CN103936858A - Antibody L5H6 with CD20-resistant antigen and application thereof - Google Patents
Antibody L5H6 with CD20-resistant antigen and application thereof Download PDFInfo
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Abstract
The invention discloses an antibody L5H6 with a CD20-resistant antigen and application thereof. The antibody L5H6 with the CD20-resistant antigen is an IgG (intravenous gamma globulin), wherein a light chain of the IgG is composed of a light chain variable region and a light chain constant region, and a heavy chain of the IgG is composed of a heavy chain variable region, a hinge region and a heavy chain constant region; CDR1, CDR2 and CDR3 in the light chain variable region are sequentially 61st-74th amino acid residues, 89th-102nd amino acid residues and 112nd-123rd amino acid residues from the N tail end of a sequence 1 in a sequence table; CDR1, CDR2 and CDR3 in the heavy chain variable region are sequentially 57th-67th amino acid residues, 81st-96th amino acid residues and 106th-119th amino acid residues from the N tail end of a sequence 3 in the sequence table. The invention also discloses the application of the antibody L5H6 to preparation of a drug for treating B-cell lymphoma. The antibody L5H6 has an important application value for treatment of B-cell lymphoma.
Description
Technical field
The present invention relates to a kind of antibody L5H6 and application thereof of anti-CD20 antigen.
Background technology
World Health Organization's hematopoiesis in 2008 and Lymphoid tissue staging have been determined over 25 kinds of B cell lymphoma histological subtypes with extensive biology and Clinical symptoms.ACS's estimation, the U.S. in 2012 has 70130 routine B cell lymphoma new cases and is diagnosed, and 18940 routine patients will die from this disease.In U.S. adults, B cell lymphoma account for all cancers 4% and cancer associated death 3%.In Europe and North America, diffuse large B cell lymphoma is the common type (accounting for about 30% case) of non-Hodgkin lymphoma (NHL), is regarded as a kind of invasive cancer that need to treat immediately.Follicular lymphoma is the second the most common histological type (accounting for the case of about 25%-30%) of non-Hodgkin lymphoma.
Traditionally, lymph atomization is all by histologic analysis, to pick out the cell surface marker of expressing in lymphocyte generation specified phase to identify.CD20 antigen is a kind of B cell-specific differentiation antigen, at mature B cell with over 95%B cell non-Hodgkin's, expresses, but not B cell progenitor cell or mature plasme cell expression in late period in early days.CD20 antigen is comprised of 297 amino-acid residues, and molecular weight is 33kD, on film, relatively exposes, easily approach, be combined with monoclonal antibody rear without remarkable internalization and come off, can be because of antigenic modulation occurs with the combination of antibody, therefore become the desirable target spot for the treatment of B cell lymphoma yet.
Rituximab (Rituximab) is a kind of mosaic monoclonal antibody (having integrated human immunoglobulin G 1 heavy chain and mouse immune globulin variable zone) of the mankind of identification CD20 antigen.The approval of in November, 1997 Rituximab acquisition food and drug administration is used for the treatment of lymphadenomatous antibody.1998, European Union also ratified Rituximab listing, and commodity are called MabThera.Rituximab has remarkable result for the treatment of in recurrent, inertia non-Hodgkin lymphoma case, has started the epoch of mab treatment cancer.
Summary of the invention
The object of this invention is to provide a kind of antibody L5H6 and application thereof of anti-CD20 antigen.
Anti-CD20 antigen provided by the invention, called after L5H6 antibody, is a kind of IgG, and its light chain is comprised of variable region of light chain and constant region of light chain, and its heavy chain is comprised of variable region of heavy chain, hinge area and CH; CDR1 in described variable region of light chain, CDR2 and CDR3 are followed successively by the sequence 1 of sequence table from N-terminal 61-74 amino acids residue, 89-102 amino acids residue and 112-123 amino acids residue; CDR1 in described variable region of heavy chain, CDR2 and CDR3 are followed successively by the sequence 3 of sequence table from N-terminal 57-67 amino acids residue, 81-96 amino acids residue and 106-119 amino acids residue.
Described light chain specifically can be (a) as follows or (b): the protein that (a) sequence 1 of sequence table forms from N-terminal 21-234 amino acids residue; (b) protein shown in the sequence 1 of sequence table;
Described heavy chain specifically can be (c) as follows or (d): the protein that (c) sequence 3 of sequence table forms from N-terminal 20-470 amino acids residue; (d) protein shown in the sequence 3 of sequence table.
The present invention also protects the gene of the described L5H6 antibody of coding, it is characterized in that:
The gene of described light chain of encoding is following (1) or (2) or (3):
(1) sequence 2 of sequence table is from the DNA molecular shown in 5 ' end 74-715 position Nucleotide;
(2) sequence 2 of sequence table is from the DNA molecular shown in 5 ' end 14-718 position Nucleotide;
(3) DNA molecular shown in the sequence 2 of sequence table;
The gene of described heavy chain of encoding is following (4) or (5) or (6):
(4) sequence 5 of sequence table is from the DNA molecular shown in 5 ' end 58-1410 position Nucleotide;
(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 described L5H6 antibody in the application for the preparation of killing and wounding in the medicine of B cell lymphoma cell.Described B cell lymphoma cell is for expressing the B cell lymphoma cell of CD20 antigen.Described B cell lymphoma cell specifically can be Daudi cell.
The present invention also protects a kind of for killing and wounding the medicine of B cell lymphoma cell, and its activeconstituents is described L5H6 antibody.Described B cell lymphoma cell is for expressing the B cell lymphoma cell of CD20 antigen.Described B cell lymphoma cell specifically can be Daudi cell.
The present invention also protects described L5H6 antibody in the application for the preparation of in B cell lymphoma medicine.
The present invention has major application value for the treatment of B cell lymphoma.
Accompanying drawing explanation
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.
Embodiment
Following embodiment is convenient to understand better the present invention, but does not limit the present invention.Experimental technique in following embodiment, if no special instructions, is ordinary method.Test materials used in following embodiment, if no special instructions, is and purchases available from routine biochemistry reagent shop.Quantitative test in following examples, all arranges and repeats experiment, results averaged for three times.
PcDNA-3.3 carrier (linear plasmid): Invitrogen company, catalog number (Cat.No.) K8300-01.POptiVEC carrier (linear plasmid): Invitrogen company, catalog number (Cat.No.) 12744-017).CHO-DG44 cell: Invitrogen company, catalog number (Cat.No.) A13737-01.OptiPRO
tMsFM nutrient solution: Invitrogen company, catalog number (Cat.No.) 12309-050.Liposome (FreeStyle
tMmAX Reagent): Invitrogen company, catalog number (Cat.No.) 16447-100.CD DG44Medium:Invitrogen company, catalog number (Cat.No.) 12610-010.CD OptiCHO
tMmedium:Invitrogen company, catalog number (Cat.No.) 12681-011.Rituximab (solution form; 100mg/10ml, colourless transparent liquid; IgG, its light chain is as shown in the sequence 6 of sequence table, its heavy chain is as shown in the sequence 7 of sequence table): German Roche Diagnostics GmbH, lot identification mark H0119, search sequence number: 10000661731142).
Rituximab has the mouse source protein of 30% left and right, and life-time service can cause mouse-anti people antibody response and cannot use.Therefore the antibody of, seeking more efficiently anti-CD20 antigen seems particularly urgent for the lymphadenomatous treatment of B.Contriver, based on groping in a large number, analyze, verifying, carries out microcomputer modelling and humanization modified, has designed a kind of antibody (called after L5H6 antibody) of anti-CD20 antigen.L5H6 antibody is IgG, and its light chain (called after light chain L5) is as shown in the sequence 1 of sequence table, and its heavy chain (called after heavy chain H6) is as shown in the sequence 3 of sequence table.
In the sequence 1 of sequence table, from N-terminal 1-20 amino acids residue, form leading peptide, 21-131 amino acids residue forms variable region of light chain VL(wherein, 61-74 amino acids residue forms CDR1,89-102 amino acids residue forms CDR1,112-123 amino acids residue composition CDR3), 132-234 amino acids residue forms constant region of light chain CL.
In the sequence 3 of sequence table, from N-terminal 1-19 amino acids residue, form leading peptide, 20-140 amino acids residue forms variable region of heavy chain VH(wherein, 57-67 amino acids residue forms CDR1,81-96 amino acids residue forms CDR2,106-119 amino acids residue composition CDR3), 141-238 amino acids residue forms CH CH1,239-253 amino acids residue forms hinge area Hinge, 254-364 amino acids residue forms CH CH2, and 365-470 amino acids residue forms CH CH3.
Embodiment 1, construction recombination plasmid
1, the DNA molecular of the coding light chain L5 shown in the sequence of sequence table 2 is inserted to pcDNA-3.3 carrier, obtain recombinant plasmid pcDNA-3.3-L5.
DNA molecular shown in the sequence 2 of sequence table is from 5 ' end 14-73 position nucleotide coding leading peptide, 74-406 position nucleotide coding VL, and 407-715 position nucleotide coding CL, 716-718 position Nucleotide is terminator codon.
2, the DNA molecular of the encoding heavy chain H6 shown in the sequence of sequence table 4 is inserted to pOptiVEC carrier, obtain recombinant plasmid pOptiVEC-H6.
DNA molecular shown in the sequence 4 of sequence table is from 5 ' end 14-70 position nucleotide coding leading peptide, 71-433 position nucleotide coding VH, 434-727 position nucleotide coding CH1 regional code CH1,728-1115 position Nucleotide is intron, 1116-1160 position nucleotide coding Hinge, 1161-1278 position Nucleotide is intron, 1279-1611 position nucleotide coding CH2,1612-1708 position Nucleotide is intron, 1709-2026 position nucleotide coding CH3,2027-2029 position Nucleotide is terminator codon.Remove after intron, the coding region in the sequence 4 of sequence table is as shown in the sequence 5 of sequence table.
Embodiment 2, preparation L5H6 antibody
1, get 10 μ g recombinant plasmid pcDNA-3.3-L5 and 10 μ g recombinant plasmid pOptiVEC-H6, use OptiPRO
tMsFM nutrient solution is settled to 500 μ l, and room temperature is placed 5min.
2, get the liposome of 20 μ l, use OptiPRO
tMsFM nutrient solution is settled to 500 μ l, and room temperature is placed 5min.
3, the solution of the solution of step 1 and step 2 is mixed, room temperature is placed 20 minutes.
4, inoculation CHO-DG44 cell (approximately 1 * 10 in the 125ml Tissue Culture Flask with vent filter (in bottle, 20ml substratum being housed)
6individual cell/bottle), when being cultured to cell density and being 80-90%, the centrifugal 4min of 800rpm, inhales and abandons culture supernatant, and every bottle adds the fresh CD DG44Medium of 4ml resuspended.
5, solution step 3 being obtained dropwise adds in the Tissue Culture Flask of completing steps 4, mixes, and is containing 8%CO
2shaking table in 37 ℃, 150rpm shaking culture within 5 days, (first cultivate 6-8 hour, then the centrifugal 4min of 800rpm, inhales and abandons supernatant, rejoins the CD OptiCHO that 30ml is fresh
tMafter Medium, continue to cultivate), the centrifugal 15min of 12000rpm, collects supernatant liquor, adjusts pH to 6.0-7.0, then uses 0.45 μ m membrane filtration, collects filtrate.
6, get the filtrate that step 5 obtains, adopt rProtein A Sepharose4B affinity column to carry out purifying.
RProtein A Sepharose4B affinity column (Pharmacia Corp, XK16 pillar): column volume is 40 milliliters, and internal diameter is 16 millimeters.
Binding buffer liquid (pH7.0): containing the 20mM phosphate buffered saline buffer of 0.15M NaCl.
Elution buffer (pH3.0): 0.1M citrate buffer solution.
Flow velocity: 1-3ml/min.
Process: (1) uses 400ml binding buffer liquid balance pillar; (2) loading; (3) with 400ml binding buffer liquid washing pillar; (4) use 200ml elution buffer wash-out target protein, elution curve is shown in Fig. 1, solution after the post excessively that collection retention volume is 32-80ml.
That 7, gets that step 6 obtains crosses solution after post, with the Tris aqueous solution (pH9.0), adjust pH to 7.0, then use the super filter tube that molecular weight cut-off is 30kd (Millipore company) to concentrate, the solution obtaining is the solution containing L5H6 antibody, called after L5H6 solution.Fig. 2 is shown in by the 10%SDS-PAGE collection of illustrative plates of L5H6 solution.
8, with pcDNA-3.3 carrier, replace recombinant plasmid pcDNA-3.3-L5, with pOptiVEC carrier, replace recombinant plasmid pOptiVEC-H6, carry out successively step 1 to 6, in elution process, do not show any elution peak.
Embodiment 3, avidity detect
Entrust Beijing company limited of Ke Nuo Xingcheng Technology to complete, concise and to the point flow process is as follows: utilize Fortebio instrument, by biotinylated CD20 epitope, (aminoacid sequence of CD20 epitope is: CEP
aNPSeKNSPSTQ
yCYSIq) immobilization is to Steptavidin chip, the antibody-solutions to be measured that flows through respectively 5 different concns (dilutes L5H6 solution or the Rituximab of embodiment 1 preparation with the PBS damping fluid of pH7.2,0.01M, obtain the antibody-solutions to be measured of different concns, protein concn in each antibody-solutions to be measured be respectively 0,25,50,75 or 100nmol/L), detect in conjunction with (Kon) and (Koff) numerical value that dissociates, thereby calculate avidity (Kd).
The avidity of Rituximab (Kd) is 6.48 * 10
-9m, the avidity of L5H6 antibody (Kd) is 2.66 * 10
-9m.
Embodiment 4, cell experiment
ADCC(antibody-dependent cell-mediated cytotoxicity, the cell-mediated cytotoxic effect that antibody relies on) and CDC(complement dependent cytotoxicity, be the cytotoxic effect of Complement Dependent) the vital role mode of antibody drug performance targeting elimination target cell.These two kinds of mechanism of action can be applicable to study in vitro in antibody drug R&D process, evaluate, screen high performance antibody drug, have very important significance.ADCC refers to that effector cell's (NK cell, scavenger cell and neutrophil leucocyte etc.) of expressing IgG Fc acceptor is by being combined with the Fc section that is combined in the IgG antibody of tumor cell surface, and the effect that kills and wounds these target cells.CDC is combined with surface of cell membrane corresponding antigens by specific antibody, forms mixture and activating complement classical pathway, and formed membrane attack complex is to target cell performance cracking effect.Daudi cell (human lymphoma cell system): ATCC catalog number (Cat.No.) CCL-213, through Flow cytometry (being the FITC Mouse Anti-Human CD20 that is 556632 purchased from BD company catalog number for detection of the traget antibody of CD20 antigen), CD20 antigen presentation rate is 92%.DIO cytolemma green fluorescence probe: Sheng Ruitai scientific & technical corporation in Beijing, catalog number (Cat.No.) 60011.PI dye liquor: Sigma company, catalog number (Cat.No.) P4170-250MG.
One, determine the optimum amount of Rituximab
By 37 ℃ of effects of Rituximab and Daudi cell, within 30 minutes, (reaction system is DMEM in high glucose substratum; The concentration of Rituximab in 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, in protein concentration; The concentration of Daudi cell in reaction system is 1 * 10
6/ ml), then adopt the CD20 antigen presentation on Flow cytometry Daudi cell, the Rituximab concentration while take its approaching zero expression is most suitable activity.
The most suitable interaction in vitro concentration of Rituximab is 30 μ g/ml.
Two, ADCC
1, adopt the separated peripheral blood lymphocyte (PBL) of Ficoll-Hapaque.
2,, with DIO cytolemma green fluorescence probe mark Daudi cell (pressing the specification sheets operation of DIO cytolemma green fluorescence probe), obtain the cell of DIO mark.
3, the cell of getting the DIO mark that step 2 obtains, in 37 ℃ of incubators, hatching 30min(reaction system with antibody to be measured is DMEM in high glucose substratum; Antibody to be measured is L5H6 solution or the Rituximab of embodiment 1 preparation, and the concentration of antibody to be measured in reaction system is 30 μ g/ml, in protein concentration; The concentration of cell in reaction system is 1 * 10
6/ ml), then collecting cell, washs 2 times with the PBS damping fluid of pH7.2,0.01M.
4, get the cell (target cell) that step 3 obtains, the PBL(effector cell who obtains with step 1) in 37 ℃ of incubators, hatch that (reaction system was DMEM in high glucose substratum in 4 hours; The concentration of target cell in reaction system is 1 * 10
4/ ml; The concentration of effector cell in reaction system is respectively 1 * 10
6/ ml, 5 * 10
5/ ml or 2.5 * 10
5/ ml, target effect is than being respectively 1:100,1:50 or 1:25), then add PI dye liquor and pass through Flow cytometry.
Each processing arranges three repeated sample, results averaged.
The intact cell of DIO mark shows green.Under effector cell's effect, target cell is broken, and PI enters nucleus dyeing, shows red.Target cell cleavage rate=red cell quantity ÷ (red cell quantity+green cell quantity) * 100%.
The results are shown in Figure 3.Result shows, in target effect, than equal in the situation that, adds the target cell cleavage rate of L5H6 antibody higher than the target cell cleavage rate that adds Rituximab, and the action effect of L5H6 antibody is better than Rituximab, can promote more significantly target cell cracking.
Three, CDC
1,, with DIO cytolemma green fluorescence probe mark Daudi cell (pressing the specification sheets operation of DIO cytolemma green fluorescence probe), obtain the cell of DIO mark.
2, get Healthy Human Serum, deactivation, obtains inactivated serum.
3, the inactivated serum that get the cell of the DIO mark that step 1 obtains, obtains with antibody to be measured (L5H6 solution or the Rituximab of embodiment 1 preparation) and step 2 hatches in 37 ℃ of incubators that (reaction system was DMEM in high glucose substratum in 4 hours; The concentration of target cell in reaction system is 1 * 10
6/ ml; The concentration of antibody to be measured in reaction system is 30 μ g/ml, in protein concentration; The concentration expressed in percentage by volume of inactivated serum in reaction system is respectively 20%, 10%; The control group that does not add inactivated serum is set, with 0% serum-concentration, represents), then collecting cell, washs 2 times with the PBS damping fluid of pH7.2,0.01M.
4, get the cell of the DIO mark that step 1 obtains, with antibody to be measured (L5H6 solution or the Rituximab of embodiment 1 preparation) with Healthy Human Serum is hatched in 37 ℃ of incubators, and within 4 hours, (reaction system is DMEM in high glucose substratum; The concentration of target cell in reaction system is 1 * 10
6/ ml; The concentration of antibody to be measured in reaction system is 30 μ g/ml, in protein concentration; The concentration expressed in percentage by volume of Healthy Human Serum in reaction system is respectively 20%, 10%; The control group that does not add Healthy Human Serum is set, with 0% serum-concentration, represents), then collecting cell, washs 2 times with the PBS damping fluid of pH7.2,0.01M.
5, get the cell that step 3 or step 4 obtain, resuspended with the PBS damping fluid of pH7.2,0.01M, obtaining cell concn is 1 * 10
5the cell suspension of/ml, then adds PI dye liquor and passes through Flow cytometry.
Each processing arranges three repeated sample, results averaged.
The intact cell of DIO mark shows green.Under effector cell's effect, target cell is broken, and PI enters nucleus dyeing, shows red.Target cell cleavage rate=red cell quantity ÷ (red cell quantity+green cell quantity) * 100%.
The results are shown in Figure 4.Result shows, in the situation that adding Healthy Human Serum, adds the target cell cleavage rate of L5H6 antibody higher than the target cell cleavage rate that adds Rituximab, and the action effect of L5H6 antibody is better than Rituximab, can promote more significantly target cell cracking.
In sum, L5H6 antibody has good anti-Daudi cell (expressing the B cell lymphoma cell of CD20 antigen) growth, is expected to become a kind of antibody drug for clinical treatment.
Claims (10)
1. an IgG, its light chain is comprised of variable region of light chain and constant region of light chain, and its heavy chain is comprised of variable region of heavy chain, hinge area and CH; CDR1 in described variable region of light chain, CDR2 and CDR3 are followed successively by the sequence 1 of sequence table from N-terminal 61-74 amino acids residue, 89-102 amino acids residue and 112-123 amino acids residue; CDR1 in described variable region of heavy chain, CDR2 and CDR3 are followed successively by the sequence 3 of sequence table from N-terminal 57-67 amino acids residue, 81-96 amino acids residue and 106-119 amino acids residue.
2. IgG as claimed in claim 1, is characterized in that:
Described light chain is following (a) or (b): the protein that (a) sequence 1 of sequence table forms from N-terminal 21-234 amino acids residue; (b) protein shown in the sequence 1 of sequence table;
Described heavy chain is following (c) or (d): the protein that (c) sequence 3 of sequence table forms from N-terminal 20-470 amino acids residue; (d) protein shown in the sequence 3 of sequence table.
3. the gene of IgG described in the claim 2 of encoding, is characterized in that:
The gene of described light chain of encoding is following (1) or (2) or (3):
(1) sequence 2 of sequence table is from the DNA molecular shown in 5 ' end 74-715 position Nucleotide;
(2) sequence 2 of sequence table is from the DNA molecular shown in 5 ' end 14-718 position Nucleotide;
(3) DNA molecular shown in the sequence 2 of sequence table;
The gene of described heavy chain of encoding is following (4) or (5) or (6):
(4) sequence 5 of sequence table is from the DNA molecular shown in 5 ' end 58-1410 position Nucleotide;
(5) DNA molecular shown in the sequence 5 of sequence table;
(6) DNA molecular shown in the sequence 4 of sequence table.
Described in claim 1 or 2 IgG in the application for the preparation of killing and wounding in the medicine of B cell lymphoma cell.
5. application as claimed in claim 4, is characterized in that: described B cell lymphoma cell is for expressing the B cell lymphoma cell of CD20 antigen.
6. application as claimed in claim 4, is characterized in that: described B cell lymphoma cell is Daudi cell.
7. for killing and wounding a medicine for B cell lymphoma cell, its activeconstituents is IgG described in claim 1 or 2.
8. medicine as claimed in claim 7, is characterized in that: described B cell lymphoma cell is for expressing the B cell lymphoma cell of CD20 antigen.
9. medicine as claimed in claim 7, is characterized in that: described B cell lymphoma cell is Daudi cell.
Described in claim 1 or 2 IgG in the application for the preparation of in B cell lymphoma medicine.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN103897059A (en) * | 2014-03-27 | 2014-07-02 | 中国人民解放军军事医学科学院生物工程研究所 | Antibody L5H7 of anit-CD20 antigen and application of antibody L5H7 |
| CN105348388A (en) * | 2015-12-11 | 2016-02-24 | 安徽大学 | Antibody L3H3 of CD20-resistant antigen and application of antibody L3H3 |
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| CN100460421C (en) * | 2002-12-16 | 2009-02-11 | 健泰科生物技术公司 | Immunoglobulin variants and uses thereof |
| US20110195022A1 (en) * | 2010-02-10 | 2011-08-11 | Immunogen Inc. | Cd20 antibodies and uses thereof |
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| CN100460421C (en) * | 2002-12-16 | 2009-02-11 | 健泰科生物技术公司 | Immunoglobulin variants and uses thereof |
| US20110195022A1 (en) * | 2010-02-10 | 2011-08-11 | Immunogen Inc. | Cd20 antibodies and uses thereof |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103897059A (en) * | 2014-03-27 | 2014-07-02 | 中国人民解放军军事医学科学院生物工程研究所 | Antibody L5H7 of anit-CD20 antigen and application of antibody L5H7 |
| CN105348388A (en) * | 2015-12-11 | 2016-02-24 | 安徽大学 | Antibody L3H3 of CD20-resistant antigen and application of antibody L3H3 |
| CN105348388B (en) * | 2015-12-11 | 2018-10-19 | 安徽大学 | The antibody L3H3 of anti-CD20 antigens and its application |
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