CN105348388B - The antibody L3H3 of anti-CD20 antigens and its application - Google Patents
The antibody L3H3 of anti-CD20 antigens and its application Download PDFInfo
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Abstract
The invention discloses a kind of antibody L3H3 of anti-CD20 antigens and its applications.Anti- CD20 antigens provided by the invention, are named as L3H3 antibody, are a kind of IgG, are made of light chain and heavy chain；CDR1, CDR2 and CDR3 in light chain variable region in the light chain is followed successively by the sequence 1 of sequence table from the 61st 79 amino acids residue of N-terminal, the 89th 102 amino acids residue and the 112nd 123 amino acids residue；CDR1, CDR2 and CDR3 in heavy chain variable region in the heavy chain is followed successively by the sequence 3 of sequence table from the 50th 60 amino acids residue of N-terminal, the 82nd 97 amino acids residue and the 107th 120 amino acids residue.The present invention also protects application of the L3H3 antibody in preparing for B cell lymphoma medicine.The present invention is worth the treatment of B cell lymphoma with major application.
Description
Technical field
The present invention relates to a kind of antibody L3H3 of anti-CD20 antigens and its applications.
Background technology
Non-Hodgkin lymphoma (Non Hodgkin ' s lymphoma, NHL) is a kind of biological characteristics and tissue morphology
Different lymphoid malignancies are one of the ten big malignant tumours for threatening human life, in lymphoid malignancies about
There is 85% to derive from B cell.
CD20 molecules are a kind of B cell differentiation antigens, it is expressed in 95% or more B cell lymphoma, and in hematopoiesis
It is not expressed in stem cell, thick liquid cell and other normal structures.CD20 molecular weight is 33KD, is made of 279 amino acid residues
Non-glycosylated protein matter, starting be expressed in pre-B cell stages, until terminating when B cell terminal differentiation plasmablast, always
It is considered as the distinctive mark in bone-marrow-derived lymphocyte surface.CD20 molecules have 4 transmembrane regions, have between the third and fourth transmembrane region
One ring region being made of 43 amino acid residues constitutes its main epitope.CD20 molecules are in malignant B film
Surface expression is stablized, and will not fall off from tumour cell film surface after being combined with antibody, also without free CD20 in blood circulation
Molecule exists, and above-mentioned distinctive expression way and biological action determine that CD20 is B cell lymphoma mab treatment
When ideal target antigen.
1997, U.S.'s food has approved the human mouse chimeric antibody Rituximab of anti-CD20 with drug surveilance office (FDA)
(Rituximab, RTX) is used for the treatment of NHL.1998, European Union also ratified RTX listings, and RTX is combined with CD20 molecules to be caused
The immune response of lymphoma cell dissolving, possible mechanism of action include：The cytotoxicity (ADCC) of antibody-dependant, complement according to
It is bad cytotoxicity (CDC), apoptosis-induced.Though RTX can enhance the biological effect of antibody, since it is people's mouse inosculating antibody
Body, therefore will produce serious human anti-mouse antibody reaction (HAMA) in clinic, to influence the performance of its function.This project
By computer simulation, it is similar to chimeric antibody to filter out conformation from anti-human antibody library, but immunogenicity low-affinity is high
Humanized antibody, and the humanization antibody A DCC and CDC effects are detected.
Invention content
The object of the present invention is to provide a kind of antibody L3H3 of anti-CD20 antigens and its applications.
Anti- CD20 antigens provided by the invention, are named as L3H3 antibody, are a kind of IgG, are made of light chain and heavy chain；It is described
CDR1, CDR2 and CDR3 in light chain variable region in light chain is followed successively by the sequence 1 of sequence table from N-terminal 61-79 bit aminos
Sour residue, 89-102 amino acids residue and 112-123 amino acids residues；In heavy chain variable region in the heavy chain
CDR1, CDR2 and CDR3 are followed successively by the sequence 3 of sequence table from N-terminal 50-60 amino acids residue, 82-97 amino acids
Residue and 107-120 amino acids residues.
The light chain is concretely following (a) or (b)：(a) sequence 1 of sequence table is from N-terminal 21-233 amino acids
The protein of residue composition；(b) protein shown in the sequence 1 of sequence table；
The heavy chain is concretely following (c) or (d)：(c) sequence 3 of sequence table is from N-terminal 20-471 amino acids
The protein of residue composition；(d) protein shown in the sequence 3 of sequence table.
The present invention also protects the gene for encoding the L3H3 antibody, it is characterised in that：
The gene for encoding the light chain is following (1) or (2) or (3)：
(1) sequence 2 of sequence table DNA molecular shown in the nucleotide of 5 ' end 80-718；
(2) sequence 2 of sequence table DNA molecular shown in the nucleotide of 5 ' end 20-721；
(3) DNA molecular shown in the sequence 2 of sequence table；
The gene for encoding the heavy chain is following (4) or (5) or (6)：
(4) sequence 5 of sequence table DNA molecular shown in the nucleotide of 5 ' end 58-1413；
(5) DNA molecular shown in the sequence 5 of sequence table；
(6) DNA molecular shown in the sequence 4 of sequence table.
The present invention also protects application of the L3H3 antibody in preparing the drug for killing B cell lymphoma cell.
The B cell lymphoma cell is the B cell lymphoma cell for expressing CD20 antigens.The B cell lymphoma cell specifically may be used
For Daudi cells.
The present invention also protects a kind of drug for killing B cell lymphoma cell, active constituent anti-for the L3H3
Body.The B cell lymphoma cell is the B cell lymphoma cell for expressing CD20 antigens.The B cell lymphoma cell is specific
Can be Daudi cells.
The present invention also protects application of the L3H3 antibody in preparing for B cell lymphoma medicine.The B is thin
Born of the same parents' lymthoma is to express the B cell lymphoma of CD20 antigens.
The present invention is worth the treatment of B cell lymphoma with major application.
Description of the drawings
Fig. 1 is the elution curve in embodiment 2.
Fig. 2 is the 10%SDS-PAGE collection of illustrative plates in embodiment 2.
Fig. 3 is the result of the ADCC in embodiment 4.
Fig. 4 is the result of the CDC in embodiment 4.
Specific implementation mode
Embodiment below facilitates a better understanding of the present invention, but does not limit the present invention.Experiment in following embodiments
Method is unless otherwise specified conventional method.Test material as used in the following examples is unless otherwise specified certainly
What routine biochemistry reagent shop was commercially available.Quantitative test in following embodiment is respectively provided with three repeated experiments, as a result makes even
Mean value.
PcDNA-3.3 carriers (linear plasmid)：Invitrogen companies, catalog number (Cat.No.) K8300-01.POptiVEC carrier (lines
Property grain)：Invitrogen companies, catalog number (Cat.No.) 12744-017.CHO-DG44 cells：Invitrogen companies, catalog number (Cat.No.)
A13737-01。OptiPROTMSFM culture solutions：Invitrogen companies, catalog number (Cat.No.) 12309-050.Liposome
(FreeStyleTMMAX Reagent)：Invitrogen companies, catalog number (Cat.No.) 16447-100.CD DG44Medium：
Invitrogen companies, catalog number (Cat.No.) 12610-010.CD OptiCHOTMMedium：Invitrogen companies, catalog number (Cat.No.) 12681-
011.Rituximab (solution form；100mg/10ml, colourless transparent liquid；IgG, 6 institute of sequence of light chain such as sequence table
Show, heavy chain is as shown in the sequence 7 of sequence table)：German Roche Diagnostics GmbH, batch number H0119 inquire sequence
Row number：10000661731142.
There is Rituximab 30% or so mouse source protein, long-time service humanized murine antibodies can be caused to react and can not make
With.Therefore, seek the antibody of more efficiently anti-CD20 antigens seems particularly urgent for the treatment of B lymthomas.Inventor's base
In largely groping, analyze, verify, computer modeling and humanization modified is carried out, a kind of antibody of anti-CD20 antigens (life is devised
Entitled L3H3 antibody).L3H3 antibody is IgG, and light chain (being named as light chain L3) is as shown in the sequence 1 of sequence table, heavy chain (life
Entitled heavy chain H3) as shown in the sequence 3 of sequence table.
In the sequence 1 of sequence table, leader peptide, 21-131 amino acids are formed from N-terminal 1-20 amino acids residues
Residue forms light chain variable region VL (wherein, 61-79 amino acids residue composition CDR1,89-102 amino acids residue groups
CDR3 is formed at CDR2,112-123 amino acids residues), 132-233 amino acids residues form constant region of light chain CL.
In the sequence 3 of sequence table, leader peptide, 20-141 amino acids are formed from N-terminal 1-19 amino acids residues
Residue forms heavy chain variable region VH (wherein, 50-60 amino acids residue composition CDR1,82-97 amino acids residues composition
CDR2,107-120 amino acids residues form CDR3), 142-239 amino acids residues form heavy chain constant region CH1, the
240-254 amino acids residues form hinge area Hinge, 255-365 amino acids residue and form heavy chain constant region CH2, the
366-471 amino acids residues form heavy chain constant region CH3.
Embodiment 1, construction recombination plasmid
1, DNA molecular shown in the sequence of sequence table 2 is inserted into pcDNA-3.3 carriers, obtains recombinant plasmid pcDNA-
3.3-L3。
DNA molecular shown in the sequence 2 of sequence table is from the nucleotide coding leader peptide of 5 ' end 20-79,80-412
Position nucleotide coding VL, 413-718 nucleotide coding CL, 719-721 nucleotide are terminator codon.
2, DNA molecular shown in the sequence of sequence table 4 is inserted into pOptiVEC carriers, obtains recombinant plasmid pOptiVEC-
H3。
DNA molecular shown in the sequence 4 of sequence table is from the nucleotide coding leader peptide of 5 ' end 14-70,71-436
Position nucleotide coding VH, 437-730 nucleotide coding CH1,731-1118 nucleotide are introne, 1119-
1163 nucleotide coding Hinge, 1164-1281 nucleotide are introne, 1282-1614 nucleotide coding CH2,
1615-1711 nucleotide are introne, 1712-2029 nucleotide coding CH3, and 2030-2032 nucleotide are
Terminator codon, 2033-2231 nucleotide are introne.After removing introne, the code area in the sequence 4 of sequence table
As shown in the sequence 5 of sequence table.
Embodiment 2 prepares L3H3 antibody
1,10 μ g recombinant plasmids pcDNA-3.3-L3 and 10 μ g recombinant plasmid pOptiVEC-H3 are taken, OptiPRO is usedTM SFM
Culture solution is settled to 500 μ l, is placed at room temperature for 5min.
2, the liposome for taking 20 μ l, uses OptiPROTMSFM culture solutions are settled to 500 μ l, are placed at room temperature for 5min.
3, by the solution mixing of the solution of step 1 and step 2,20 minutes are placed at room temperature for.
4, CHO-DG44 cells are inoculated in the 125ml Tissue Culture Flasks (30ml culture mediums are housed in bottle) with vent filter
(about 3 × 106A cell/bottle), 800rpm centrifuges 4min before transfecting, and culture supernatant is abandoned in suction, and every bottle is added the fresh CD of 4ml
DG44Medium is resuspended.
5, the solution that step 3 obtains is added dropwise in the Tissue Culture Flask for completing step 4, mixing, containing 8%CO2's
37 DEG C in shaking table, (abandon supernatant, add again by first culture 6-8 hours, then 800rpm centrifugations 4min, suction within 5 days for 150rpm shaken cultivations
Enter the fresh CD OptiCHO of 30mlTMContinue to cultivate after Medium), 12000rpm centrifuges 15min, collects supernatant, adjusts pH extremely
6.0-7.0 collects filtrate then with 0.45 μm of membrane filtration.
6, the filtrate for taking step 5 to obtain is purified using rProtein A Sepharose 4B affinity columns.
RProtein A Sepharose 4B affinity columns (Pharmacia Corp, XK16 pillars)：Column volume is 40 millis
It rises, internal diameter is 16 millimeters.
Combination buffer (pH7.0)：20mM phosphate buffers containing 0.15MNaCl.
Elution buffer (pH3.0)：0.1M citrate buffer solutions.
Flow velocity：1-3ml/min.
Process：(1) 400ml binding buffer balance column are used；(2) loading；(3) 400ml combination buffer column scrubbers are used
Son；(4) 200ml elution buffers are used to elute destination protein, elution curve is shown in Fig. 1, collects retention volume and crosses column for 36-80ml
Solution afterwards.
7, the solution after crossing column that step 6 obtains is taken, pH to 7.0 is adjusted with Tris aqueous solutions (pH9.0), then using retention point
The super filter tube (Millipore companies) that son amount is 30kd is concentrated, and obtained solution is the solution of the antibody containing L3H3, name
For L3H3 solution.The 10%SDS-PAGE collection of illustrative plates of L3H3 solution is shown in Fig. 2.
8, recombinant plasmid pcDNA-3.3-L3 is replaced with pcDNA-3.3 carriers, recombinant plasmid is replaced with pOptiVEC carriers
POptiVEC-H3 carries out step 1 to 6, any eluting peak is not shown in elution process successively.
Embodiment 3, affinity detection
Beijing Co., Ltd of Ke Nuo Xingcheng Technologies is entrusted to complete, brief flow is as follows：It, will be biological using Fortebio instruments
(amino acid sequence of CD20 epitopes is the CD20 epitopes of elementization：CEPANPSEKNSPSTQYCYSIQ) immobilization arrives
On Steptavidin chips, the test antibodies solution for respectively flowing through 5 various concentrations (uses the PBS buffer solution of pH7.2,0.01M
L3H3 solution or Rituximab prepared by embodiment 1 are diluted, the test antibodies solution of various concentration, each test antibodies are obtained
Protein concentration in solution is respectively 0,25,50,75 or 100nmol/L), detection combines (Kon) and dissociation (Koff) numerical value,
To calculate affinity (Kd).
The affinity (Kd) of Rituximab is 6.48 × 10-9The affinity (Kd) of M, L3H3 antibody is 3.28 × 10-9M。
Embodiment 4, cell experiment
ADCC (antibody-dependent cell-mediated cytotoxicity, antibody-dependant it is cell-mediated
Cytotoxic effect) and CDC (complement dependent cytotoxicity, the cytotoxicity of Complement Dependent are made
With) it is the important function mode that antibody drug plays that targeting eliminates target cell.Both mechanism of action are researched and developed in antibody drug
Process can be applied to study in vitro, evaluate, screen high performance antibody drug, have very important significance.ADCC refers to
Express IgGFc receptors effector cell's (NK cells, macrophage and neutrophil leucocyte etc.) by with have been incorporated into tumour cell
The Fc sections of the IgG antibody on surface combine, and kill the effect of these target cells.CDC is by specific antibody and cell membrane table
Face corresponding antigens combine, and form compound and activating complement classical pathway, are formed by membrane attack complex and play target cell and split
Solve effect.Daudi cells (human lymphoma cell system)：ATCC catalog number (Cat.No.) CCL-213, through Flow cytometry (for detecting
The labelled antibody of CD20 antigens be 556632 purchased from BD Products catalog number (Cat.No.)s FITC Mouse Anti-Human
CD20), CD20 antigen presentations rate is 92%.DIO cell membrane green fluorescence probes：Sheng Ruitai scientific ＆ technical corporation in Beijing, catalog number (Cat.No.)
60011.PI dye liquors：Sigma companies, catalog number (Cat.No.) P4170-250MG.
One, the optimum amount of Rituximab is determined
37 DEG C of Rituximab and Daudi cells are acted on 30 minutes, and (reaction system is 1640 culture mediums of RPMI；Profit is appropriate
The concentration of former times monoclonal antibody in the reaction system is respectively 10 μ g/ml, 20 μ g/ml, 30 μ g/ml, 40 μ g/ml or 50 μ g/ml, with albumen
Densimeter；Daudi cells in the reaction system a concentration of 1 × 106/ ml), then use Flow cytometry Daudi thin
CD20 antigen presentations on born of the same parents, with its close to zero expression when a concentration of most suitable activity of Rituximab.
A concentration of 30 μ g/ml of the most suitable interaction in vitro of Rituximab.
Two, ADCC
1, using Ficoll-Hapaque separation peripheral blood lymphocytes (PBL).
2, (explanation of DIO cell membrane green fluorescence probes is pressed with DIO cell membrane green fluorescence probes label Daudi cells
Book operates), obtain the cell of DIO labels.
3, the cell that the DIO that step 2 obtains is marked is taken, 30min (reactants are incubated in 37 DEG C of incubators with test antibodies
System is 1640 culture mediums of RPMI；Test antibodies are L3H3 solution or Rituximab prepared by embodiment 1, and test antibodies are anti-
A concentration of 30 μ g/ml in system are answered, with albumen densimeter；Cell in the reaction system a concentration of 1 × 106/ ml), then
Cell is collected, is washed 2 times with the PBS buffer solution of pH7.2,0.01M.
4, the cell (target cell) that step 3 obtains is taken, the PBL obtained with step 1 (effector cell) is in 37 DEG C of incubators
Being incubated 4 hours, (reaction system is 1640 culture mediums of RPMI；Target cell in the reaction system a concentration of 1 × 104/ml；Effect
The concentration of cell in the reaction system is respectively 5 × 105/ ml or 2.5 × 105/ ml, i.e. target effect are than being respectively 1:50 or 1:25),
Then PI dye liquors are added and pass through Flow cytometry.
Three repeated samples of each processing setting, results are averaged.
The intact cell display green of DIO labels.Under the action of effector cell, target cell is broken, and PI enters nucleus
And dye, it is displayed in red.Target cell lysis rate=red cell quantity ÷ (red cell quantity+green cell quantity) ×
100%.
As a result see Fig. 3.The result shows that target effect than it is equal in the case of, the target cell lysis rate that L3H3 antibody is added is high
In the target cell lysis rate that Rituximab is added, i.e. the function and effect of L3H3 antibody are better than Rituximab, can more show
The promotion target cell lysis of work.
Three, CDC
1, (explanation of DIO cell membrane green fluorescence probes is pressed with DIO cell membrane green fluorescence probes label Daudi cells
Book operates), obtain the cell of DIO labels.
2, Healthy Human Serum is taken, inactivates, obtains inactivated serum.
3, the cell and test antibodies (L3H3 solution or rituximab prepared by embodiment 1 that the DIO that step 1 obtains is marked are taken
Monoclonal antibody) and the obtained inactivated serum of step 2 be incubated 4 hours in 37 DEG C of incubators (reaction system be RPMI1640 culture mediums；Target
Cell in the reaction system a concentration of 1 × 106/ml；A concentration of 30 μ g/ml of test antibodies in the reaction system, with albumen
Densimeter；The concentration expressed in percentage by volume of inactivated serum in the reaction system is respectively 20%, 10%；It is arranged and is added without inactivated serum
Control group is indicated with 0% serum-concentration), cell is then collected, is washed 2 times with the PBS buffer solution of pH7.2,0.01M.
4, the cell and test antibodies (L3H3 solution or rituximab prepared by embodiment 1 that the DIO that step 1 obtains is marked are taken
Monoclonal antibody) and Healthy Human Serum be incubated in 37 DEG C of incubators 4 hours (reaction system be 1640 culture mediums of RPMI；Target cell is anti-
Answer a concentration of 1 × 10 in system6/ml；A concentration of 30 μ g/ml of test antibodies in the reaction system, with albumen densimeter；It is strong
The concentration expressed in percentage by volume of health human serum in the reaction system is respectively 20%, 10%；The control for being added without Healthy Human Serum is set
Group is indicated with 0% serum-concentration), cell is then collected, is washed 2 times with the PBS buffer solution of pH7.2,0.01M.
5, the cell for taking step 3 or step 4 to obtain is resuspended with the PBS buffer solution of pH7.2,0.01M, obtains cell concentration
It is 1 × 105Then the cell suspension of/ml is added PI dye liquors and passes through Flow cytometry.
Three repeated samples of each processing setting, results are averaged.
The intact cell display green of DIO labels.Under the action of effector cell, target cell is broken, and PI enters nucleus
And dye, it is displayed in red.Target cell lysis rate=red cell quantity ÷ (red cell quantity+green cell quantity) ×
100%.
As a result see Fig. 4.The result shows that in the case where Healthy Human Serum is added, the target cell lysis of L3H3 antibody is added
Rate is better than Rituximab, Ke Yigeng higher than the target cell lysis rate that Rituximab is added, the i.e. function and effect of L3H3 antibody
Add significant promotion target cell lysis.
In conclusion L3H3 antibody has good anti-Daudi cells (the B cell lymphoma cell of expression CD20 antigens)
Growth is expected to become a kind of antibody drug for clinical treatment.
Claims (7)
1. a kind of IgG, is made of light chain and heavy chain；
The light chain is for following (a) or (b)：(a) sequence 1 of sequence table is formed from N-terminal 21-233 amino acids residues
Protein；(b) protein shown in the sequence 1 of sequence table；
The heavy chain is for following (c) or (d)：(c) sequence 3 of sequence table is formed from N-terminal 20-471 amino acids residues
Protein；(d) protein shown in the sequence 3 of sequence table.
2. encoding the gene of IgG described in claim 1, it is characterised in that：
The gene for encoding the light chain is following (1) or (2) or (3)：
(1) sequence 2 of sequence table DNA molecular shown in the nucleotide of 5 ' end 80-718；
(2) sequence 2 of sequence table DNA molecular shown in the nucleotide of 5 ' end 20-721；
(3) DNA molecular shown in the sequence 2 of sequence table；
The gene for encoding the heavy chain is following (4) or (5) or (6)：
(4) sequence 5 of sequence table DNA molecular shown in the nucleotide of 5 ' end 58-1413；
(5) DNA molecular shown in the sequence 5 of sequence table；
(6) DNA molecular shown in the sequence 4 of sequence table.
3. applications of the IgG described in claim 1 in preparing the drug for killing B cell lymphoma cell；The B cell leaching
Bar oncocyte is the B cell lymphoma cell for expressing CD20 antigens.
4. application as claimed in claim 3, it is characterised in that：The B cell lymphoma cell is Daudi cells.
5. a kind of drug for killing B cell lymphoma cell, active constituent is IgG described in claim 1；The B is thin
Born of the same parents' lymphoma cell is the B cell lymphoma cell for expressing CD20 antigens.
6. drug as claimed in claim 5, it is characterised in that：The B cell lymphoma cell is Daudi cells.
7. applications of the IgG described in claim 1 in preparing for B cell lymphoma medicine；The B cell lymphoma is thin
Born of the same parents are the B cell lymphoma cell for expressing CD20 antigens.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102050878A (en) * | 2009-10-30 | 2011-05-11 | 上海抗体药物国家工程研究中心有限公司 | Anti-human CD20 humanized antibody and preparation method and application thereof |
| CN103936858A (en) * | 2014-03-27 | 2014-07-23 | 安徽大学 | Antibody L5H6 with CD20-resistant antigen and application thereof |
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| SI1558648T1 (en) * | 2002-10-17 | 2012-05-31 | Genmab As | Human monoclonal antibodies against cd20 |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102050878A (en) * | 2009-10-30 | 2011-05-11 | 上海抗体药物国家工程研究中心有限公司 | Anti-human CD20 humanized antibody and preparation method and application thereof |
| CN103936858A (en) * | 2014-03-27 | 2014-07-23 | 安徽大学 | Antibody L5H6 with CD20-resistant antigen and application thereof |
Non-Patent Citations (2)
| Title |
|---|
| New anti-CD20 monoclonal antibodies: which is the best?;Anne-Laure Gagez;《Leukemia & Lymphoma》;20150131;第56卷(第1期);第1-2页 * |
| 抗CD20 人源化抗体的制备及生物学活性鉴定;杨扬;《现代免疫学》;20091130;第29卷(第6期);第491-496页 * |
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Effective date of registration: 20230109 Address after: Room 2275, Building D8, Innovation Industrial Park, No. 800, West Wangjiang Road, High tech Zone, Hefei City, Anhui Province, 230000 Patentee after: Anhui Zhongsheng Anlan Health Industry Co.,Ltd. Address before: C123, Science and Technology Building, Anda New Area, No. 111, Jiulong Road, Hefei City, Anhui Province, 230601 Patentee before: ANHUI University |