CN112679614B - Antibody for specifically binding RANKL targeted therapeutic drug and application thereof - Google Patents
Antibody for specifically binding RANKL targeted therapeutic drug and application thereof Download PDFInfo
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Abstract
The invention provides an antibody specifically binding to a RANKL targeted therapeutic drug, which consists of 2 identical heavy chains and 2 identical light chains, wherein the variable region of the heavy chain is provided with three epitope regions, and the amino acid sequences of the three epitope regions of the variable region of the heavy chain are shown in SEQ ID NO.3, 4 and 5; the variable region of the light chain has three antigenic determinant regions, and the amino acid sequences of the three antigenic determinant regions of the variable region of the light chain are shown in SEQ ID NO.6, 7 and 8. The antibody can be specifically combined with the dessertumab, so that the dessertumab in serum can be effectively, accurately, qualitatively and quantitatively detected.
Description
Technical Field
The invention belongs to the field of biochemistry, and particularly relates to an antibody for specifically binding RANKL targeted therapeutic drugs (such as denosumab and/or analogs thereof), a kit containing the antibody, a nucleotide sequence for coding the antibody, a carrier containing the nucleotide sequence, application of a detection reagent for preparing an anti-drug antibody specifically binding the RANKL targeted therapeutic drugs, and a method for detecting the anti-drug antibody of the RANKL targeted therapeutic drugs.
Background
Denosumab (Denosumab) is a monoclonal antibody produced by american advancer (Amgen) for resisting osteoporosis and bone cancer metastasis, which can specifically bind to a nuclear factor-kappa B Receptor activator ligand (RANKL), thereby blocking binding of RANKL to its membrane Receptor RANK and blocking signal transduction activation signals of RANKL-RANK in osteoclasts.
Dessumab may induce a degree of drug resistance antibodies (ADA) during administration that may be harmless, reduce potency, reduce half-life, or be life-threatening. Both FDA (united states food and drug administration) and EMA (european medicines administration) recommend and provide guidance for immunogenicity testing of therapeutic protein products during early and late clinical trials to understand the effect of ADA on a given drug. The evaluation and characterization of ADA is an important aspect of assessing the safety of biopharmaceuticals. The most popular ADA detection method at present is a bridging assay based on MSD electrochemiluminescence, which provides a robust and sensitive assay protocol, but is complex to operate and not sensitive enough.
Disclosure of Invention
The present invention is directed to solve the above problems, and an object of the present invention is to provide an anti-drug antibody capable of specifically binding to a RANKL-targeted therapeutic agent, thereby efficiently and accurately detecting the RANKL-targeted therapeutic agent present in serum.
In order to achieve the above objects, the present invention provides an antibody specifically binding to RANKL targeted therapeutic drugs, the antibody consisting of 2 identical heavy chains and 2 identical light chains, the variable region of the heavy chain having three epitope regions, the amino acid sequences of the three epitope regions of the variable region of the heavy chain being shown in SEQ ID nos. 3, 4, and 5; the variable region of the light chain has three antigenic determinant regions, and the amino acid sequences of the three antigenic determinant regions of the variable region of the light chain are shown in SEQ ID NO.6, 7 and 8.
Preferably, the RANKL targeted therapeutic drug includes, but is not limited to, denosumab, preferably denosumab or an analog thereof.
The antibody is preferably a murine monoclonal antibody obtained by a mouse immunization method.
In a preferred embodiment, the amino acid sequence of the variable region of the heavy chain is shown in SEQ ID NO.1, and the amino acid sequence of the variable region of the light chain is shown in SEQ ID NO. 2.
The invention also provides a kit containing the antibody. Preferably, the kit further comprises a washing solution, a developing solution and a stop solution.
The invention also provides nucleotide sequences encoding the antibodies.
The invention also provides a host cell comprising the vector and used for expressing the antibody.
On the other hand, the invention also provides application of the antibody in preparing a molecular diagnostic reagent for detecting the anti-drug antibody of the RANKL targeted therapeutic drug.
In another aspect, the present invention also provides a method for detecting an anti-drug antibody of a RANKL-targeted therapeutic drug, in particular a method for detecting an anti-drug antibody of a RANKL-targeted therapeutic drug present in serum, which employs the antibody as a standard.
Preferably, according to the method, the sensitivity of the detected concentration is 50ng/ml and the upper limit of detection is 3200 ng/ml.
The antibody provided by the invention is used as a standard substance, and can be used for effectively and accurately detecting the anti-drug antibody of the RANKL targeted therapeutic drug in serum.
Drawings
FIG. 1 is a binding curve of anti-disitumumab and disitumumab of the present invention, showing the binding force EC of the two 50 A constant.
FIG. 2 is a graph representing OD values fitted to a standard curve.
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, which will become apparent from the following description. It is noted that some conventional technical procedures, reagents and apparatuses are not described in detail in the following examples for the sake of brevity and clarity, but it is understood that the conventional technical procedures, reagents and apparatuses are obvious to those skilled in the art if not specifically stated.
The RANKL targeted therapeutic drug provided by the invention refers to a drug having a targeted blocking effect on RANKL, and includes but is not limited to monoclonal antibodies, pharmaceutical preparations containing monoclonal antibodies as active ingredients, fusion proteins, antisense nucleotides, kinase inhibitors, compounds, traditional Chinese medicine extracts, traditional Chinese medicine compound extracts, or a combination thereof. More preferably, the RANKL targeted therapeutic includes, but is not limited to, denosumab. The following examples illustrate Denosumab (Denosumab), and an antibody targeted to bind Denosumab may be referred to as "anti-Denosumab".
The invention relates to a preparation method of anti-disitumumab (antibody of targeting combined disitumumab)
Dessuzumab was mixed with Freund's Complete Adjuvant (CFA) at a ratio of 1:1 volume ratio to prepare immunogen, Balb/c mice were immunized by a first subcutaneous injection of 30. mu.L per injection site for a total of 8 injection sites, 240. mu.L per mouse. 14 days later, diskinumab was mixed with InComplete Adjuvant (IFA) at a 1:1 volume ratio to prepare an immunogen, and Balb/c mice were immunized by a second subcutaneous injection at 30. mu.L per injection point for a total of 8 injection points, 240. mu.L per mouse. After 10 days, the denosumab was mixed with incomplete adjuvant IFA at a 1:1 volume ratio to prepare an immunogen, and Balb/c mice were immunized by a third subcutaneous injection at 30. mu.L per injection point for 8 injection points, 240. mu.L per mouse. After a total third subcutaneous immunization, the tail blood titer of the mice was measured.
After the mice meeting the conditions are sacrificed by cervical dislocation, splenocytes and SP 2/0 cells are taken and fused and planted in 10 96-well plates, the cells are cultured in a selective culture medium to be monoclonal cell strains, then the selected clones are selected for detecting the binding activity. The enzyme-linked plate (5. mu.g/mL) was coated with diskinumab, 50. mu.L of the coated plate was added to each well, and the reaction was performed overnight at 4 ℃. The plate was washed 3 times with PBS solution and blocked with 5% mik-PBS for 1h at room temperature; the plate was then washed 1 time with PBS solution. The monoclonal cell supernatant was mixed with 5% mil-K-PBS containing 10. mu.g/ml human IgG at a volume ratio of 1:1, reacted at room temperature for 1 hour, and then added to the wells and reacted at room temperature for 1 hour. The plate was then washed 3 times with PBS solution, patted dry, and then added with HRP-labeled goat anti-mouse Fc secondary antibody diluted 1:8000, and reacted at room temperature for 1 h. Washing the plate with PBS solution for 5 times, drying, adding TMB reaction substrate, keeping out of the sun, and reacting for 5min at room temperature; then 50 μ L of stop solution was added, mixed well and then OD450 value was read on a microplate reader. The anti-diskinumab positive clone (OD 2.638) of the present invention was obtained.
The anti-dessertumab of the present invention is detected to be a murine whole antibody (IgG) comprising two identical heavy chains and two identical light chains. Wherein the variable region of the heavy chain and the variable region of the light chain are each composed of 3 antigen Complementarity Determining Regions (CDRs) and 4 framework regions (Framwork). The antigen complementarity determining regions of the variable regions of the heavy chain and the variable regions of the light chain determine the binding specificity of the antibody for antigen. The amino acid sequences of the constant regions of the heavy and light chains generally do not affect the binding specificity of the antibody for the antigen.
The amino acid sequence of the heavy chain variable region of the anti-dessuzumab disclosed by the invention can be shown as SEQ ID No.1, wherein the amino acid sequences of 3 antigen complementarity determining regions of the heavy chain variable region are shown as H _ CDR1(SEQ ID No.3), H _ CDR2(SEQ ID No.4) and H _ CDR2(SEQ ID No. 5).
The amino acid sequence of the light chain variable region of the anti-disitumumab can be shown as SEQ ID No.2, wherein the amino acid sequences of 3 antigen complementarity determining regions of the light chain variable region are shown as L _ CDR1(SEQ ID No.6), L _ CDR2(SEQ ID No.7) and L _ CDR3(SEQ ID No. 8).
The amino acid sequence of the heavy chain variable region may be combined with the amino acid sequence of the light chain variable region to construct an antibody comprising 2 heavy chains and 2 light chains. The following will describe the use of this antibody as an example, but it should be understood that the antibody of the present invention is not limited to these specific examples.
The amino acid sequence of anti-dessuzumab of the present invention can be detected by commercial agencies or known methods.
Example 1: detection of binding force of disitumumab to disitumumab
The binding force of the anti-disitumumab antibody of the invention to disitumumab is detected by ELISA method.
Firstly, the denosumab is diluted to 2 mu g/mL by using a sodium carbonate buffer solution (CBS, pH9.6) with the pH of 9.6, 50 mu L/hole is inoculated into an enzyme label plate, and the plate is incubated for 2 hours at the temperature of 37 ℃. After incubation was complete, the plates were washed 3 times with PBST (phosphate buffered saline (PBS) + Tween-20) at 300. mu.L/well. 5% BSA was added to each well at 100. mu.L/well and incubated at 37 ℃ for 60 min. After incubation was complete, the plates were washed 3 times with PBST, 300. mu.L/well. BSA (bovine serum albumin) is set as a negative control, the anti-desserts monoclonal antibody of the invention is a group to be tested, and is incubated with the desserts monoclonal antibody coated by the enzyme label plate according to a concentration gradient of 1000.00, 333.33, 111.11, 37.04, 12.35, 4.12, 1.37, 0.46, 0.152, 0.051 and 0.017ng/ml at 37 ℃ and shaking for incubation for 60 min. After incubation was complete, the plates were washed 3 times with PBST, 300. mu.L/well. Commercial anti-mouse antibody labeled with HRP (horseradish peroxidase) (Jackson, # 115-. After incubation was complete, the plates were washed 5 times with PBST, 300. mu.L/well. Adding 100 μ L of TMB color developing solution into each well for color development reaction, and incubating for 3-5 min. After the color development reached a predetermined end point, 50. mu.L of a reaction terminator (1mol/L sulfuric acid solution) was added. The absorbance (OD) of the 96-well plate at 450nm and the reference wavelength of 650nm was measured by a microplate reader.
The binding curve of the anti-disketted antibody and the disketted antibody of the invention is shown in FIG. 1, which shows the binding force EC of the anti-disketted antibody and the disketted antibody of the invention 50 A constant. As shown in FIG. 1, the binding force EC of the anti-disitumumab and the disitumumab of the invention 50 It was 2.5 ng/ml.
Example 2: detection method for establishing anti-disking antibody (namely anti-drug antibody of disking monoclonal antibody) in serum by taking anti-disking antibody of the invention as standard
In this example, the response value of the standard was measured by a standard curve method, and the precision, the curve repeatability, the sensitivity of the method, and the drug resistance of each standard were calculated.
The anti-dessicant antibody is diluted into 3200, 1600, 800, 400, 200, 100, 50 and 0ng/ml by blank cynomolgus monkey serum respectively to be used as a standard substance, the standard substance is diluted by 40 times by using 10% bovine serum PBS solution as a diluent, and then is added into an enzyme label plate coated by the dessicant antibody according to the design of 2 multiple wells, and the shaking incubation is carried out for 60min at 37 ℃ and 200 rpm. After incubation was complete, the plates were washed 3 times with PBST, 350. mu.L/well. Then HRP-labeled dessertumab was added at 100. mu.L/well, incubated at 37 ℃ for 60min with shaking at 200 rpm. After incubation was complete, the plates were washed 3 times with PBST, 350. mu.L/well. 50. mu.L of a developing solution A (Abmax, Cat. SI1003, Lot #600226) and 50. mu.L of a developing solution B (Abmax, Cat. SI1004, Lot #600227) were added to each well, respectively, to carry out a developing reaction, and the reaction was developed in the dark at 25 ℃ for 10 min. 50 μ L of 1mol/L sulfuric acid solution of the reaction stop solution was added thereto and mixed gently. And selecting an enzyme labeling instrument to detect the wavelength of 450nm and the reference wavelength of 630nm, and determining the light absorption value (OD value) of each hole.
Using the theoretical concentration and the corresponding OD of the standard 450-650nm The values were fitted with four parameters to obtain a standard curve and its parameters, see figure 2.
The formula for the standard curve is as follows:
Y＝(A-D)/(1+(X/C)^B)+D
wherein A is 0.0664, B is 1.14, X represents the drug concentration, C is 1.64e +03, D is 3.81, and the fitting efficiency R2 of the curve is 1.
The in-batch precision, repeatability of the fitted curve and sensitivity of the method (LOD) were calculated for each standard and are shown in Table 1. In Table 1, CV means coefficient of variation (coeffient of variation).
Table 1: precision within each standard batch, repeatability of the fitted curve, and sensitivity of the method (LOD)
Drug resistance and specificity verification: the tolerance degree of the detection method to the antibody drug disitumumab under the condition of 100ng/mL sensitivity and the specificity of the detection method in a detection matrix are detected. As shown in Table 2, the detection method has the advantages that the drug resistance of the antibody drug disitumumab is 1200 mu g/mL under the condition of 100ng/mL sensitivity, the disitumumab with 1200 mu g/mL is added for competition, the OD values of three QC samples are reduced to the NC level, and the specificity of the detection method is good.
Table 2: drug resistance and specificity verification
Selective verification: the blank matrices from 20 individuals were tested for selectivity and the results are shown in table 3. The 90% sample inhibition rate is less than 25%, the inhibition rate is good, and the individual selectivity is qualified.
Table 3: selective testing
Inhibition rate 1-dosed OD mean/non-dosed OD mean 100%.
Therefore, the antibody provided by the invention is used as a standard substance, so that the anti-drug antibody of the RANKL targeted therapeutic drug in serum can be effectively and accurately detected.
The above embodiments are merely exemplary and do not limit the scope of the present invention in any way. It will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the spirit and scope of the invention, and that such changes and modifications may be made without departing from the spirit and scope of the invention.
Sequence listing
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Claims (6)
1. An antibody specifically binding to a RANKL targeted therapeutic drug, which consists of 2 identical heavy chains and 2 identical light chains, and is characterized in that the variable region of the heavy chain has three epitope regions, and the amino acid sequences of the three epitope regions of the variable region of the heavy chain are shown as SEQ ID NO.3, 4 and 5 in sequence; the variable region of the light chain is provided with three antigenic determinant regions, and the amino acid sequences of the three antigenic determinant regions of the variable region of the light chain are sequentially shown as SEQ ID NO.6, 7 and 8; the RANKL targeted therapeutic drug is denosumab.
2. The antibody of claim 1, wherein the amino acid sequence of the variable region of the heavy chain is set forth in SEQ ID No.1, and the amino acid sequence of the variable region of the light chain is set forth in SEQ ID No. 2.
3. A kit comprising the antibody of claim 1 or 2.
4. A nucleic acid molecule encoding the antibody of claim 1 or 2.
5. A vector comprising the nucleic acid molecule of claim 4.
6. Use of the antibody according to claim 1 or 2 for the preparation of a molecular diagnostic reagent for the detection of anti-drug antibodies to a RANKL-targeted therapeutic drug, which is denosumab.
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| CN105385694A (en) * | 2015-11-20 | 2016-03-09 | 中国人民解放军第四军医大学 | Anti-human CD98 monoclonal antibody 98-3H3 light /heavy chain variable region gene and applications thereof |
| CN109912714A (en) * | 2017-12-12 | 2019-06-21 | 深圳宾德生物技术有限公司 | 17 monoclonal antibody 6H2H5 of AntiCD3 McAb and its application |
| CN111808198A (en) * | 2020-07-27 | 2020-10-23 | 佛山安普泽生物医药股份有限公司 | Antibody specifically binding RANKL targeted therapeutic drug and application thereof |
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| EP2014681A1 (en) * | 2007-07-12 | 2009-01-14 | Pierre Fabre Medicament | Novel antibodies inhibiting c-met dimerization, and uses thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN105385694A (en) * | 2015-11-20 | 2016-03-09 | 中国人民解放军第四军医大学 | Anti-human CD98 monoclonal antibody 98-3H3 light /heavy chain variable region gene and applications thereof |
| CN109912714A (en) * | 2017-12-12 | 2019-06-21 | 深圳宾德生物技术有限公司 | 17 monoclonal antibody 6H2H5 of AntiCD3 McAb and its application |
| CN111808198A (en) * | 2020-07-27 | 2020-10-23 | 佛山安普泽生物医药股份有限公司 | Antibody specifically binding RANKL targeted therapeutic drug and application thereof |
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