CN119569877A - Anti-sST 2 antibody and application thereof - Google Patents
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Abstract
本发明公开了一种抗sST2的抗体及其应用，涉及抗体领域。本发明公开的抗sST2抗体包括重链互补决定区和轻链互补决定区，该抗体为sST2的检测提供了重要的原料来源，且具有良好的亲和力或活性。
The invention discloses an anti-sST2 antibody and its application, and relates to the field of antibodies. The anti-sST2 antibody disclosed in the invention comprises a heavy chain complementary determining region and a light chain complementary determining region, and the antibody provides an important raw material source for the detection of sST2 and has good affinity or activity.
Description
Technical Field
The invention relates to the technical field of antibodies, in particular to an anti-sST 2 antibody and application thereof.
Background
The growth stimulatory gene 2 protein (ST 2), also known as the T1, IL1RL1 or Fit1 gene, is located on chromosome 2q12 in humans, about 40KD, the transcription product of the ST2 gene has 4 subtypes, two of which are most important due to the subtype regulated by the different promoters, the first being transmembrane ST2 (ST 2L), consisting of 3 extracellular immunoglobulin G domains, one transmembrane domain and one intracellular domain, being a membrane receptor member of the interleukin-1 receptor family, and the other being soluble ST2 (sST 2), sST2 being free flowing in the blood due to the lack of transmembrane and intracellular domains, so that it can be detected in serum.
Cardiovascular disease (CVD) is the leading cause of death worldwide, brain Natriuretic Peptide (BNP) and brain natriuretic peptide precursor NT-proBNP are the most well known markers of Heart Failure (HF), troponin markers improve the diagnosis of acute and chronic coronary artery disease, however, single biomarkers can only reflect a unilateral pathology of heart failure, but also be affected by pulmonary arterial hypertension, etc. due to renal function, age, BMI, etc., reducing the accuracy of these biomarkers. With the increasing awareness of the effects of sST2 and ST2L on the cardiovascular system, one began to consider the assessment of plasma sST2 levels as a new marker of cardiovascular events, particularly the indices and clinical conditions associated with heart failure and ischemic heart disease, and sST2 was not affected by indices of kidney function, age, body weight, etc. sST2 is also considered a possible biomarker for patients with acute heart failure and associated asthma. Studies also prove that sST2 plays a role in predicting mortality, sST2 can be combined with other biomarkers to serve as a prognosis biomarker, sST2 can also be used for monitoring the pharmacological response of heart failure, has a correlation with the recommended therapeutic drugs for heart failure, and can provide a reference for clinical selection of the therapeutic drugs and the scheme. At present, the main methods for detecting sST2 in China comprise an enzyme-linked immunosorbent assay (ELISA), a magnetic particle chemiluminescence method, a gold-labeled method and the like, and different detection methods all need specific monoclonal antibodies aiming at sST 2. Thus, there is a strong need in the art for antibodies that are effective and bind to sST2 and detect it.
Disclosure of Invention
The application provides an anti-sST 2 antibody or antigen binding fragment thereof, which provides an important raw material source for the detection of sST2 and has good activity or affinity.
In order to achieve the above object, according to one aspect of the present invention, there is provided an anti-sST 2 antibody or antigen-binding fragment thereof having three complementarity determining regions of any one of the heavy chain variable regions of amino acid sequences SEQ ID NO:21, 22, 23, 24 and three complementarity determining regions of any one of the light chain variable regions of amino acid sequences SEQ ID NO:29, 30.
In order to achieve the above object, according to a second aspect of the present invention, there is provided an anti-sST 2 antibody or antigen-binding fragment thereof, comprising the following complementarity determining regions:
HCDR1 comprising or consisting of the amino acid sequence set forth in SEQ ID NO. 1;
HCDR2 comprising or consisting of the amino acid sequence shown in SEQ ID No. 2;
HCDR3 comprising or consisting of the amino acid sequence shown in SEQ ID No. 3;
LCDR1 comprising or consisting of the amino acid sequence shown in SEQ ID NO. 4;
LCDR2 comprising or consisting of the amino acid sequence shown in SEQ ID NO. 5, and
LCDR3 comprising or consisting of the amino acid sequence shown in SEQ ID NO. 6.
In order to achieve the above object, according to a third aspect of the present invention, there is provided an anti-sST 2 antibody or antigen-binding fragment thereof, comprising a heavy chain variable region having an amino acid sequence as shown in any one of SEQ ID NOS: 21, 22, 23, 24 and/or a light chain variable region having an amino acid sequence as shown in any one of SEQ ID NOS: 29, 30.
In order to achieve the above object, according to a fourth aspect of the present invention, there is provided an anti-sST 2 antibody or antigen-binding fragment thereof, comprising a heavy chain having an amino acid sequence shown in any one of SEQ ID NOS 25, 26, 27, 28 and/or a light chain having an amino acid sequence shown in any one of SEQ ID NOS 31, 32.
In order to achieve the above object, according to a fifth aspect of the present invention, there is provided an antibody conjugate comprising the above-mentioned anti-sST 2 antibody or antigen-binding fragment thereof.
In order to achieve the above object, according to a sixth aspect of the present invention, there is provided a reagent or kit comprising the above-mentioned anti-sST 2 antibody or antigen-binding fragment thereof or the above-mentioned antibody conjugate.
In order to achieve the above object, according to a seventh aspect of the present invention, there is provided a method for detecting sST2 comprising a) contacting the above-mentioned anti-sST 2 antibody or antigen binding fragment thereof, antibody conjugate, or reagent or kit with sST2 in a sample to be detected under conditions sufficient for an antibody/antigen binding reaction to occur to form an immune complex, and b) detecting the presence of said immune complex, the presence of said complex being indicative of the presence of said antigen in said test sample.
In order to achieve the above object, according to an eighth aspect of the present invention, there is provided a nucleic acid encoding the above-mentioned anti-sST 2 antibody or antigen-binding fragment thereof.
In order to achieve the above object, according to a ninth aspect of the present invention, there is provided a vector comprising the nucleic acid described above.
In order to achieve the above object, according to a tenth aspect of the present invention, there is provided a cell comprising the above nucleic acid, vector or expression of the above anti-sST 2 antibody or antigen-binding fragment thereof.
In order to achieve the above object, according to an eleventh aspect of the present invention, there is provided a method for producing the above anti-sST 2 antibody or antigen-binding fragment thereof, the method comprising culturing the above cell.
In order to achieve the above object, according to a twelfth aspect of the present invention, there is provided the use of the above-mentioned anti-sST 2 antibody or antigen-binding fragment thereof, antibody conjugate, reagent or kit for the preparation of a product for detecting sST 2.
Drawings
In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the drawings that are needed in the embodiments will be briefly described below, it being understood that the following drawings only illustrate some embodiments of the present invention and therefore should not be considered as limiting the scope, and other related drawings may be obtained according to these drawings without inventive effort for a person skilled in the art.
FIG. 1 shows the result of reducing SDS-PAGE of Anti-sST2 9G8 Rmb1-6.
Detailed Description
In a first aspect, embodiments of the present invention provide an anti-sST 2 antibody or antigen binding fragment thereof, said anti-sST 2 antibody or antigen binding fragment thereof having three complementarity determining regions of any one of the heavy chain variable regions of amino acid sequences SEQ ID NO. 21, 22, 23, 24 and three complementarity determining regions of any one of the light chain variable regions of amino acid sequences SEQ ID NO. 29, 30.
The HCDR1, HCDR2 and HCDR3 are amino acid sequences identical to the HCDR1, HCDR2 and HCDR3 of the same heavy chain variable region defined in the anti-sST 2 antibody or antigen-binding fragment thereof according to the first aspect, and the LCDR1, LCDR2 and LCDR3 are amino acid sequences identical to the LCDR1, LCDR2 and LCDR3 of the same light chain variable region defined in the anti-sST 2 antibody or antigen-binding fragment thereof according to the first aspect.
For example, the HCDR1, HCDR2 and HCDR3 are amino acid sequences identical to HCDR1, HCDR2 and HCDR3 of the heavy chain variable region shown in SEQ ID NO. 21, and the LCDR1, LCDR2 and LCDR3 are amino acid sequences identical to LCDR1, LCDR2 and LCDR3 of the light chain variable region shown in SEQ ID NO. 29.
In the present invention, the term "antibody" is used in the broadest sense and may include full length monoclonal antibodies, bispecific or multispecific antibodies, and chimeric antibodies so long as they exhibit the desired biological activity.
In the present invention, the terms "complementarity determining regions", "CDRs" or "CDRs" refer to the highly variable regions of the heavy and light chains of immunoglobulins, and refer to regions comprising one or more or even all of the major amino acid residues responsible for the binding of an antibody or antigen-binding fragment to the antigen or epitope recognized by it.
In the present invention, the heavy chain complementarity determining region is represented by HCDR and includes HCDR1, HCDR2 and HCDR3, and the light chain complementarity determining region is represented by LCDR and includes LCDR1, LCDR2 and LCDR3.
CDR definition methods are well known in the art and include Kabat definition, chothia definition, IMGT definition, contact definition and AbM definition. As used herein, "Kabat definition" refers to the definition system described by Kabat et al, U.S. Dept. Of HEALTH AND Human Services, "Sequence of Proteins of Immunological Interest" (1983). "Chothia definition" see Chothia et al, J Mol Biol 196:901-917 (1987). Still other CDR definition methods may not strictly follow one of the above schemes, but still overlap at least a portion of the Kabat-defined CDR regions, although they may be shortened or lengthened depending on the predicted or experimental outcome of a particular residue or group of residues. Exemplary defined CDRs are listed in table 1 below, with slightly different definitions in the different documents. Given the variable region amino acid sequence of an antibody, one of skill in the art can routinely determine which residues comprise a particular CDR. It should be noted that CDRs defined by other methods not limited to table 1 are also within the scope of the disclosure.
TABLE 1 CDR definition 1
1 The numbering of all CDR definitions in Table 1 is according to the Kabat numbering system (see below), with the amino acid numbers on the heavy chain being indicated by "H+ numbers" and the amino acid numbers on the light chain being indicated by "L+ numbers". The Kabat numbering system can be specifically mapped to any variable region sequence by one of ordinary skill in the art without relying on any experimental data outside of the sequence itself. As used herein, "Kabat numbering" refers to the numbering system described by Kabat et al, U.S. Dept. Of HEALTH AND HumanServices, "Sequence of Proteins of Immunological Interest" (1983).
2 The "AbM" as used in table 1 has a lower case "b" referring to CDRs defined by the "AbM" antibody modeling software of Oxford Molecular.
3 CDR-H1 ends at position 35 if both H35A and H35B are absent, CDR-H1 ends at position 35A if only H35A is present, and CDR-H1 ends at position 35B if both H35A and H35B are present.
4 CDR-H1 ends at bit 32 if both H35A and H35B are absent, at bit 33 if only H35A is present, and at bit 34 if both H35A and H35B are present.
5 CDR-H1 ends at position 33 if both H35A and H35B are absent, CDR-H1 ends at position 34 if only H35A is present, and CDR-H1 ends at position 35 if both H35A and H35B are present.
According to an embodiment of the present invention, the HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 or LCDR3 is defined by any one system or combination of systems Kabat, chothia, IMGT, abM or contacts.
In some alternative embodiments of the invention, the HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3 are defined by a Kabat system.
In some alternative embodiments of the invention, the HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3 are defined by a Chothia system.
In some alternative embodiments of the invention, the HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3 are defined by an IMGT system.
In some alternative embodiments of the invention, the HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3 are defined by an AbM system.
In some alternative embodiments of the invention, the HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3 are defined by a Contact system.
In some alternative embodiments of the invention, the HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3 are defined by Kabat, chothia, IMGT, abM or Contact system combinations.
According to an embodiment of the present invention, the amino acid sequences of HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 or LCDR3 defined by the Kabat, chothia, abM or IMGT system correspond to the following Kabat numbering positions:
In a second aspect, embodiments of the present invention provide an anti-sST 2 antibody or antigen-binding fragment thereof, comprising the following complementarity determining regions:
HCDR1 comprising or consisting of the amino acid sequence set forth in SEQ ID NO. 1;
HCDR2 comprising or consisting of the amino acid sequence shown in SEQ ID No. 2;
HCDR3 comprising or consisting of the amino acid sequence shown in SEQ ID No. 3;
LCDR1 comprising or consisting of the amino acid sequence shown in SEQ ID NO. 4;
LCDR2 comprising or consisting of the amino acid sequence shown in SEQ ID NO. 5, and
LCDR3 comprising or consisting of the amino acid sequence shown in SEQ ID NO. 6.
According to an embodiment of the invention, HCDRs and LCDRs are defined by the Kabat system.
In the present invention, a "framework region" or "FR" region includes a heavy chain framework region and a light chain framework region, which refers to regions of an antibody heavy chain variable region and a light chain variable region other than CDRs, wherein the heavy chain framework region can be further subdivided into contiguous regions separated by CDRs, including HFR1, HFR2, HFR3, and HFR4 framework regions, and the light chain framework region can be further subdivided into contiguous regions separated by CDRs, including LFR1, LFR2, LFR3, and LFR4 framework regions.
In the present invention, the heavy chain variable region is obtained by ligating the CDRs numbered from HFR1-HCDR1-HFR2-HCDR2-HFR3-HCDR3-HFR4 with the FRs in a combinatorial arrangement, and the light chain variable region is obtained by ligating the CDRs numbered from LFR1-LCDR1-LFR2-LCDR2-LFR3-LCDR3-LFR4 with the FRs in a combinatorial arrangement.
In alternative embodiments, the anti-sST 2 antibody or antigen-binding fragment thereof of the first or second aspect comprises a heavy chain variable region comprising HFR1, HFR2, HFR3, HFR4 and a light chain variable region comprising LFR1, LFR2, LFR3, and LFR4.
In alternative embodiments, the HFR1 comprises/is as set forth in SEQ ID NO 7 or an amino acid sequence having at least 80% identity thereto;
the HFR2 comprises/has an amino acid sequence as shown in SEQ ID NO 8 or having at least 80% identity thereto;
The HFR3 comprises/has as SEQ ID NO 9 or an amino acid sequence having at least 80% identity thereto;
The HFR4 comprises/has an amino acid sequence as shown in SEQ ID NO 10 or having at least 80% identity thereto;
the LFR1 comprises/is as SEQ ID No. 11 or an amino acid sequence having at least 80% identity thereto;
The LFR2 comprises/is as SEQ ID No. 12 or an amino acid sequence having at least 80% identity thereto;
the LFR3 comprises/has as SEQ ID NO 13 or an amino acid sequence having at least 80% identity thereto, and
The LFR4 comprises/is as set forth in SEQ ID No. 14 or an amino acid sequence having at least 80% identity thereto.
In other embodiments, each of the framework region amino acid sequences of the anti-sST 2 antibodies or antigen binding fragments thereof provided herein may have at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the corresponding framework region (SEQ ID NO:7, 8, 9, 10, 11, 12, 13 or 14) described above.
In alternative embodiments, the HFR3 includes/is as shown in any one of SEQ ID NOs 17, 18, 19.
In an alternative embodiment, the LFR2 comprises/is shown as SEQ ID NO. 20.
In alternative embodiments, the anti-sST 2 antibody or antigen-binding fragment thereof binds sST2 with an affinity of KD <8.44 x10 -8 M.
In an alternative embodiment, the anti-sST 2 antibody or antigen-binding fragment thereof binds sST2 with an affinity of KD≤10-7M、KD≤10- 8M、KD≤10-9M、KD≤10-10M、KD≤10-11M、KD≤10-12M、KD≤10-13M.
In an alternative embodiment, the anti-sST 2 antibody or antigen binding fragment thereof binds sST2 with an affinity of KD.ltoreq.6.00×10 -9 M.
Antibody affinity (KD) assays are widely varied and can be classified into thermodynamic, kinetic and dynamic equilibrium assays based on the principle of detection. Among them, thermodynamic detection methods are commonly known as Isothermal Titration Calorimetry (ITC), kinetic detection methods are commonly known as Surface Plasmon Resonance (SPR) and biological membrane light interferometry (BLI), and dynamic equilibrium detection methods are commonly known as enzyme-linked immunosorbent assay (ELISA).
In a third aspect, embodiments of the present invention provide an anti-sST 2 antibody or antigen binding fragment thereof, comprising a heavy chain variable region having an amino acid sequence as shown in any one of SEQ ID NOs 21, 22, 23, 24 and/or a light chain variable region having an amino acid sequence as shown in any one of SEQ ID NOs 29, 30.
In an alternative embodiment, the combination of the heavy chain variable region and the light chain variable region of the first, second or third aspect is selected from any one of the following combinations:
| Combination of two or more kinds of materials | Heavy chain variable region | Light chain variable region |
| 1 | SEQ ID NO:21 | SEQ ID NO:29 |
| 2 | SEQ ID NO:23 | SEQ ID NO:29 |
| 3 | SEQ ID NO:24 | SEQ ID NO:29 |
| 4 | SEQ ID NO:21 | SEQ ID NO:30 |
| 5 | SEQ ID NO:22 | SEQ ID NO:29 |
| 6 | SEQ ID NO:23 | SEQ ID NO:30 |
。
In an alternative embodiment, the anti-sST 2 antibody or antigen-binding fragment thereof of the first, second or third aspects above further comprises a constant region.
In alternative embodiments, the constant region comprises a heavy chain constant region and/or a light chain constant region.
In alternative embodiments, the heavy chain constant region is selected from the group consisting of the heavy chain constant region of any one of IgG, igA, igM, igE, igD or a combination of multiple constant region segments.
In alternative embodiments, the heavy chain constant region comprises CH1 of IgG, hinge region of IgG, CH2 of IgM, CH3 of IgM, and/or CH4 of IgM.
In alternative embodiments, the IgG is selected from IgG1, igG2, igG3, or IgG4.
In alternative embodiments, the light chain constant region is selected from kappa-type or lambda-type light chain constant regions.
In alternative embodiments, the constant region is of a species derived from a cow, horse, cow, pig, sheep, rat, mouse, dog, cat, rabbit, donkey, deer, mink, chicken, duck, goose, turkey, chicken, or human.
In an alternative embodiment, the constant region is of murine species origin.
In an alternative embodiment, the heavy chain constant region sequence (CH) is shown in SEQ ID NO. 15 and the light chain constant region (CL) sequence is shown in SEQ ID NO. 16.
In other embodiments, the constant region sequence may have at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the constant region (SEQ ID NO:15 or 16) described above.
In alternative embodiments, the antigen binding fragment is selected from any one of F (ab) 2, F (ab ') 2, fab', fab, fv, and scFv of the antibody.
The antigen binding fragments of the above antibodies typically have the same binding specificity as the antibody from which they were derived. It will be readily appreciated by those skilled in the art from the teachings herein that antigen binding fragments of the above antibodies may be obtained by methods such as enzymatic digestion (including pepsin or papain) and/or by methods of chemical reduction cleavage of disulfide bonds. The antigen binding fragments described above are readily available to those skilled in the art based on the disclosure of the structure of the intact antibodies.
The antigen binding fragments of the above antibodies may also be synthesized by recombinant genetic techniques also known to those skilled in the art or by, for example, automated peptide synthesizers such as those sold by Applied BioSystems and the like.
In a fourth aspect, the invention provides an anti-sST 2 antibody or antigen binding fragment thereof, comprising a heavy chain and/or a light chain, wherein the amino acid sequence of the heavy chain is shown as any one of SEQ ID NO. 25, 26, 27 and 28, and the amino acid sequence of the light chain is shown as any one of SEQ ID NO. 31 and 32.
In an alternative embodiment, the antibody or antigen binding fragment thereof of the first, second, third or fourth aspects above, comprises a heavy chain and a light chain in any one of the following combinations:
| Combination of two or more kinds of materials | Heavy chain | Light chain |
| 1 | SEQ ID NO:25 | SEQ ID NO:31 |
| 2 | SEQ ID NO:27 | SEQ ID NO:31 |
| 3 | SEQ ID NO:28 | SEQ ID NO:31 |
| 4 | SEQ ID NO:25 | SEQ ID NO:32 |
| 5 | SEQ ID NO:26 | SEQ ID NO:31 |
| 6 | SEQ ID NO:27 | SEQ ID NO:32 |
。
In a fifth aspect, the invention provides an antibody conjugate comprising an anti-sST 2 antibody or antigen-binding fragment thereof as described above.
In an alternative embodiment, the above antibody conjugate further comprises biotin or a biotin derivative conjugated to the anti-sST 2 antibody or antigen-binding fragment thereof.
In alternative embodiments, the antibody conjugate further comprises a label conjugated to the anti-sST 2 antibody or antigen-binding fragment thereof.
In an alternative embodiment, the above-mentioned marker refers to a substance having a property such as luminescence, color development, radioactivity, etc., which can be directly observed by naked eyes or detected by an instrument, by which qualitative or quantitative detection of the corresponding target can be achieved.
In alternative embodiments, the labels include, but are not limited to, fluorescent dyes, enzymes, radioisotopes, chemiluminescent reagents, and nanoparticle-based labels.
In the actual use process, a person skilled in the art can select a suitable marker according to the detection conditions or actual needs, and no matter what marker is used, the marker belongs to the protection scope of the invention.
In alternative embodiments, the fluorescent dyes include, but are not limited to, fluorescein-based dyes and derivatives thereof (including, but not limited to, fluorescein Isothiocyanate (FITC) hydroxy-light (FAM), tetrachlorolight (TET), and the like, or analogs thereof), rhodamine-based dyes and derivatives thereof (including, but not limited to, red Rhodamine (RBITC), tetramethyl rhodamine (TAMRA), rhodamine B (TRITC), and the like, or analogs thereof), cy-based dyes and derivatives thereof (including, but not limited to, cy2, cy3B, cy3.5, cy5, cy5.5, cy3, and the like, or analogs thereof), alexa-based dyes and derivatives thereof (including, but not limited to, alexa fluor350, 405, 430, 488, 532, 546, 555, 568, 594, 610, 33, 647, 680, 700, 750, and the like, or analogs thereof), and protein-based dyes and derivatives thereof (including, but not limited to, for example, phycoerythrin (PE), phycocyanin (PC), allophycocyanin (APC), polyazosin (preCP), and the like).
In alternative embodiments, the enzymes include, but are not limited to, horseradish peroxidase, alkaline phosphatase, beta-galactosidase, glucose oxidase, carbonic anhydrase, acetylcholinesterase, and glucose 6-phosphate deoxygenase.
In alternative embodiments, the radioisotope includes, but is not limited to 212Bi、131I、111In、90Y、186Re、211At、125I、188Re、153Sm、213Bi、32P、94mTc、99mTc、203Pb、67Ga、68Ga、43Sc、47Sc、110mIn、97Ru、62Cu、64Cu、67Cu、68Cu、86Y、88Y、121Sn、161Tb、166Ho、105Rh、177Lu、172Lu and 18F.
In alternative embodiments, the chemiluminescent reagents include, but are not limited to, luminol and its derivatives, lucigenin, crustacean fluorescein and its derivatives, ruthenium bipyridine and its derivatives, acridinium esters and its derivatives, dioxane and its derivatives, lomustine and its derivatives, and peroxyoxalate and its derivatives.
In alternative embodiments, the nanoparticle-based labels include, but are not limited to, nanoparticles, colloids, organic nanoparticles, magnetic nanoparticles, quantum dot nanoparticles, and rare earth complex nanoparticles.
In alternative embodiments, the colloids include, but are not limited to, colloidal metals, disperse dyes, dye-labeled microspheres, and latex.
In alternative embodiments, the colloidal metals include, but are not limited to, colloidal gold, colloidal silver, and colloidal selenium.
In an alternative embodiment, the colloidal metal is colloidal gold.
In an alternative embodiment, the above antibody conjugate further comprises a solid support coupled to the anti-sST 2 antibody or antigen-binding fragment thereof.
In alternative embodiments, the solid support is selected from the group consisting of microspheres, plates, and membranes.
In alternative embodiments, the solid support includes, but is not limited to, magnetic microspheres, plastic microparticles, microplates, glass, capillaries, nylon, and nitrocellulose membranes.
In a sixth aspect, the invention provides a reagent or kit comprising an anti-sST 2 antibody or antigen-binding fragment thereof as described above or an antibody conjugate as described above.
As previously mentioned, the anti-sST 2 antibodies or antigen-binding fragments thereof in some embodiments or examples of the invention are capable of efficiently binding to sST2, and therefore, reagents or kits comprising the sST2 anti-sST 2 antibodies or antigen-binding fragments thereof are capable of efficiently performing qualitative or quantitative detection of sST 2. The reagent or the kit provided by the invention can be used for detection of specific binding performance of sST2 and antibodies thereof, such as immunoblotting, immunoprecipitation and the like. As previously mentioned, the anti-sST 2 antibodies or antigen-binding fragments thereof in some embodiments or examples of the invention have higher binding activity or affinity to sST2, and thus reagents or kits comprising the anti-sST 2 antibodies or antigen-binding fragments thereof have higher detection sensitivity or specificity.
In a seventh aspect, the invention provides a method of detecting sST2 comprising a) contacting an anti-sST 2 antibody or antigen binding fragment, antibody conjugate, reagent or kit as described above with sST2 in a sample to be detected under conditions sufficient for an antibody/antigen binding reaction to occur to form an immune complex, and b) detecting the presence of said immune complex, the presence of said complex being indicative of the presence of said antigen in said test sample;
In an alternative embodiment, the immune complex further comprises a second antibody that binds to the anti-sST 2 antibody or antigen-binding fragment thereof.
In an alternative embodiment, the immune complex further comprises a second antibody that binds to sST 2.
In an eighth aspect, the invention provides a nucleic acid molecule encoding an anti-sST 2 antibody or antigen-binding fragment thereof as described above.
In a ninth aspect, the present invention provides a vector comprising the nucleic acid molecule described above.
In a tenth aspect, the present invention provides a cell comprising the vector described above.
In an eleventh aspect, the invention provides a method of preparing an anti-sST 2 antibody or antigen binding fragment thereof, comprising culturing a cell as described above.
In a twelfth aspect, the invention provides the use of an anti-sST 2 antibody as described above or an antigen-binding fragment thereof, an antibody conjugate or a reagent or kit as described above for the preparation of a product for the detection of sST 2.
Based on the present disclosure of the amino acid sequence of an anti-sST 2 antibody or antigen-binding fragment thereof, it will be readily apparent to those skilled in the art that the preparation of the anti-sST 2 antibody or antigen-binding fragment thereof by genetic engineering techniques or other techniques (chemical synthesis, recombinant expression), e.g., isolation and purification from a culture product of recombinant cells capable of recombinantly expressing an anti-sST 2 antibody or antigen-binding fragment thereof as described in any of the above, is within the scope of the present disclosure, irrespective of the technique used to prepare the anti-sST 2 antibody or antigen-binding fragment thereof.
In order to make the objects, technical solutions and advantages of the embodiments of the present invention more clear, the technical solutions of the embodiments of the present invention will be clearly and completely described below. The specific conditions are not noted in the examples and are carried out according to conventional conditions or conditions recommended by the manufacturer. The reagents or apparatus used were conventional products commercially available without the manufacturer's attention.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of formulations or unit doses herein, some methods and materials are now described. Unless otherwise indicated, techniques employed or contemplated herein are standard methods. The materials, methods, and examples are illustrative only and not intended to be limiting.
Unless otherwise indicated, practice of the present invention will employ conventional techniques of cell biology, molecular biology (including recombinant techniques), microbiology, biochemistry and immunology, which are within the ability of a person skilled in the art. Such techniques are well explained in the literature, e.g., in the molecular cloning laboratory Manual (Molecular Cloning: ALaboratory Manual), second edition (Sambrook et al, 1989), oligonucleotide Synthesis (Oligonucleotide Synthesis) (M.J.Gait et al, 1984), animal cell Culture (ANIMAL CELL Culture) (R.I. Freshney, 1987), enzymatic methods (Methods in Enzymology) (academic Press Co., ltd. (ACADEMIC PRESS, inc.), experimental immunology Manual (Handbook of Experimental Immunology) (D.M.Weir and C.Blackwell, inc.), mammalian cell gene transfer Vectors (GENE TRANSFER Vectors for MAMMALIAN CELLS) (J.M.Miller and M.P.Calos, 1987), contemporary molecular biology methods (F.M.Ausubel et al, 1987), polymerase chain reactions (28) (J.M.Weir. And C.Blackwell, inc.), PCR methods (J.34.J.37, J.J.37, J.F.37) and PCR methods (J.37, J.F.37, J.J.F.37, J.J.J.J.F.37, J.J.J.J.J.J.J.J.F.J.J.J.J.J.F.J.J.J.L).
The features and capabilities of the present invention are described in further detail below in connection with the examples.
Example 1 preparation of Anti-sST2 9G8 monoclonal antibody
Restriction enzymes, PRIME STAR DNA polymerase in this example were purchased from Takara. MagExtractor-RNA extraction kit was purchased from TOYOBO company. BD SMART TM RACE cDNA Amplification Kit kit was purchased from Takara. Plasmid extraction kits were purchased from Tiangen. Primer synthesis and gene sequencing were accomplished by Invitrogen corporation. The hybridoma cell strain secreting the Anti-sST2 9G8 monoclonal antibody is an existing hybridoma cell strain, and is recovered for later use.
1.1 Preparation of Anti-sST2 9G8 antibody Gene
MRNA is extracted from hybridoma cell strain secreting Anti-sST2 9G8 monoclonal antibody, DNA product is obtained through RT-PCR method, and is inserted into pMD-18T vector, transformed into DH5 alpha competent cells, positive clones of HEAVY CHAIN and LIGHT CHAIN genes are taken respectively after colony growth, and 4 clones are sent to gene sequencing company for sequencing.
1.2 Sequence analysis of the variable region Gene of Anti-sST2 9G8 antibody
The gene sequence obtained by sequencing is placed in a KABAT antibody database for analysis, and VNTI 11.5.5 software is used for analysis to determine that the amplified genes of the heavy chain and light chain primer pair are correct, wherein the VL gene sequence in the LIGHT CHAIN amplified gene fragment is 318bp, the front of the VL gene sequence is 57bp leader peptide sequence, and the VH gene sequence in the HEAVY CHAIN primer pair amplified gene fragment is 357bp, belongs to the VH1 gene family, and the front of the VL gene fragment is 57bp leader peptide sequence.
1.3 Construction of recombinant antibody expression plasmids
pcDNATM3.4Vector is constructed eukaryotic expression vector of recombinant antibody, which is modified to introduce polyclonal enzyme cutting site and 3.4A expression vector, VL and VH gene specific primers of Anti-sST29G8 antibody are designed based on the result of the gene sequencing of antibody variable region in pMD-18T, and the two ends have restriction enzyme cutting site and protecting base, and the LIGHT CHAIN gene segment of 0.70Kb and the HEAVY CHAIN gene segment of 1.39Kb are amplified by PCR amplification method.
The HEAVY CHAIN and LIGHT CHAIN gene fragments are respectively subjected to double enzyme digestion by adopting restriction enzymes, the 3.4A vector is subjected to double enzyme digestion by adopting restriction enzymes, and the HEAVY CHAIN gene and LIGHT CHAIN gene after the fragments and the vector are purified and recovered are respectively connected with the 3.4A expression vector to respectively obtain recombinant expression plasmids HEAVY CHAIN and LIGHT CHAIN.
2. Sample preparation of recombinant antibodies
Resuscitate HEK293 cells in advance, subculture to a 200ml system to enable the cell density to reach 3-5×10 6 cells/ml, the cell density to reach the concentration of selected antibodies and cell viability to be more than 95%, centrifugally clean the cells, re-dissolve the cells with a culture medium, simultaneously adjust the cell density to 2.9×10 6 cells/ml, re-dissolve the cells with the culture medium, and simultaneously serve as a cell dilution. The medium was used to prepare dilutions of plasmid DNA and transfection reagent, respectively. Adding transfection reagent diluent into plasmid DNA diluent, mixing uniformly, standing at room temperature for 15min, slowly adding the mixture into cell diluent within 1min, mixing uniformly, sampling, counting, recording and observing activity of transfected cells, culturing in a 35 ℃ constant temperature incubator at a rotating speed 120rmp and a CO2 content of 8%, and centrifuging and collecting samples after 13 days. The supernatant was affinity purified using a proteona affinity column. 6ug of the purified antibody was subjected to reducing SDS-PAGE, and the electrophoresed pattern was as shown. Two bands were shown after reducing SDS-PAGE, 1 Mr was 50KD (heavy chain) and the other Mr was 28KD (light chain).
The obtained antibody was designated as Anti-sST2 9G8Rmb, and the Anti-sST2 9G8Rmb was subjected to mutation to obtain a mutant antibody, the sequences of the heavy chain (H) and the light chain (L) of which are shown in the following table:
TABLE 2 antibody sequences
| Antibody name | Heavy chain | Light chain |
| Anti-sST2 9G8Mb1 | SEQ ID NO:25 | SEQ ID NO:31 |
| Anti-sST2 9G8Mb2 | SEQ ID NO:27 | SEQ ID NO:31 |
| Anti-sST2 9G8Mb3 | SEQ ID NO:28 | SEQ ID NO:31 |
| Anti-sST2 9G8Mb4 | SEQ ID NO:25 | SEQ ID NO:32 |
| Anti-sST2 9G8Mb5 | SEQ ID NO:26 | SEQ ID NO:31 |
| Anti-sST2 9G8Mb6 | SEQ ID NO:27 | SEQ ID NO:32 |
1. Affinity analysis
The antibody is diluted and purified in advance, meanwhile, the sST2 recombinant antigen (obtained from the Phpeng organism) is subjected to gradient dilution, the binding dissociation curve of the antigen antibody is tested on Biacore 8K+ equipment by utilizing a CM5 chip which is coupled with goat anti-mouse IgG in advance, and the affinity constant, the binding rate and the dissociation rate are obtained by automatic fitting of an instrument. (KD represents equilibrium dissociation constant, i.e., affinity constant; ka represents binding rate; KD represents dissociation rate).
TABLE 3 affinity data
| Sample name | KD(M) | ka | kd |
| Control | 8.44E-08 | 9.74E+04 | 8.22E-03 |
| Anti-sST2 9G8Mb1 | 1.56E-09 | 4.00E+05 | 6.24E-04 |
| Anti-sST2 9G8Mb2 | 1.64E-09 | 2.94E+05 | 4.82E-04 |
| Anti-sST2 9G8Mb3 | 2.40E-09 | 2.78E+05 | 6.65E-04 |
| Anti-sST2 9G8Mb4 | 4.21E-09 | 3.11E+05 | 1.31E-03 |
| Anti-sST2 9G8Mb5 | 2.40E-09 | 2.91E+05 | 7.00E-04 |
| Anti-sST2 9G8Mb6 | 6.00E-09 | 3.17E+05 | 1.90E-03 |
2. Activity assay
The coating solution (NaHCO 3 as main component) dilutes sST2 recombinant antigen to 1ug/ml, 100uL per well, 4 ℃ overnight, the next day, the washing solution (Na 2HPO4+NaCl as main component) washes 2 times, the drying by beating, the adding of blocking solution (20% BSA+80% PBS) per well 120uL,37 ℃ for 1h, the drying by beating, the adding of diluted purified antibody and control antibody, 100uL per well, 37 ℃ for 30min, the washing solution washes 5 times, the drying by beating, the adding of goat anti-mouse IgG-HRP, 100uL per well, 37 ℃ for 30min, the washing solution washes 5 times, the drying by beating, the adding of chromogenic solution A (50 uL per well), the adding of chromogenic solution B (50 uL per well), the drying by beating, the adding of stop solution, the reading of OD value at 450nm (reference 630 nm) on an ELISA reader.
The remarks are liquid A (main component citric acid+sodium acetate+acetanilide+carbamide peroxide), liquid B (main component citric acid+EDTA.2Na+TMB+HCL), and stop solution (EDTA.2Na+H 2SO 4).
TABLE 4 Activity data
| Concentration (ng/ml) | 6.25 | 3.13 | 1.56 | 0.78 | 0.39 | 0.00 |
| Control | 1.116 | 0.611 | 0.383 | 0.201 | 0.101 | 0.009 |
| Anti-sST2 9G8Mb1 | 1.882 | 1.477 | 0.822 | 0.464 | 0.356 | 0.022 |
| Anti-sST2 9G8Mb2 | 1.864 | 1.383 | 0.803 | 0.498 | 0.314 | 0.026 |
| Anti-sST2 9G8Mb3 | 1.818 | 1.397 | 0.790 | 0.506 | 0.331 | 0.027 |
| Anti-sST2 9G8Mb4 | 1.977 | 1.410 | 0.849 | 0.531 | 0.255 | 0.025 |
| Anti-sST2 9G8Mb5 | 1.914 | 1.668 | 1.214 | 0.722 | 0.470 | 0.025 |
| Anti-sST2 9G8Mb6 | 1.941 | 1.596 | 1.029 | 0.595 | 0.418 | 0.032 |
3. Stability assessment
Placing the antibody at 4 ℃, -80 ℃ (refrigerator) and 37 ℃ (incubator) for 21 days, taking 7 days, 14 days and 21 days for state observation, and detecting the activity of the 21 days, wherein the results show that no obvious protein state change is seen in the antibody placed for 21 days under three examination conditions, and the activity is not in a descending trend along with the increase of the examination temperature, thus indicating that the antibody is stable. The following table shows the results of the detection of OD by the antibody Anti-sST2 9G8Rmb for 21 days of enzyme-free activity.
Table 5 stability data
| Sample concentration (ng/ml) | 3.13 | 1.56 | 0.00 |
| 4 ℃ 21 Day sample | 1.668 | 1.212 | 0.018 |
| -80 ℃,21 Day sample | 1.672 | 1.223 | 0.018 |
| 37 ℃ 21 Day sample | 1.633 | 1.271 | 0.019 |
The above description is only of the preferred embodiments of the present invention and is not intended to limit the present invention, but various modifications and variations can be made to the present invention by those skilled in the art. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
The partial amino acid sequences involved in the present application are shown in Table 6:
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| US20110256635A1 (en) * | 2010-04-09 | 2011-10-20 | Critical Care Diagnostics, Inc. | Soluble human st-2 antibodies and assays |
| CN110357963A (en) * | 2019-07-31 | 2019-10-22 | 北京智仁美博生物科技有限公司 | Anti-human ST2 antibody and application thereof |
| CN115703837A (en) * | 2021-08-17 | 2023-02-17 | 东莞市朋志生物科技有限公司 | Recombinant antibody of anti-long-stimulation expression gene 2 protein |
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| US20110256635A1 (en) * | 2010-04-09 | 2011-10-20 | Critical Care Diagnostics, Inc. | Soluble human st-2 antibodies and assays |
| CN110357963A (en) * | 2019-07-31 | 2019-10-22 | 北京智仁美博生物科技有限公司 | Anti-human ST2 antibody and application thereof |
| CN115703837A (en) * | 2021-08-17 | 2023-02-17 | 东莞市朋志生物科技有限公司 | Recombinant antibody of anti-long-stimulation expression gene 2 protein |
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