MD6 serum free medium is used when cultivating sp2/0 cell.After fusion cell use the culture of HAT culture medium, specifically at
Divide as follows: 10% fetal calf serum and HAT being added in MD6 serum free medium.
Cell fusion.
3 days after exempting from eventually, selects 3 high mouse of potency and carry out cell fusion.It sterile taking-up mouse spleen and prepares in advance
Good sp2/0 cell after cell count, is mixed in the ratio of 10:1, PEG3350 is added and carries out cell fusion.Cell after fusion
It is incubated in 96 porocyte culture plates using HAT culture medium.
The detection of fused cell.
The 10th day after fusion, each hole largely becomes yellow in tissue culture plate in 96 orifice plates, and cell clone group accounts for about
The 20%-30% of entire bottom hole, carries out ELISA screening positive clone.It is specific as follows: using people's PD-1-Fc recombinant protein of purchase
(RD) 96 hole elisa plates are coated with, fused cell supernatant is added and is incubated for as primary antibody, concurrently sets sp2/0 cell conditioned medium
Liquid is negative control, and mountain sheep anti mouse IgG-Fc-HRP is added and is incubated for as secondary antibody, developing solution, OD450 readings is added.Positive colony
Is defined as: 2 times that supernatant OD450 value is greater than sp2/0 supernatant OD450 value are detected after cell fusion.
The subclone of positive fused cell screens.
The fused cell that will test the rear positive is incubated in 6 porocyte culture plates, cell count good to cell state,
It is laid in 96 porocyte culture plates, average 1, every hole cell.After culture 10 days, the cell for selecting single clonal population is carried out
ELISA detection, OD450 value detects highest cell and carries out second of subclone, after 3-5 subclone, until detection knot
Until fruit is 100% positive, the stability of cell is determined.
The preparation of antibody.
The monoclonal cell of acquisition is tied up into progress shaking flask culture in MD6 culture medium, expression time is usually 7-14 days,
Cell culture supernatant is harvested when viable cell density is lower than 50%.Using Protein A affinity column from cell culture
Purpose antibody is isolated and purified in supernatant.
Example 3.
Anti- hPD1 monoclonal antibody Function Identification.
Affinity identification.
Using hPD-L1-Fc(RD) 96 hole elisa plates of coating；Blocking antibody carries out 3 times of dilutions as primary antibody, totally 12 ladders
Degree is added to hPD-L1-Fc and is coated in 96 hole elisa plates.Mountain sheep anti mouse IgG-Fc-HRP(SANT Cruz is added
BIotechnology it) is used as secondary antibody, developing solution is added, OD450 value is read after termination.Use Graphpad Software Create EC50
Concentration.The EC50 of this antibody is 1.0667nM, and the EC50 of positive control is 0.5344nM, from the results, it was seen that screening obtains
Antibody there is apparent affinity, and (see figure 1) close with positive reference substance to PD-1.
Function Identification of the antibody blocking hPD-1 in conjunction with hPD-L1.
Using hPD-L1-Fc(RD) 96 hole elisa plates of coating；The hPD-1 antibody of purifying is subjected to 4 times of dilutions, totally 4 ladders
Degree is acted on hPD-1-Fc respectively.The mixed liquor of the hPD-1 antibody of various concentration and hPD-1-Fc effect is added to hPD-
In the coated 96 hole elisa plate of L1-Fc.Rabbit-anti hPD-1 antibody (Divine Land Yi Qiao, Beijing) is added and is used as primary antibody, it is anti-goat is added
Rabbit igg-Fc-HRP(SANT Cruz BIotechnology) it is used as secondary antibody, developing solution is added, reads OD450 value.It filters out
Antibody has the function of blocking hPD-1 in conjunction with HPDL1.
The blocking effect of antibody is further detected by Biocore.HPD-1-Fc is coupled on chip, by purifying
HPD-1 antibody carries out 2 times of dilutions, totally 7 gradients, acts on respectively with hPD-1-Fc.Upper machine testing.It is raw using Graphpad software
At EC50 concentration, the EC50 of this antibody is 64.42nM, and the EC50 of positive control is 26.59nM,.From the results, it was seen that screening
The combination of obtained antibodies block PD-1 and its ligand B7-H1, with positive reference substance in the same order of magnitude (see figure
2).
Example 4.
The subgroup identification and stability test of antibody.
Subgroup identification is carried out to antibody referring to mouse antibody subtype identification kit (Pierce, 37503) specification, is as a result weighed
Chain is IgG1, light chain Kappa.
After hybridoma cell strain in vitro culture continuous passage 3 months, supernatant antibody titer is measured, and by cell strain
It recovers after freezing 4 months, detects supernatant antibody titer.It does not change.Show to obtain the stable hybridoma of secretory antibody
Cell strain.
Example 5.
The acquisition of antibody gene sequences.
Referring to SMARTer RACE kit (clonetech, 634859) operation instructions, according to mouse heavy chain IgG1 and gently
The Fc segment conserved regions design downstream primer of chain Kappa, using RACE round pcr, to blocking effect heavy chain of antibody and
Light-chain variable region gene is expanded and is sequenced.
In conclusion the present invention effectively overcomes various shortcoming in the prior art and has high industrial utilization value.
The above-described embodiments merely illustrate the principles and effects of the present invention, and is not intended to limit the present invention.It is any ripe
The personage for knowing this technology all without departing from the spirit and scope of the present invention, carries out modifications and changes to above-described embodiment.Cause
This, institute is complete without departing from the spirit and technical ideas disclosed in the present invention by those of ordinary skill in the art such as
At all equivalent modifications or change, should be covered by the claims of the present invention.
Claims (6)
1. the anti-human PD-1 monoclonal antibody or its antigen-binding portion thereof of separation, it includes:
A) the heavy chain variable region CDR1 of amino acid sequence shown in SEQ ID NO:5；
B) the heavy chain variable region CDR2 of amino acid sequence shown in SEQ ID NO:7；
C) the heavy chain variable region CDR3 of amino acid sequence shown in SEQ ID NO:9；
D) the light chain variable region CDR1 of amino acid sequence shown in SEQ ID NO:6；
E) the light chain variable region CDR2 of amino acid sequence shown in SEQ ID NO:8；
F) the light chain variable region CDR3 of amino acid sequence shown in SEQ ID NO:10.
2. the anti-human PD-1 monoclonal antibody or its antigen-binding portion thereof of separation, it includes:
A) heavy chain variable region of the 20th to 134 amino acid sequence shown in SEQ ID NO:3；
B) light chain variable region of the 20th to 131 amino acid sequence shown in SEQ ID NO:4.
3. encoding anti-human PD-1 monoclonal antibody gene as claimed in claim 2, it is characterised in that:
A) the 58th of the nucleotide sequence of encoding heavy chain variable region such as SEQ ID NO.1 is to shown in 402；
B) the 58th of the nucleotide sequence of coding light chain variable region such as SEQ ID NO.2 is to shown in 393.
4. a kind of expression vector includes gene as claimed in claim 3.
5. a kind of expressive host includes expression vector as claimed in claim 4.
6. the anti-human PD-1 monoclonal antibody of separation described in any one of claims 1 or 2 or its antigen-binding portion thereof are being made
The purposes being ready for use in the drug of following aspect:
A) improves activated immune cell；
B) treating cancer；
C) treatment infection or infectious diseases.
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| CN106749666B (en) * | 2016-12-22 | 2018-12-25 | 福州大学 | A kind of source of people programmed death receptor hPD-1 monoclonal antibody |
| CN106831988B (en) * | 2016-12-29 | 2019-03-15 | 深圳先进技术研究院 | The monoclonal antibody and its preparation method and application of anti-human PD-1 |
| CN106928348B (en) * | 2017-03-06 | 2020-08-21 | 哈尔滨医科大学 | Fully human monoclonal antibody for regulating and controlling human innate immunity and preparation method and application thereof |
| CN107365383B (en) * | 2017-07-12 | 2019-04-30 | 苏州大学附属第一医院 | A kind of Humanized anti-human PD-1 monoclonal antibody and preparation method thereof, purposes and drug |
| US20210061912A1 (en) * | 2018-03-20 | 2021-03-04 | WuXi Biologics Ireland Limited | Novel anti-pd-1 antibodies |
| CN108948203B (en) * | 2018-08-09 | 2019-06-04 | 南京鼓楼医院 | Anti- PD-1 monoclonal antibody and its preparation method and application |
| CN109593135B (en) * | 2018-12-29 | 2021-01-15 | 百奥赛图江苏基因生物技术有限公司 | Anti-human PD-L1 monoclonal antibody and application thereof |
| CN109776678A (en) * | 2019-03-08 | 2019-05-21 | 安徽安科生物工程（集团）股份有限公司 | A kind of humanization PD-L1 monoclonal antibody, preparation method and application |
| EP4039704A4 (en) * | 2019-09-30 | 2023-09-20 | Sichuan Kelun-Biotech Biopharmaceutical Co., Ltd. | Anti-pd-1 antibody and use thereof |
| US20230331848A1 (en) * | 2020-08-31 | 2023-10-19 | Biosion Inc. | Pd-1 binding antibodies and uses thereof |
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