CN109400709B - Bifunctional antibodies and uses thereof - Google Patents
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Abstract
The invention provides a bifunctional antibody, which is a divisional application of Chinese patent 201510782939.2. The bifunctional antibody of the invention can be specifically combined with human TNF-alpha; and at the same time, can be specifically combined with human P40. The bifunctional antibody can effectively block the combination of the human IL-12 and the IL-12 receptor and the combination of the human TNF-alpha and the TNF-alpha receptor. The bifunctional antibody can simultaneously bind human TNF-alpha and human P40 protein, can effectively inhibit the combination of TNF-alpha and IL-12 and corresponding receptors, thereby respectively inhibiting the secretion of inflammatory cytokines and IFNgamma molecules, and can be used for treating rheumatoid arthritis, chronic plaque psoriasis, moderate-to-severe Crohn's disease, moderate-to-severe ulcerative colitis, ankylosing spondylitis, psoriatic arthritis, moderate-to-severe polyarthritis juvenile idiopathic arthritis and Crohn's disease children patients.
Description
The present application is a divisional application entitled "bifunctional antibody and use thereof" on Chinese application date 2015, 11/13/application number 201510782939.2.
Technical Field
The present invention relates to antibodies, and in particular to bifunctional antibodies capable of simultaneously blocking the binding of human TNF- α to the TNF- α receptor and blocking the binding of human IL-12 to the IL-12 receptor.
Background
Humira (Adalilimumab) is a recombinant fully humanized tumor necrosis factor alpha monoclonal antibody expressed in Chinese hamster ovary cells. In addition to moderate to severe rheumatoid arthritis, FDA approved indications include the therapeutic use of moderate to severe chronic plaque psoriasis, moderate to severe crohn's disease, moderate to severe ulcerative colitis, ankylosing spondylitis, psoriatic arthritis, moderate to severe polyarticular juvenile idiopathic arthritis, crohn's disease pediatric patients. In 2013, among ten popular brand medicines worldwide, adalimumab sales were $ 106.6 billion, growth rate was 15.0%, and ranked the first.
The monoclonal antibody Stelara (Ustekinumab) acts on the common subunit P40 of IL-12 and IL-23, and plays a role in resisting psoriasis by blocking the downstream signaling pathways of IL-12 and IL-23. Stellara was approved by the us FDA in 2009 for the treatment of severe psoriasis in adults. A phase III clinical study in patients with moderate to severe psoriasis showed that p40 mab was more therapeutically superior and required far fewer injections than etanercept. According to the 17 th meeting report of European academy of dermatology: treatment was performed for 12 weeks with p40 mab (both low 45mg and high 90 mg) and etanercept, respectively, with the p40 mab group co-administered 2 times at the start of treatment and week 4, and the etanercept group 2 times per week. The results showed that the psoriasis severity remission rate reached 75%, 68% and 74% for the p40 mab 45mg and 90mg dose groups, respectively, and 57% for the etanercept group.
The monoclonal antibody is targeted at a single target, a large number of complex diseases such as tumors, rheumatoid arthritis, tumors, autoimmune diseases, organ complications of metabolic diseases, senile degenerative diseases and the like have multiple pathogenesis, and various pathogenesis can affect each other and are sometimes in a network shape, so that the diseases are caused together. Monoclonal antibodies directed against a single target of a disease have limited potency. The bifunctional antibody intervenes in the most important pathogenesis (signal path) in the disease process simultaneously, and is expected to obtain the addition or the cooperation of the drug effects and obtain better clinical curative effect. The simultaneous intervention and blocking of TNF-alpha and P40 is expected to achieve better curative effect in psoriasis treatment compared with single target intervention. There is therefore a need to develop bifunctional antibodies that antagonize both TNF- α and anti-P40.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provides three bifunctional antibodies, wherein the three antibodies can block the combination of human TNF-alpha and TNF-alpha receptor and can also block the combination of human IL-12 and IL-12 receptor, and the invention also provides the application of the three bifunctional antibodies.
In order to realize the purpose, the technical scheme is as follows: a bifunctional antibody comprises 2 identical light chains and 2 identical heavy chains, wherein the amino acid sequences of the light chains are shown as SEQ ID NO.1, and the amino acid sequences of the heavy chains are shown as SEQ ID NO. 2. The bifunctional antibody described herein was designated bifunctional antibody BIAU 003.
A bifunctional antibody comprises 2 identical light chains and 2 identical heavy chains, wherein the amino acid sequences of the light chains are shown as SEQ ID NO.4, and the amino acid sequences of the heavy chains are shown as SEQ ID NO. 3. The bifunctional antibody described herein was named bifunctional antibody BIAU 022.
A bifunctional antibody comprises 2 identical light chains and 2 identical heavy chains, wherein the amino acid sequences of the light chains are shown as SEQ ID NO.1, and the amino acid sequences of the heavy chains are shown as SEQ ID NO. 5. The bifunctional antibody described herein was designated bifunctional antibody BIAU 023.
The invention provides application of the three bifunctional antibodies in preparing a preparation for blocking the combination of human TNF-alpha and TNF-alpha receptor and/or blocking the combination of human IL-12 and IL-12 receptor.
The invention also provides application of the three bifunctional antibodies in preparing a medicament for treating rheumatoid arthritis, chronic plaque psoriasis, moderate-to-severe Crohn's disease, moderate-to-severe ulcerative colitis, ankylosing spondylitis, psoriatic arthritis, moderate-to-severe polyarticular juvenile idiopathic arthritis or pediatric patients with Crohn's disease.
The invention has the beneficial effects that: the invention provides three bifunctional antibodies, wherein 3 bifunctional antibodies can be specifically combined with human TNF-alpha; meanwhile, 3 bifunctional antibodies can be specifically combined with human P40. The three bifunctional antibodies can effectively block the combination of the IL-12 and the IL-12 receptor and can effectively block the combination of the TNF-alpha and the TNF-alpha receptor. The 3 bifunctional antibodies can simultaneously bind to human TNF-alpha and human P40 protein, can effectively inhibit the combination of TNF-alpha and IL-12 and corresponding receptors, thereby respectively inhibiting the secretion of inflammatory cytokines and IFNgamma molecules, and can be used for treating rheumatoid arthritis, chronic plaque psoriasis, moderate-to-severe Crohn's disease, moderate-to-severe ulcerative colitis, ankylosing spondylitis, psoriatic arthritis, moderate-to-severe polyarticular juvenile idiopathic arthritis and Crohn's disease pediatric patients.
Drawings
FIG. 1 is a schematic structural diagram of the bifunctional antibody BIAU003 of the present invention;
FIG. 2 is a schematic structural diagram of the bifunctional antibody BIAU022 of the present invention;
FIG. 3 is a schematic structural diagram of the bifunctional antibody BIAU 023;
FIG. 4 shows the results of detection of the binding ability (A) to p40 and the binding ability (B) to TNF-. alpha.of the bifunctional antibodies BIAU003, BIAU022 and BIAU023 according to the present invention by ELISA method in example 4 of the present invention;
FIG. 5 shows the results of the inhibition of TNF-. alpha.induced cell surface adhesion molecule ELAM-1 expression by the bifunctional antibodies BIAU003, BIAU022 and BIAU023 of the present invention in example 5 of the present invention;
FIG. 6 shows the results of the inhibition of IL-12-induced IFNgamma secretion by the bifunctional antibodies BIAU003, BIAU022 and BIAU023 of the present invention in example 6 of the present invention;
FIG. 7 shows the results of the inhibition of skin thickening in psoriatic mice by the bifunctional antibodies BIAU003, BIAU022 and BIAU023 of the present invention.
Detailed Description
To better illustrate the objects, aspects and advantages of the present invention, the present invention will be further described with reference to specific examples. The amino acid sequence of the light chain of the bifunctional antibody BIAU003 is shown as SEQ ID NO.1, and the amino acid sequence of the heavy chain of the bifunctional antibody BIAU003 is shown as SEQ ID NO. 2; the amino acid sequence of the light chain of the bifunctional antibody BIAU022 is shown as SEQ ID NO.4, and the amino acid sequence of the heavy chain of the bifunctional antibody BIAU003 is shown as SEQ ID NO. 3; the amino acid sequence of the light chain of the bifunctional antibody BIAU003 is shown as SEQ ID NO.1, and the amino acid sequence of the heavy chain of the bifunctional antibody BIAU003 is shown as SEQ ID NO. 5.
The structural schematic diagram of the bifunctional antibody BIAU003 is shown in FIG. 1, wherein the heavy chain consists of the following parts: a heavy chain variable region of the first antibody-a first antibody heavy chain constant region-GGGGS amino acid linker-a second antibody heavy chain variable region-GGGGS amino acid linker-a second antibody light chain variable region; that is, the complete heavy chain of the first antibody is linked to the heavy chain variable region of the second antibody-the light chain variable region of the second antibody by amino acids. The light chain is composed of the following parts: the intact light chain of the first antibody.
The structural schematic diagram of the bifunctional antibody BIAU022 of the invention is shown in FIG. 2, wherein the heavy chain is composed of the following parts: heavy chain variable region of second antibody-GGGGS amino acid linker-heavy chain variable region of first antibody-heavy chain constant region of first antibody; that is, the heavy chain variable region of the second antibody is amino acid-linked to the entire heavy chain of the first antibody. The light chain is composed of the following parts: light chain variable region of second antibody-GGGGS amino acid linker-light chain variable region of first antibody-light chain constant region of first antibody; that is, the light chain variable region of the second antibody is linked to the entire light chain of the first antibody by amino acids.
The structural schematic diagram of the bifunctional antibody BIAU023 is shown in figure 3, wherein a heavy chain consists of the following parts: the complete heavy chain of the first antibody-GGGGS amino acid linker-the heavy chain variable region of the second antibody-the light chain constant region of the second antibody-GGGGS amino acid linker-the light chain variable region of the second antibody-the heavy chain constant region of the second antibody 1; the light chain is composed of the following parts: intact light chain of primary antibody.
Example 1: preparation of proteins of bifunctional antibodies BIAU003, BIAU022 and BIAU023 of the invention
The cDNA of the heavy chain and the light chain of the bifunctional antibodies BIAU003, BIAU022 and BIAU023 are artificially synthesized respectively according to the heavy chain and the light chain amino acid sequences of the bifunctional antibodies BIAU003, BIAU022 and BIAU 023. All cdnas were codon optimized and used for mammalian cell expression. The synthesized cDNAs were cloned into pcDNA3.1 plasmid, respectively, and the plasmid construction was confirmed by sequencing to be correct. The sequenced plasmid was transformed into TOP10 strain, a single colony was picked up and inoculated into 0.5L LB liquid medium to an OD600 of 0.8, the cells were collected by centrifugation, and the plasmid was extracted using a plasmid macroextraction kit (purchased from Qiagen). The plasmid containing the light chain of the bifunctional antibody BIAU003 and the plasmid containing the heavy chain of the bifunctional antibody BIAU003, which are identified by sequencing, are co-transfected into the same 293F cell, the plasmid containing the light chain of the bifunctional antibody BIAU022, which is identified by sequencing, and the plasmid containing the heavy chain of the bifunctional antibody BIAU022, which is identified by sequencing, are co-transfected into another 293F cell, and the plasmid containing the light chain of the bifunctional antibody BIAU023, which is identified by sequencing, and the plasmid containing the heavy chain of the bifunctional antibody BIAU023, which is identified by sequencing, are co-transfected into another 293F cell. Transfected cells were cultured at 37 degrees, 5% CO2, 130 rpm/min. After 7 days of culture, the supernatant was collected by centrifugation. Centrifuging the supernatant at 6000rpm for 10min, filtering with 0.45 μm filter membrane, and collecting filtrate; adding 500mM NaCl into the filtrate; the pH was adjusted to 7.4. After re-filtration through a 0.2 μm filter, the sample was applied to a HiTrap MabSelect column (from GE) equilibrated with PBS; after the sample is applied, the sample is washed with PBS at a flow rate of 5ml/min and UV-monitoring is horizontal. Followed by elution with elution Buffer (0.5M Glycine, pH 3.0) at a flow rate of 1ml/min, and collection of the effluent peak neutralized with Tris to pH 7.4. Concentrating the eluted peak with ultrafiltering concentration tube, and transferring the buffer solution to PBS with desalting column to obtain 3 kinds of bifunctional antibodies including BIAU003, BIAU022 and BIAU 023.
Example 2: SPR measurement of the antigen binding Capacity of the bifunctional antibodies of the invention, BIAU003, BIAU022 and BIAU023
Affinity for p40 and TNF-. alpha.and binding kinetics were analyzed by SPR (obtained from GE). P40 or TNF-. alpha.was covalently attached to the chip via primary amines (carboxymethyl dextran coated chip) using standard amine coupling chemistry and chips supplied by GE corporation. The recombinant fusion protein was covalently coupled to biotin using a biotin labeling kit (Pierce), and then passed through an avidin-labeled SA chip (purchased from GE) to achieve a reaction value RU of 450. Binding and dissociation constants were measured by flowing the antibody in PBS buffer at concentrations of 0.01, 0.03, 0.09, 0.27. mu.M and a flow rate of 50. mu.l/min. Antigen-antibody binding kinetics were followed for 3 minutes and dissociation kinetics were followed for 10 minutes. Binding and dissociation curves were fitted to a 1: 1 Langmuir (Langmuir) binding model using BIAEvaluation software and the assay results indicated: BIAU003, BIAU022 and BIAU023 are all capable of binding to p40 and TNF-alpha. The results of the Kd, Kon and Koff values determined are shown in tables one and two.
TABLE-SPR measurement of the ability of the bifunctional antibodies of the present invention to bind to antigen p40
| Name of antibody | Kon(105M-1S-1) | Koff(10-5S-1) | Kd(nm) |
| BIAU003 | 1.87 | 2.02 | 0.11 |
| BIAU022 | 1.74 | 2.19 | 0.13 |
| BIAU023 | 0.87 | 2.96 | 0.34 |
TABLE-SPR results of determination of the ability of the bifunctional antibodies of the present invention to bind to the antigen TNF- α
Example 3: competitive ELISA method for determining bifunctional antibodies BIAU003, BIAU022 and BIAU023 of the invention compete with TNF-alpha receptor for binding antigen TNF-alpha
TNF-alpha-mFc is used for coating an enzyme label plate, 1% BSA is used for blocking, antibodies BIAU003, BIAU022 and BIAU023 with different concentrations and TNF-alpha receptor-hFc are respectively mixed, enzyme-labeled secondary antibody is added for incubation for 30 minutes at 37 ℃ after incubation at 37 ℃. And detecting the light absorption value of 450nm on a microplate reader. The results of the bifunctional antibody and the antigen TNF-alpha show that the bifunctional antibodies BIAU003, BIAU022 and BIAU023 can effectively compete with TNF-alpha receptor for binding TNF-alpha protein, and the binding efficiency is in a dose-dependent relationship. By the analysis of the competitive ELISA result of the bound bifunctional antibody, the binding efficiency IC50 of antagonistic TNF-alpha receptor and antigen TNF-alpha of the curve simulated bifunctional antibodies BIAU003, BIAU022 and BIAU023 is respectively as follows: 0.5nm, 2.3nm and 1.8 nm.
Example 4: detection of antigen binding Capacity of bifunctional antibodies BIAU003, BIAU022 and BIAU023 of the invention
The 4-valent bifunctional antibodies BIAU003, BIAU022 and BIAU023 can be targeted to simultaneously bind to p40 and TNF-alpha protein. The binding capacity of the bifunctional antibody to these two antigens was tested by ELISA. First, 2ug/ml of antigen was coated, 4 ℃ overnight, washed 3 times with PBST to remove unbound antigen, and then different concentrations of bifunctional antibody were added directly and incubated at room temperature for 2 hours. After incubation, PBST was washed 3 times to wash away the antibody that did not bind antigen. Then a secondary antibody against the His tag (HRP-tag) was added and incubated for 1 hour. After PBST was washed 3 times, the color was developed by DAB method and then read by a multifunctional microplate reader. As shown in the data of FIG. 4, the bifunctional antibodies BIAU003, BIAU022 and BIAU023 and the positive antibody all have strong binding ability to the respective antigens (FIG. 4A is binding to p40, and FIG. 4B is binding to TNF-. alpha.).
Example 5: the bifunctional antibodies BIAU003, BIAU022 and BIAU023 of the invention inhibit ELAM-1 protein expression
The expression of cell surface adhesion molecule ELAM-1 is regulated by TNF-alpha, and the regulation of adhesion molecule is the important embodiment of TNF-alpha biological effect. This experiment investigated the situation where cells expressed ELAM-1 protein after blocking the TNF- α pathway. 2 × 105/well HUVEC cells are inoculated in a 6-well plate, after the cells are attached to the wall, 10ng/ml and different concentrations of the bifunctional antibodies BIAU003, BIAU022 and BIAU023 are respectively added, and then the cells are placed in a cell culture box for further culture for 24 hours. After 24h, the cells were trypsinized and washed with PBS and placed on ice, followed by addition of FITC-labeled anti-ELAM-1 antibody and incubation for 30 min. Then, the cell surface fluorescence intensity was analyzed by a flow cytometer, and the fluorescence intensity data of the flow cytometer was converted and plotted by Prism software. As shown in FIG. 5, the results show that the bifunctional antibodies BIAU003, BIAU022 and BIAU023 of the invention can completely block the TNF-alpha-induced ELAM-1 protein expression, and the blocking degree has a dose-dependent relationship with the concentration of the bifunctional antibody (FIG. 5)
Example 6: the bifunctional antibodies BIAU003, BIAU022 and BIAU023 of the invention inhibit the secretion of IFNgamma
The bifunctional antibodies BIAU003, BIAU022 and BIAU023 can be targeted to bind to the p40 subunit of the cytokine IL-12, thereby inhibiting the biological function of the IL-20. The experiment detects whether the bifunctional antibodies BIAU003, BIAU022 and BIAU023 can inhibit the IFNgamma expression regulated by IL-12. Purified T cells were activated and proliferated by culturing in a medium containing cytokine IL-2 for 3 days, and on day 4, T cells were seeded at a density of 1X 105/well in a 96-well plate, and the bifunctional antibodies of the present invention, BIAU003, BIAU022 and BIAU023, were added at the set concentrations. Then the culture medium is placed in a 37-degree carbon dioxide incubator to be cultured for 24 hours. After 24 hours, the cell culture medium was collected and centrifuged to take the supernatant. Taking 10ul of supernatant to carry out IFNgamma quantitative analysis, carrying out experiment according to the instruction method of the quantitative kit, and reading the experimental result by using a multifunctional microplate reader. As shown in the results of FIG. 6, T cells significantly secrete IFNgamma under the action of IL-2 and IL-12, the secretion of IFNgamma is inhibited more obviously with the increase of the concentration of the bifunctional antibody of the invention, and the T cells cannot be induced to secrete IFNgamma by IL-2 stimulation alone (FIG. 6)
Example 7: the drug effect of the bifunctional antibodies BIAU003, BIAU022 and BIAU023 on psoriasis mice
DBA-1 mice were used, and the mice were induced to develop psoriatic lesions by subcutaneous injection of recombinant human IL-12(30ug) in combination with recombinant human TNF- α (10ug) at the back. BiAU003, BiAU022 and BiAU 02320 mg/kg are administered 1 day before the first subcutaneous injection of human IL-12 and TNF-alpha, the injection is continuously performed for 3 days, the dorsal skin is fixed on the 4 th day, and the thickness of the epidermis of the psoriasis mouse is observed after HE staining.
The thickness of the mouse epidermis is shown in figure 7. As can be seen, BiAU003, BiAU022 and BiAU023 can effectively reduce the thickness of the epidermis of the mouse, and the drug effect is superior to that of the single Ustekinumab and Adalilimumab groups.
Finally, it should be noted that the above embodiments are only used for illustrating the technical solutions of the present invention and not for limiting the protection scope of the present invention, and although the present invention is described in detail with reference to the preferred embodiments, it should be understood by those skilled in the art that modifications or equivalent substitutions can be made on the technical solutions of the present invention without departing from the spirit and scope of the technical solutions of the present invention.
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Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
180 185 190
Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln
195 200 205
Tyr Asn Ile Tyr Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile
210 215 220
Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp
225 230 235 240
Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn
245 250 255
Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu
260 265 270
Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp
275 280 285
Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr
290 295 300
Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser
305 310 315 320
Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
325 330
<210> 5
<211> 945
<212> PRT
<213> Artificial sequence
<400> 5
Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu
1 5 10 15
Ser Leu Lys Ile Ser Cys Lys Gly Ser Gly Tyr Ser Phe Thr Thr Tyr
20 25 30
Trp Leu Gly Trp Val Arg Gln Met Pro Gly Lys Gly Leu Asp Trp Ile
35 40 45
Gly Ile Met Ser Pro Val Asp Ser Asp Ile Arg Tyr Ser Pro Ser Phe
50 55 60
Gln Gly Gln Val Thr Met Ser Val Asp Lys Ser Ile Thr Thr Ala Tyr
65 70 75 80
Leu Gln Trp Asn Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys
85 90 95
Ala Arg Arg Arg Pro Gly Gln Gly Tyr Phe Asp Phe Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser Ser Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys
210 215 220
Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro
225 230 235 240
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
245 250 255
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
260 265 270
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
275 280 285
Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val
290 295 300
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
305 310 315 320
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys
325 330 335
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
340 345 350
Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr
355 360 365
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
370 375 380
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
385 390 395 400
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys
405 410 415
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
420 425 430
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
435 440 445
Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
450 455 460
Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu
465 470 475 480
Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe
485 490 495
Thr Phe Asp Asp Tyr Ala Met His Trp Val Arg Gln Ala Pro Gly Lys
500 505 510
Gly Leu Glu Trp Val Ser Ala Ile Thr Trp Asn Ser Gly His Ile Asp
515 520 525
Tyr Ala Asp Ser Val Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala
530 535 540
Lys Asn Ser Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr
545 550 555 560
Ala Val Tyr Tyr Cys Ala Lys Val Ser Tyr Leu Ser Thr Ala Ser Ser
565 570 575
Leu Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser
580 585 590
Val Ala Ala Pro Ser Val Thr Leu Phe Pro Pro Ser Ser Glu Glu Leu
595 600 605
Gln Ala Asn Lys Ala Thr Leu Val Cys Tyr Ile Ser Asp Phe Tyr Pro
610 615 620
Gly Ala Val Thr Val Ala Trp Lys Ala Asp Ser Ser Pro Val Lys Ala
625 630 635 640
Gly Val Glu Thr Thr Thr Pro Ser Lys Gln Ser Asn Asn Lys Tyr Ala
645 650 655
Ala Trp Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys Ser His Arg
660 665 670
Ser Tyr Ser Cys Gln Val Thr His Glu Gly Ser Thr Val Glu Lys Thr
675 680 685
Val Ala Pro Thr Glu Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
690 695 700
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
705 710 715 720
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile
725 730 735
Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg
740 745 750
Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Arg Asn Tyr Leu Ala
755 760 765
Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ala
770 775 780
Ala Ser Thr Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly
785 790 795 800
Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp
805 810 815
Val Ala Thr Tyr Tyr Cys Gln Arg Tyr Asn Arg Ala Pro Tyr Thr Phe
820 825 830
Gly Gln Gly Thr Lys Val Glu Ile Lys Ser Ser Ala Ser Thr Lys Gly
835 840 845
Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly
850 855 860
Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val
865 870 875 880
Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val Ala Thr Gly
885 890 895
Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val
900 905 910
Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val
915 920 925
Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys
930 935 940
Ser
945
Claims (2)
1. A bifunctional antibody, which comprises 2 identical light chains and 2 identical heavy chains, wherein the amino acid sequence of the light chains is shown as SEQ ID NO.1, and the amino acid sequence of the heavy chains is shown as SEQ ID NO. 5.
2. Use of a bifunctional antibody as defined in claim 1 for the manufacture of a medicament for the treatment of rheumatoid arthritis, chronic plaque psoriasis, moderate to severe crohn's disease, moderate to severe ulcerative colitis, ankylosing spondylitis, psoriatic arthritis, moderate to severe polyarticular juvenile idiopathic arthritis, or pediatric crohn's disease.
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| CN201811283836.1A CN109400709B (en) | 2015-11-13 | 2015-11-13 | Bifunctional antibodies and uses thereof |
| CN201510782939.2A CN105294863B (en) | 2015-11-13 | 2015-11-13 | Bifunctional antibody and application thereof |
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| CN201510782939.2A Division CN105294863B (en) | 2015-11-13 | 2015-11-13 | Bifunctional antibody and application thereof |
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| CN201811283836.1A Active CN109400709B (en) | 2015-11-13 | 2015-11-13 | Bifunctional antibodies and uses thereof |
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| CN201510782939.2A Active CN105294863B (en) | 2015-11-13 | 2015-11-13 | Bifunctional antibody and application thereof |
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| CA3145909A1 (en) * | 2019-07-30 | 2021-02-04 | Yu Xia | Anti-human p40 protein domain antibody and use thereof |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007120656A2 (en) * | 2006-04-10 | 2007-10-25 | Abbott Biotechnology Ltd. | Uses and compositions for treatment of rheumatoid arthritis |
| CN102458471A (en) * | 2009-05-28 | 2012-05-16 | 葛兰素集团有限公司 | Antigen-binding proteins |
| CN103251945A (en) * | 2004-04-09 | 2013-08-21 | 艾博特生物技术有限公司 | Multiple-variable dose regimen for treating tnfalpha-related disorders |
| CN103562221A (en) * | 2011-03-28 | 2014-02-05 | 赛诺菲 | Dual variable region antibody-like binding proteins having cross-over binding region orientation |
-
2015
- 2015-11-13 CN CN201811282587.4A patent/CN109293777A/en active Pending
- 2015-11-13 CN CN201510782939.2A patent/CN105294863B/en active Active
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103251945A (en) * | 2004-04-09 | 2013-08-21 | 艾博特生物技术有限公司 | Multiple-variable dose regimen for treating tnfalpha-related disorders |
| WO2007120656A2 (en) * | 2006-04-10 | 2007-10-25 | Abbott Biotechnology Ltd. | Uses and compositions for treatment of rheumatoid arthritis |
| CN102458471A (en) * | 2009-05-28 | 2012-05-16 | 葛兰素集团有限公司 | Antigen-binding proteins |
| CN103562221A (en) * | 2011-03-28 | 2014-02-05 | 赛诺菲 | Dual variable region antibody-like binding proteins having cross-over binding region orientation |
Non-Patent Citations (2)
| Title |
|---|
| Bioengineering a Unique Deimmunized Bispecific Targeted Toxin That Simultaneously Recognizes Human CD22 and CD19 Receptors in a Mouse Model of B-Cell Metastases;Vallera D A等;《Molecular Cancer Therapeutics》;20100630;第9卷(第6期);第1872-1883页 * |
| Dual targeting strategies with bispecific antibodies;Kontermann,RE等;《mAbs》;20120301;第4卷(第2期);第182-197页 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN109400709A (en) | 2019-03-01 |
| CN109293777A (en) | 2019-02-01 |
| CN105294863B (en) | 2019-01-22 |
| CN105294863A (en) | 2016-02-03 |
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