CN105566496A - Monoclonal antibody with function of blocking human programmed death factors 1 (PD-1), encoding gene of monoclonal antibody and application thereof - Google Patents
Monoclonal antibody with function of blocking human programmed death factors 1 (PD-1), encoding gene of monoclonal antibody and application thereof Download PDFInfo
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Abstract
The invention discloses a monoclonal antibody with a function of blocking human programmed death factors 1 (PD-1), an encoding gene of the monoclonal antibody and application thereof. The monoclonal antibody comprises heavy chains and light chains. Amino acid sequences of the heavy chains are shown as 20<th> bits to 132<th> bits of SEQ ID NO.3, and amino acid sequences of the light chains are shown as 20<th> bits to 130<th> bits of SEQ ID NO.4. The monoclonal antibody 43-H-8 with the function of blocking the human programmed death factors PD-1, the encoding gene of the monoclonal antibody and the application have the advantages that the monoclonal antibody 43-H-8 can be specifically bound with human PD-1 antigens, the medium effective concentration EC50 (50% effective concentration) is 1.0665nM, accordingly, PD-1/PD-L suppression signals can be specifically blocked, the monoclonal antibody 43-H-8 can be used as a blocker for PD-1 passages, and a novel medicine can be provided for tumor immunotherapy and treatment on chronic virus infectious diseases and autoimmune diseases.
Description
Technical field
The present invention relates to biomedicine technical field, particularly relate to the preparation of anti-human PD-1 monoclonal antibody and variable region sequences and application.
Background technology
The programmed death factor 1 (programmedcelldeath1, PD-1) be the inhibitive ability of immunity acceptor (Yao expressed on the surface at activating T cell and B cell, Zhuetal.Advancesintargetingcellsurfacesignallingmolecule sforimmunemodulation.NatRevDrugDiscov, 2013,12 (2): 130-146).During initial discovery, because its similar is in CD28 molecule, PD-1 is CD28 superfamily member by accreditation.But PD-1 albumen for want of mediates the MYPPPY sequence that CD28/CTLA-4 and B7.1/B7.2 combines, and the FDPPPF sequence that mediation ICOS and ICOS-L combines, thus structurally there is notable difference with CD28, CTLA-4 and ICOS.Therefore, the combination of PD-1 and part is very special, does not produce cross coupled with other B7 family molecule.
PD-1 has two part: PD-L1 and PD-L2.PD-L1 is called B7DC or CD273 also known as B7H1 or CD274, PD-L2.PD-1 is mainly expressed in the onthe surface of monocytes of CD4+T cell, CD8+T cell, NKT cell, B cell and activation, the main abduction delivering being subject to φt cell receptor (TCR) or B-cell receptor (BCR) signal, TNF can strengthen the expression (Francisco of PD-1 at these cell surfaces, Sageetal., ThePD-1pathwayintoleranceandautoimmunity.ImmunolRev, 2010,236:219-242).PD-L1 and PD-L2 is expressed in different cell colony (Shimauchi, Kabashimaetal., Augmentedexpressionofprogrammeddeath-linbothneoplastican dnon-neoplasticCD4+T-cellsinadultT-cellleukemia/lymphoma .IntJCancer, 2007, 121 (12): 2585-2590), large quantifier elimination shows, PD-1 in the T cell of PD-L1 and activation interacts can the biological function of remarkable retarding effect T cell, PD-1, the expression change of PD-L1 or PD-L2 causes PD-1/PD-L to suppress approach to occur extremely, and then hyperfunction/low property disease of body generation immunologic function, PD-1 knock out mice can cause various autoimmune disease.
Research shows, PD-1 signal path also participates in process that is viral and microbial infectious diseases.Multiple chronic and acute virus also escapes human immunity monitoring by PD-1 and PD-L1 signal.Such as: in HIV person's body the expression level of PD-1 and the degree of exhaustion of T cell closely related, and can be used as one of the mark of AIDS disease progression (Trabattoni, Saresellaetal., B7-H1isup-regulatedinHIVinfectionandisanovelsurrogatemar kerofdiseaseprogression.Blood, 2003,101 (7): 2514-2520).This phenomenon is suitable for Chronic Hepatitis B (Evans too, Rivaetal., Programmeddeathlexpressionduringantiviraltreatmentofchro nichepatitisB:ImpactofhepatitisB-antigenseroconversion., Hepatology, 2008,48 (3): 759-769).Experimentation on animals shows, and PD-1 gene knockout mice controls virus infection better than normal mouse; And HBV Idiotype T cell is transferred in HBV transgenic animal and can be caused hepatitis.Experiment confirms to block the clinical treatment that PD-1 signal is likely applied to the virus infectiones such as HIV.
PD-1 and PD-L1 interacts and in tumour and virus infection, obtains a large amount of checking with the activation of regulable control T cell.PD-L1 is expressed in kinds of tumor cells surface, and these tumour cells comprise: lung cancer, liver cancer, ovarian cancer, cervical cancer, skin carcinoma, bladder cancer, colorectal carcinoma, mammary cancer, neurospongioma, kidney, cancer of the stomach, esophagus cancer, oral squamous cell carcinoma, head and neck cancer.And the CD8+T cell of great expression PD-L1 is have also discovered at these cancer peripheries.Clinical statistics shows, the high expression level of PD-L1 on tumour cell relevant to cancer patients's poor prognosis (Okazaki and Honjo2007, the same).Interaction between PD-1 and PD-L1 causes infiltrating the lymphopenia of tumour, the propagation of φt cell receptor mediation reduces and immune evasion (people (2003) J.Mol.Med.81:281-7 such as Dong of cancerous cells; The people such as Blank (2005) CancerImmunol.Immunother.54:307-314; The people such as Konishi (2004) Clin.CancerRes.10:5094-100).Research finds by suppressing the local of PD-1 and PD-L1 mutually to do reversible immunosuppression, and has cumulative effects (people (2002) Proc.Nat ' l.Acad.Sci.USA99:12293-7 such as Iwai when the interaction of PD-1 and PD-L2 is also blocked; The people such as Brown (2003) J.Immunol.170:1257-66).
In sum, suppress signal can make the responsiveness cellular-restoring biological function of anergy in body by specific inhibition PD-1/PD-L, promote tumour and the activation and proliferation of virus-specific CD8+T cell and the secretion of cytokine, strengthen lymphocyte to the lethality of the virus of tumour antigen, exotic invasive etc., improve immunity of organisms, remove tumour cell and virus in time.Therefore, PD-1/PD-L is expected to the effective target molecule becoming immunotherapy of tumors, also for HIV chronic diseases poison infectious diseases and the treatment of autoimmune disorder provide a new strategy.
Summary of the invention
The object of the present invention is to provide antibody hPD-1 (people PD-1) being had to very high-affinity, Antibody Designation is 43-H-8.This antibodies block hPD-1 acceptor is combined with its part B7-H1, can be applied in medicines such as treating antitumor, anti-infective and autoimmune disorder.
The invention provides the hybridoma cell strain of 1 strain stably express antibody protein, and be deposited in Wuhan University's China typical culture collection center.Depositary institution address be Wuchang District, Wuhan City, Hubei Province Bayi Road No. 299 Wuhan Universitys in the school, Wuhan University's preservation center.Preservation date is on September 28th, 2015, and deposit number is CCTCCC2015153.Temporary without Classification And Nomenclature.
The invention provides a kind of DNA. molecule of separation, the heavy chain of described anti-hPD-1 human antibody of encoding and or the variable region of light chain or full length amino acid.
The 58th that the nucleotide sequence of antibody heavy chain variable region is SEQIDNO:1 to the nucleotide sequence shown in 1407; The 58th that the nucleotide sequence of its antibody chain variable region is SEQIDNO:2 to the nucleotide sequence shown in 1407.
The aminoacid sequence of antibody heavy chain variable region is SEQIDNO:3 or its conservative form variation sequence; The aminoacid sequence of its antibody chain variable region is SEQIDNO:4 or its conservative form variation sequence.
SEQIDNO.1 and 2 the 1st is nucleotide sequences of coded signal peptide sequence to 57 bit base sequences.
SEQIDNO.3 and 4 the 1st is signal peptide sequences to 19 amino acids sequences.
Described anti-hPD-1 monoclonal antibody can be the full length sequence of antibody, also can be the fragment of anti-PD-1 antibody, above-mentioned albumen and antibody comprise: recombinant protein, recombinant antibodies, ScFv antibody, humanized antibody, chimeric antibody, bi-specific antibody, single domain antibody and ADC coupled antibody and albumen.
Described antibody also can provide the derivative of described anti-hPD-1 antibody further, and described derivative is fragment, antibody/antibody fragment-factor fusion protein, the antibody/antibody fragment-chemical coupling thing of hPD-1 antibody.
New discovery of the present invention a kind to have the monoclonal antibody 43-H-8 of remarkable high-affinity to hPD-1.This monoclonal antibody can not only be combined with hPD-1 antigen-specific, and medium effective concentration with close with reference to product, and can block the ability of hPD-1 and its ligand binding.
The present invention obtains the gene order of object antibody from monoclonal cell strain, in order to build carrier for expression of eukaryon, can rebuild the activity of antibody after expression, obtain anti-hPD-1 monoclonal antibody.
Anti-hPD-1 monoclonal antibody of the present invention can be used to preparation and antitumorly (comprises the lung cancer of high expression level hPD-1, liver cancer, mammary cancer, squamous cell carcinoma, ovarian cancer, colorectal cancer, cancer of the stomach, gastrointestinal stromal tumor, bladder cancer, thyroid carcinoma, melanoma, neck cancer, prostate cancer) medicine, it is anti-infective that (infectious diseases comprises HIV, HBV, the disease that the virus infectiones such as HCV cause) medicine and be used for preparation autoimmune disorder (comprise systemic lupus erythematous, rheumatoid arthritis, SV, psoriatic, multiple sclerosis, ulcerative colitis) medicine for the treatment of, its preparation method is for main component with anti-PD-1 monoclonal antibody, add acceptable auxiliary material and/or additive in pharmacopedics, through frozen dried, be prepared into pharmaceutically acceptable medicament.
The invention has the advantages that this antibody has very high avidity to hPD-1.High expression in zooblast, can be used for suitability for industrialized production.Experiment proves, anti-hPD-1 monoclonal antibody blocks hPD-1 acceptor of the present invention is combined with its part B7-H1.
So the treatment of antibodies on tumor of the present invention, infectious diseases and autoimmune disorder is with a wide range of applications.
Accompanying drawing explanation
Fig. 1 is the avidity capacity experimental of anti-PD-1 antibody.
Fig. 2 is the blocking test of anti-PD-1 antibody
Embodiment
Below by way of specific specific examples, embodiments of the present invention are described, protection scope of the present invention is not limited to following specific specific embodiments
Embodiment 1
The stabilizing membrane of hPD-1 is expressed
The cell strain of hPD-1 albumen is expressed as immunogen in order to obtain surface of cell membrane.The cDNA buying encoding human PD-1 total length open reading frame clones (Sino Biological Inc. HG10377-CF, Genbank accession number NM-005018.2), its orientation is inserted in pCDNA3.1 (+) (invitrogen company) carrier, after order-checking determines that hPD-1 genes encoding frame is correct.Be transformed into by plasmid electricity in CHO-DG44 cell, pressurization screening, clone obtains the CHO-DG44 cell of stably express hPD-1.Called after hPD-1/DG44.
Embodiment 2
Animal immune
Select 10 6-8 A/J mouse in age in week, carry out 5 immunity altogether, each immunization interval 14 days.Each immune 107 hPD-1/DG44 cells, subcutaneous and abdominal cavity multiple spot immunity.First immunisation adopts equal-volume Freund's complete adjuvant and cell suspension mixing, and all the other 4 immunity are Freund's incomplete adjuvant and cell suspension mixing.
The configuration of cell culture medium
MD6 serum free medium is adopted when cultivating sp2/0 cell.After merging, cell adopts HAT culture medium culturing, and concrete composition is as follows: add foetal calf serum and the HAT of 10% in MD6 serum free medium.
Cytogamy
Exempt from latter 3 days eventually, select 6 mouse of tiring high and carry out cytogamy.Aseptic taking-up mouse spleen and preprepared sp2/0 cell, after cell counting, in the ratio mixing of 10: 1, add PEG3350 and carry out cytogamy.After merging, cell adopts HAT culture medium culturing in 96 porocyte culture plates.
The detection of fused cell
Merge latter 10th day, in 96 orifice plates, in Tissue Culture Plate, each hole major part becomes yellow, and cell clone colony accounts for the 20%-30% at the bottom of whole hole, carries out ELISA screening positive clone.Specific as follows: to adopt people PD-1-Fc recombinant protein (RD) bag bought by 96 hole elisa plates, add the cell conditioned medium liquid after fusion to hatch as primary antibodie, set sp2/0 cell conditioned medium liquid is negative control simultaneously, add goat against murine IgG-Fc-HRP anti-to hatch as two, add nitrite ion, OD450 reads value.Positive colony is defined as: detect 2 times that supernatant OD450 value is greater than sp2/0 supernatant OD450 value after cytogamy.
The subclone screening of positive fused cell
Be incubated at detecting rear positive fused cell in 6 porocyte culture plates, treat that cell state is good, cell counting, is laid in 96 porocyte culture plates, average every 1, hole cell.Cultivate after 10 days, the cell selecting single clonal population carries out ELISA detection, and OD450 value detects the highest cell and carries out second time subclone, after 3-5 subclone, till detected result is 100% positive, determines the stability of cell.
The preparation of antibody
Tied up in MD6 substratum by the monoclonal cell of acquisition and carry out shake-flask culture, expression time is generally 7-14 days, when viable cell density lower than 50% time harvested cell nutrient solution supernatant.Adopt ProteinA affinity column separation and purification object antibody from cells and supernatant.
Example 3
Anti-hPD1 monoclonal antibody Function Identification
Avidity is identified
Adopt hPD-L1-Fc (RD) bag by 96 hole elisa plates; Blocking antibody carries out 3 times of dilutions as primary antibodie, totally 12 gradients, joins hPD-L1-Fc bag by 96 hole elisa plates.Add goat against murine IgG-Fc-HRP (SANTCruzBIotechnology) to resist as two, add nitrite ion, after stopping, read OD450 value.Use Graphpad Software Create EC50 concentration.The EC50 of this antibody is 1.0665nM, and the EC50 of positive control is 0.5344nM, as can be seen from the results, screens the antibody obtained and has obvious avidity to PD-1, and with positive reference substance at the same order of magnitude.(see Fig. 1).
The Function Identification that antibody blocking hPD-1 and hPD-L1 combines
Adopt hPD-L1-Fc (RD) bag by 96 hole elisa plates; The hPD-1 antibody of purifying is carried out 4 times of dilutions, totally 4 gradients, respectively with hPD-1-Fc effect.The hPD-1 antibody of different concns and the mixed solution of hPD-1-Fc effect are joined in the 96ELISA plate of hPD-L1-Fc bag quilt.Add the anti-hPD-1 antibody of rabbit (Yi Qiao Divine Land, Beijing) as primary antibodie, adding, goat anti-rabbit igg-Fc-HRP (SANTCruzBIotechnology) is anti-as two, adds nitrite ion, reads OD450 value.The antibody filtered out has the function blocking hPD-1 and HPDL1 and combine.
The blocking effect of antibody is detected further by Biocore.HPD-1-Fc is coupled on chip, the hPD-1 antibody of purifying is carried out 2 times of dilutions, totally 7 gradients, respectively with hPD-1-Fc effect.Upper machine testing.Use Graphpad Software Create EC50 concentration, the EC50 of this antibody is 25.18nM, and the EC50 of positive control is 26.59nM.As can be seen from the results, screen the combination of antibodies block PD-1 and its part B7-H1 obtained, and this antibody is more better than the blocking effect of positive reference substance.(see Fig. 2).
Example 4
The subgroup identification of antibody and stability test
Carry out subgroup identification with reference to murine antibody hypotype identification kit (Pierce, 37503) specification sheets antagonist, result heavy chain is IgG1, and light chain is Kappa.
By the continuous passage of hybridoma cell strain vitro culture after 3 months, measure supernatant liquor antibody titer, and recovered after frozen for cell strain 4 months, detect supernatant liquor antibody titer.All do not change.Show to obtain the stable hybridoma cell strain of secretory antibody.
Example 5
The acquisition of antibody gene sequences
With reference to SMARTerRACE test kit (c1onetech, 634859) working instructions, according to the Fc fragment conserved regions design downstream primer of mouse heavy chain IgG1 and light chain Kappa, utilize RACEPCR technology, the heavy chain of antibody and chain variable region gene with blocking effect is increased and checked order.
In sum, the present invention effectively overcomes various shortcoming of the prior art and tool high industrial utilization.
Above-described embodiment is illustrative principle of the present invention and effect thereof only, but not for limiting the present invention.Any person skilled in the art scholar all without prejudice under spirit of the present invention and category, can modify above-described embodiment or changes.Therefore, such as have in art usually know the knowledgeable do not depart from complete under disclosed spirit and technological thought all equivalence modify or change, must be contained by claim of the present invention.
Claims (11)
1. the anti-human PD-1 monoclonal antibody be separated or its antigen-binding portion thereof, it comprises:
A) the variable region of heavy chain CDR1 being selected from SEQIDNO:5 aminoacid sequence is comprised;
B) the variable region of heavy chain CDR2 being selected from SEQIDNO:7 aminoacid sequence is comprised;
C) the variable region of heavy chain CDR3 being selected from SEQIDNO:9 aminoacid sequence is comprised;
D) the variable region of light chain CDR1 being selected from SEQIDNO:6 aminoacid sequence is comprised;
E) the variable region of light chain CDR2 being selected from SEQIDNO:8 aminoacid sequence is comprised;
F) the variable region of light chain CDR3 being selected from SEQIDNO:10 aminoacid sequence is comprised.
2. the anti-human PD-1 monoclonal antibody be separated or its antigen-binding portion thereof, it comprises:
A) variable region of heavy chain of the aminoacid sequence of the 20th to 132 that are selected from SEQIDNO:3 is comprised;
B) variable region of light chain of the aminoacid sequence of the 20th to 130 that are selected from SEQIDNO:4 is comprised.
3. coding anti-human PD-1 monoclonal antibody gene according to claim 2, is characterized in that:
A) nucleotide sequence of encoding heavy chain is as the 58th of SEQIDNO.1 the to shown in 396.
B) nucleotide sequence of coding light chain is as the 58th of SEQIDNO.2 the to shown in 390.
4. anti-human PD-1 variable region of mab according to claim 2 sequence, change at least one amino-acid residue at least one variable region antibody sequence, described sequence is selected from variable fragments of heavy chain sequence and variable region of light chain antibody sequence, is expressed as protein to create at least one through the antibody sequence of change with by the antibody sequence through changing.
5. anti-human PD-1 variable region of mab according to claim 3 sequence, still has the nucleotide sequence with aminoacid sequence that described nucleotide sequence produce with identical activity after replacing, lack or adding through one or several bases.
6. an expression vector, comprises the nucleotide sequence described in claim 1 to 5 any one.
7. an expressive host, comprises expression vector according to claim 6.
8. the application prepared on albumen and antibody is listed according to the nucleotides sequence described in claim 1 to 5, above-mentioned albumen and antibody comprise: recombinant protein, recombinant antibodies, ScFv antibody, humanized antibody, chimeric antibody, bi-specific antibody, single domain antibody and ADC coupled antibody and albumen.
9. the antibody any one of claim 1-8 or antibody fragment are for the preparation of the purposes in the medicine in following:
A). improve activated immune cell;
B). Therapeutic cancer;
C). treatment is infected or infectious diseases.
10. the antibody any one of claim 1-11 or antibody fragment are used for the purposes of diagnostic use.
11. 1 kinds of pharmaceutical compositions, comprise the described anti-PD-1 antibody for the treatment of significant quantity.
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| 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 |
| CN106928348A (en) * | 2017-03-06 | 2017-07-07 | 哈尔滨医科大学 | A kind of full human monoclonal antibody of regulation and control human body inherent immunity and its preparation method and application |
| CN108840932B (en) * | 2018-04-28 | 2022-03-29 | 中国科学院微生物研究所 | PD-1 specific antibody and anti-tumor application thereof |
| CN108840932A (en) * | 2018-04-28 | 2018-11-20 | 中国科学院微生物研究所 | A kind of PD-1 specific antibody and its antitumor application thereof |
| CN114206379A (en) * | 2019-06-18 | 2022-03-18 | 爱尔兰詹森科学公司 | Combination of Hepatitis B Virus (HBV) vaccine and anti-PD-1 antibody |
| CN112225809A (en) * | 2019-06-30 | 2021-01-15 | 福州创方医药科技有限公司 | Monoclonal antibody targeting PD-1 and application thereof |
| WO2021000813A1 (en) * | 2019-06-30 | 2021-01-07 | 方树彬 | Monoclonal antibody targeting pd-1 and use thereof |
| CN112225809B (en) * | 2019-06-30 | 2023-09-05 | 福州创方医药科技有限公司 | PD-1 targeting monoclonal antibody and application thereof |
| CN110478472B (en) * | 2019-09-29 | 2020-08-28 | 北京鼎成肽源生物技术有限公司 | PD-1 sealant and application thereof |
| CN110478472A (en) * | 2019-09-29 | 2019-11-22 | 北京鼎成肽源生物技术有限公司 | PD-1 sealer and its application |
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