Anti-quetiapine antibody or antigen binding fragment thereof and application thereof

Abstract

The invention provides an anti-quetiapine antibody or an antigen binding fragment thereof and application thereof, and relates to the technical field of biology. The antibody or the antigen binding fragment thereof contains a complementarity determining region of a heavy chain variable region and a complementarity determining region of a light chain variable region, wherein the complementarity determining region of the heavy chain variable region comprises amino acid sequences consistent with HCDR1, HCDR2 and HCDR3 of the heavy chain variable region as shown in SEQ ID NO.1; the complementarity determining region of the light chain variable region comprises amino acid sequences consistent with LCDR1, LCDR2 and LCDR3 of the light chain variable region as shown in SEQ ID NO.2. The antibody or the antigen binding fragment thereof can be combined with quetiapine, and can be used for a method or a product for detecting quetiapine based on an immunological principle.

Description

Technical Field

[0001] The present invention relates to the field of biotechnology, and in particular to an anti-quetiapine antibody or an antigen-binding fragment thereof and an application thereof. Background Art

[0002] The following statements merely provide background information related to the present disclosure and do not necessarily constitute prior art.

[0003] Quetiapine, also known as quetiapine fumarate, quetiapine fumarate, quetiapine is a new type of phenothiazine antipsychotic drug. 21 H 25 N3O2S, molecular weight 383.51. It is a multi-neurotransmitter receptor antagonist in the brain, which can block a variety of neurotransmitter receptors in the brain. Quetiapine is effective for both positive and negative symptoms of schizophrenia, and can also alleviate depression, anxiety and cognitive deficits associated with schizophrenia. Since quetiapine mainly has central nervous system effects, it should be used with caution when combined with other centrally acting drugs or alcohol. The pharmacokinetics of lithium will not be affected when quetiapine is used in combination with lithium. Quetiapine does not induce the liver enzyme system related to antipyrine metabolism, and co-administration with phenytoin (a microsomal enzyme inducer) can increase the clearance of quetiapine. If quetiapine is used in combination with phenytoin or other liver enzyme inducers (such as carbamazepine, barbiturates, rifampicin), the dose of quetiapine should be increased to maintain the effect of antipsychotic symptoms. If phenytoin is discontinued and replaced with a non-inducing agent (such as sodium valproate), the dose of quetiapine needs to be reduced. Co-administration of the antipsychotic drugs risperidone or haloperidol did not significantly alter the pharmacokinetics of quetiapine. Co-administration of the antidepressants imipramine (a known CYP2D6 inhibitor) or fluoxetine (a known CYP3A4 and CYP2D6 inhibitor) did not significantly alter the pharmacokinetics of quetiapine.

[0004] At present, the detection of quetiapine mainly relies on high performance liquid chromatography (HPLC), gas chromatography (GC), thin layer chromatography (TLC), mass spectrometry (MS) etc., but there is expensive instrument, detection is time-consuming, and needs professional and technical personnel to operate, and can not meet the requirement of modern detection to fast and accurate. Therefore, it is very necessary to establish a fast, sensitive and accurate detection technology. In order to solve the problem of large-scale application on site, immunological method is because its detection speed is fast, cost is low, and flux is high, and part of immunological detection method (colloidal gold paper chromatography) also has simple operation, does not need the advantages such as additional equipment, and is highly valued. Therefore, developing excellent quetiapine diagnosis antigen antibody has become the key to determine the application prospect of immunological method.

[0005] In view of this, the present invention is proposed. Summary of the invention

[0006] In a first aspect, an anti-quetiapine antibody or an antigen-binding fragment thereof is provided, wherein the antibody or the antigen-binding fragment thereof comprises the complementarity determining regions HCDR1, HCDR2 and HCDR3 of the heavy chain variable region, and the complementarity determining regions LCDR1, LCDR2 and LCDR3 of the light chain variable region;

[0007] The HCDR1, HCDR2 and HCDR3 include amino acid sequences consistent with HCDR1, HCDR2 and HCDR3 of the heavy chain variable region shown in SEQ ID NO.1; the LCDR1, LCDR2 and LCDR3 include amino acid sequences consistent with LCDR1, LCDR2 and LCDR3 of the light chain variable region shown in SEQ ID NO.2.

[0008] In a second aspect, a biomaterial is also provided, wherein the biomaterial is selected from any one of (i) to (iii):

[0009] (i) a polynucleotide encoding the nucleotide sequence of the anti-quetiapine antibody or antigen-binding fragment thereof according to the first aspect.

[0010] (ii) a vector carrying the polynucleotide described in (i).

[0011] (iii) a cell, wherein the cell carries the polynucleotide described in (i), or contains the vector described in (ii), or expresses the anti-quetiapine antibody or its antigen-binding fragment.

[0012] In a third aspect, a composition containing an antibody is also provided, wherein the composition containing an antibody comprises the following (I) and (II) connected or separately packaged:

[0013] (I) The anti-quetiapine antibody or antigen-binding fragment thereof according to the first aspect.

[0014] (II) Tracing marker and / or solid phase carrier.

[0015] In a fourth aspect, a conjugate containing an antibody is also provided, wherein the conjugate comprises the anti-quetiapine antibody or its antigen-binding fragment as described in the first aspect and a functional molecule, wherein the functional molecule is covalently linked to the antibody or its antigen-binding fragment, and the functional molecule comprises one or more of sugars, proteins, polypeptides, lipids, nucleic acids and small molecule compounds.

[0016] In the fifth aspect, there is provided the use of the anti-quetiapine antibody or antigen-binding fragment thereof described in the first aspect, or the biological material described in the second aspect, or the antibody-containing composition described in the third aspect, or the antibody-containing conjugate described in the fourth aspect in detecting quetiapine for non-diagnostic and therapeutic purposes, or in preparing a product for detecting quetiapine.

[0017] In the sixth aspect, a kit for detecting quetiapine is also provided, the kit comprising the anti-quetiapine antibody or antigen-binding fragment thereof of the first aspect, or the antibody-containing composition of the third aspect, or the antibody-containing conjugate of the fourth aspect.

[0018] Compared with the prior art, the present invention has the following beneficial effects:

[0019] The present invention uses quetiapine to immunize Balb / c mice, obtains mouse spleen cells and fuses with myeloma cells, obtains highly specific hybridoma cells through specific high-throughput screening, obtains a large amount of mouse ascites through culture and re-immunization, and then obtains high-purity, high-sensitivity and high-specific anti-quetiapine monoclonal antibody anti-Quetiapine-mab1 through multi-step separation and purification, and provides the required raw materials for developing immunoassay products for detecting quetiapine. The anti-quetiapine antibody or its antigen-binding fragment of the present invention has good specific binding ability after verification, and can provide a stable and reliable source of raw materials for the method for detecting quetiapine based on immunological principles, reduce the dependence of the product on purchased raw materials, and reduce the product cost. At the same time, the detection rate and sensitivity of quetiapine rapid diagnosis products such as gold-label test strips, ELISA kits, etc. are improved, and the false positive rate is reduced. BRIEF DESCRIPTION OF THE DRAWINGS

[0020] In order to more clearly illustrate the specific implementation methods of the present invention or the technical solutions in the prior art, the drawings required for use in the specific implementation methods or the description of the prior art will be briefly introduced below. Obviously, the drawings described below are some implementation methods of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying creative work.

[0021] Figure 1 These are photos of the test results of the colloidal gold immunochromatographic test paper coated with the A1-1 antibody in Example 3 of the present invention respectively testing a negative sample, quetiapine 500 ng / ml and quetiapine 750 ng / ml. DETAILED DESCRIPTION

[0022] The technical solution of the present invention will be clearly and completely described below in conjunction with the embodiments. Obviously, the described embodiments are part of the embodiments of the present invention, rather than all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0023] Generally, the nomenclature and its technology used in conjunction with cell and tissue culture, molecular biology, immunology, microbiology, genetics, and protein and nucleic acid chemistry and hybridization described herein are those well-known and commonly used in the art. Unless otherwise indicated, the methods and techniques of the present invention are generally carried out according to conventional methods as well-known in the art, and as described in various general and more specific references, which are cited and discussed throughout this specification. Enzymatic reactions and purification techniques are carried out according to the manufacturer's specifications, as generally achieved in the art, or as described herein. The nomenclature and its laboratory procedures and technology used in conjunction with analytical chemistry, synthetic organic chemistry, and medical and pharmaceutical chemistry described herein are those well-known and commonly used in the art.

[0024] The term "anti-quetiapine antibody or antigen-binding fragment thereof" herein means that the antibody or antigen-binding fragment thereof can specifically bind to quetiapine. Specific binding to quetiapine includes but is not limited to specific binding to quetiapine or a conjugate of quetiapine with other molecules.

[0025] Antibodies herein generally refer to all proteins and protein fragments that contain a complementary determining region (CDR region). The terms "antibody" and "full-length antibody" include polyclonal antibodies and monoclonal antibodies. In addition, the term "antibody" includes naturally occurring antibodies as well as non-naturally occurring antibodies, including, for example, chimeric, bifunctional and humanized antibodies, and related synthetic isoforms. Non-naturally occurring antibodies are also referred to herein as "recombinant antibodies," and the term "antibody" can be used interchangeably with "immunoglobulin."

[0026] Antigen binding fragments are fragments that contain part or all of the antibody CDRs, which lack at least some of the amino acids present in the full-length chain but are still able to specifically bind to the antigen. Such fragments are biologically active because they bind to the target antigen and can compete with other antigen binding molecules (including intact antibodies) for binding to a given epitope. Such fragments are selected from, but not limited to, F(ab')2, Fab', Fab, Fv (composed of VH and VL), ScFv (single-chain antibody, VH and VL are connected by a connecting peptide), dsFv (disulfide stabilized Fv fragments, dsFv), bispecific antibodies, nanobodies, and any one of the minimum recognition units of antibodies. In addition to the above functional fragments, any fragments with increased half-life are also included.

[0027] The "variable region" or "variable domain" of an antibody refers to the domain at the amino terminus of the heavy chain or light chain of the antibody that recognizes and binds to the antigen. The composition and arrangement of the amino acids in this segment determine the specificity of the antibody in recognizing the antigen. The heavy chain variable domain can be referred to as "VH". The variable domain of the light chain can be referred to as "VL". These domains are usually the most variable parts of the antibody and contain the antigen binding site. The variable regions of the heavy and light chains are each composed of three complementarity-determining regions (CDR) (also called hypervariable regions) connected by four framework regions (FR). The extent of the framework region and CDR has been precisely defined, for example, in Kabat (see Sequences of Proteins of Immunological Interest, E. Kabat et al.) and Chothia. Any CDR determination method well known in the art, including a combination of methods, can identify the CDRs of the variable domain. The CDRs in each chain are held together closely by FRs to form the variable region. Generally, the variable regions VL / VH of the heavy and light chains can be obtained by arranging and connecting the following numbered CDRs and FRs in the following combinations: FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4.

[0028] The term "constant region" or "constant domain" of an antibody refers to the constant region of an antibody light chain or the constant region of an antibody heavy chain, either alone or in combination. The heavy chain of an antibody has one variable domain (VH), followed by a number of constant domains or regions, such as one or more of a hinge, CH1, CH2, CH3, and CH4, the CH1 domain being adjacent to the VH domain and at the amino terminus of the hinge region of the antibody heavy chain, and not forming part of the Fc region of the antibody; the hinge region includes the portion of the heavy chain molecule that connects the CH1 domain to the CH2 domain; the N-terminus of CH2 is usually the CH3 domain, which usually forms the C-terminal portion of the antibody, and in some antibody types, such as IgM and IgE, the constant region also includes a CH4 domain. The constant region of an antibody can be derived from IgG1, IgG2, IgG3, IgG4, IgA, IgM, IgE, and IgD, as well as subclasses and mutant forms of the constant regions thereof.

[0029] The present invention does not limit the method for obtaining anti-quetiapine antibodies or antigen-binding fragments. In some optional embodiments, the polynucleotide encoding the anti-quetiapine antibody or antigen-binding fragment is connected to a vector and then expressed in a cell to obtain the corresponding antibody. The above-mentioned vector can be introduced into eukaryotic cells, especially mammalian cells, to construct and obtain the anti-quetiapine antibody or antigen-binding fragment that can express it. In other optional embodiments, the anti-quetiapine antibody or antigen-binding fragment can also be obtained by recombinant genetics techniques known to those skilled in the art or by peptide synthesis, such as automatic peptide synthesizers (e.g., automatic peptide synthesizers sold by Applied BioSystems, etc.); the antigen-binding fragment can also be optionally produced by enzymatic cleavage of antigen-binding molecules (including complete antibodies), such as pepsin or papain cleavage; or chemical cleavage, such as obtaining the above-mentioned antigen-binding fragment by chemical reduction splitting disulfide bonds.

[0030] The terms "specific recognition", "selective binding", "selectively binds" and "specifically binds" or similar expressions refer to the binding of an antibody or its antigen-binding fragment to a predetermined epitope on an antigen. -5 M, for example, less than about 10 -5 M, 10 -6 M, 10 -7 M, 10 -8 M, 10 -9 M or 10 -10 The Kd value of an antibody can be determined using methods well established in the art. Other standard assays for evaluating the binding ability of a ligand such as an antibody to a target are known in the art and include, for example, ELISA, Western blot, RIA, and flow cytometry analysis.

[0031] The term "polynucleotide" herein refers to a polymer form of nucleotides of any length, including ribonucleotides and / or deoxyribonucleotides. Examples of polynucleotides include, but are not limited to, single-stranded, double-stranded or multi-stranded DNA or RNA, genomic DNA, cDNA, DNA-RNA hybrids, or polymers containing purine and pyrimidine bases or other natural, chemically or biochemically modified, non-natural or derived nucleotide bases. The polynucleotide encodes the above-mentioned anti-quetiapine antibody or antigen-binding fragment, and the encoding is optionally encoding a sense strand or an antisense strand. The polynucleotide can be naturally occurring, synthetic, recombinant, or any combination thereof. The terms "polynucleotide" and "nucleic acid" are used interchangeably herein.

[0032] The term "vector" herein refers to a nucleic acid delivery vehicle into which a polynucleotide can be inserted. When a vector can express a protein encoded by the inserted polynucleotide, the vector is called an expression vector. The vector can be introduced into a host cell by transformation, transduction or transfection so that the genetic material elements it carries are expressed in the host cell.

[0033] The vector is well known to those skilled in the art, including but not limited to: plasmid, episomal plasmid, minicircle DNA, phagemid, cosmid; artificial chromosome, such as yeast artificial chromosome (YAC), bacterial artificial chromosome (BAC) or P1-derived artificial chromosome (PAC); bacteriophage such as λ phage or M13 phage and animal virus, etc. Animal viruses that can be used as vectors include but are not limited to retrovirus (including lentivirus), adenovirus, adeno-associated virus, herpes virus (such as herpes simplex virus), poxvirus, baculovirus, papillomavirus, papillomavirus. In some embodiments, the vector of the present invention contains regulatory elements commonly used in genetic engineering, such as enhancers, promoters, internal ribosome entry sites (IRES) and other expression control elements (such as transcription termination signals, or polyadenylation signals and poly-U sequences, etc.).

[0034] As used herein, the expressions "cell", "cell line" and "cell culture" are used interchangeably, and all such designations include progeny. Progeny may not necessarily be identical to the original cell due to natural, accidental or deliberate mutation, and may differ from the original cell in morphology and / or in genomic DNA. "Transformants" and "transformed cells" include the primary subject cell and cultures derived therefrom.

[0035] As used herein, the term "conjugate" refers to a compound formed by covalently linking at least two molecules, and the covalent linking may be direct covalent linking of the two molecules or covalent linking through a linker. Each molecule independently includes, but is not limited to, at least one of sugars, proteins, polypeptides, lipids, nucleic acids, and small molecules. "Antibody-containing conjugate" refers to a conjugate formed by covalently linking an antibody to, but is not limited to, at least one of sugars, proteins, polypeptides, lipids, nucleic acids, and small molecules.

[0036] As used herein, the term "tracing marker" refers to a marker that can provide a detectable signal that can be directly observed by the naked eye or detected by conventional instruments acceptable in the art; the tracing marker can directly provide a signal, such as color (e.g., colloidal gold, colored microspheres), fluorescence (fluorescent molecules), magnetism, radiation, or luminescence; or it can indirectly provide a signal through a subsequent reaction in which the tracing marker participates, such as catalyzing a specific substrate reaction to produce any of the above signals.

[0037] In this document, unless otherwise stated, arbitrary numbering is used to distinguish one entity or behavior from another entity or behavior, and does not necessarily require or imply any actual relationship, order, or importance between these entities or behaviors, such as numbers (I), (II)...(VII).

[0038] As used herein, unless otherwise stated, "optionally", "optional", "optional" or "optional" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs or does not occur.

[0039] Herein, the terms "comprise" or "comprising" are intended to include stated elements, integers or steps, but not to exclude any other elements, integers or steps.

[0040] In a first aspect, an anti-quetiapine antibody or an antigen-binding fragment thereof is provided, wherein the antibody or the antigen-binding fragment thereof comprises the complementarity determining regions HCDR1, HCDR2 and HCDR3 of the heavy chain variable region, and the complementarity determining regions LCDR1, LCDR2 and LCDR3 of the light chain variable region;

[0041] The HCDR1 includes an amino acid sequence consistent with HCDR1 of the heavy chain variable region shown in SEQ ID NO.1, the HCDR2 includes an amino acid sequence consistent with HCDR2 of the heavy chain variable region shown in SEQ ID NO.1, and the HCDR3 includes an amino acid sequence consistent with HCDR3 of the heavy chain variable region shown in SEQ ID NO.1; and the LCDR1 includes an amino acid sequence consistent with LCDR1 of the light chain variable region shown in SEQID NO.2, the LCDR2 includes an amino acid sequence consistent with LCDR2 of the light chain variable region shown in SEQ ID NO.2, and the LCDR3 includes an amino acid sequence consistent with LCDR3 of the light chain variable region shown in SEQ ID NO.2.

[0042] It is understood that other regions except the CDR region in the variable region shown in SEQ ID NO.1 and 2 are not used to limit the anti-quetiapine antibody or antigen-binding fragment thereof provided by the present invention. For example, if the antibody or antigen-binding fragment thereof provided in the present application contains a framework region, it may be different from the framework region in the variable region shown in SEQ ID NO.1 and 2. The CDR region in the variable region shown in SEQ ID NO.1 and 2 can be divided according to an optional method known in the art. Optionally, the HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 or LCDR3 of the variable region is defined by any one of the systems of Kabat, Chothia, IMGT, ABM or Contact or a combination of multiple definition systems. Taking the definition of Kabat, Chothia, IMGT, ABM or Contact as examples, the amino acid sequences of HCDR1, HCDR2 and HCDR3 of the heavy chain variable region shown in SEQ ID NO.1 are shown in Table 1, and the amino acid sequences of LCDR1, LCDR2 and LCDR3 of the light chain variable region shown in SEQ ID NO.2 are shown in Table 2:

[0043] Table 1

[0044]

[0045] Table 2

[0046]

[0047] In an optional embodiment, the heavy chain variable region further contains at least one framework region, such as one framework region, two framework regions, three framework regions or four framework regions.

[0048] In an alternative embodiment, the light chain variable region further comprises at least one framework region, such as one framework region, two framework regions, three framework regions or four framework regions.

[0049] In an optional embodiment, the species origin of the framework region includes but is not limited to one or more of rabbits, cows, horses, dairy cows, pigs, sheep, goats, rats, mice, dogs, cats, camels, donkeys, deer, minks, chickens, ducks, geese, turkeys, fighting cocks, humans and their mutants.

[0050] In an optional embodiment, the framework region FR1 of the heavy chain variable region includes an amino acid sequence consistent with FR1 of the heavy chain variable region shown in SEQ ID NO.1; and / or the framework region FR2 includes an amino acid sequence consistent with FR2 of the heavy chain variable region shown in SEQ ID NO.1; the framework region FR3 includes an amino acid sequence consistent with FR3 of the heavy chain variable region shown in SEQ ID NO.1; and the framework region FR4 includes an amino acid sequence consistent with FR4 of the heavy chain variable region shown in SEQ ID NO.1.

[0051] In an optional embodiment, the framework region FR1 of the light chain variable region includes an amino acid sequence consistent with FR1 of the light chain variable region shown in SEQ ID NO.2; and / or the framework region FR2 includes an amino acid sequence consistent with FR2 of the light chain variable region shown in SEQ ID NO.2; the framework region FR3 includes an amino acid sequence consistent with FR3 of the light chain variable region shown in SEQ ID NO.2; and the framework region FR4 includes an amino acid sequence consistent with FR4 of the light chain variable region shown in SEQ ID NO.2.

[0052] In an optional embodiment, the heavy chain variable region of the antibody or antigen-binding fragment thereof is shown as SEQ ID NO.1, and the light chain variable region is shown as SEQ ID NO.2.

[0053] In an optional embodiment, the antigen-binding fragment includes one or more of F(ab')2, Fab', Fab, Fv, scFv, dsFv and the minimum recognition unit of an antibody.

[0054] In an alternative embodiment, the antibody or antigen-binding fragment thereof comprises a portion or all of the sequence of the constant region.

[0055] In an optional embodiment, the constant region sequence is selected from the sequence of a partial or complete constant region of any one of IgG1, IgG2, IgG3, IgG4, IgA, IgM, IgE or IgD, and the IgG1, IgG2, IgG3, IgG4, IgA, IgM, IgE or IgD include their subclasses and mutant forms.

[0056] In an optional embodiment, the species origin of the constant region is one or more of rabbit, cow, horse, dairy cow, pig, sheep, goat, rat, mouse, dog, cat, camel, donkey, deer, mink, chicken, duck, goose, turkey, fighting cock, human and their mutants.

[0057] In an optional embodiment, the antibody comprises a heavy chain constant region and a light chain constant region, is a full-length antibody, the light chain of the antibody is a κ chain, and the antibody is an IgG antibody. In an optional embodiment, the full-length antibody is a mouse antibody.

[0058] In a second aspect, a biomaterial is also provided, wherein the biomaterial is selected from any one of (i) to (iii):

[0059] (i) a polynucleotide encoding the nucleotide sequence of the anti-quetiapine antibody or antigen-binding fragment thereof according to the first aspect.

[0060] In an optional embodiment, the polynucleotide contains a nucleotide sequence as shown in SEQ ID NO.3, which encodes the heavy chain variable region shown in SEQ ID NO.1.

[0061] In an optional embodiment, the polynucleotide contains a nucleotide sequence as shown in SEQ ID NO.4, which encodes the light chain variable region shown in SEQ ID NO.2.

[0062] (ii) a vector carrying the polynucleotide described in (i).

[0063] (iii) a cell, wherein the cell carries the polynucleotide described in (i) above, or contains the vector described in (ii) above, or expresses the anti-quetiapine antibody or its antigen-binding fragment.

[0064] In a third aspect, a composition containing an antibody is also provided, wherein the composition containing an antibody comprises the following (I) and (II) connected or separately packaged:

[0065] (I) The anti-quetiapine antibody or antigen-binding fragment thereof according to the first aspect.

[0066] (II) Tracing marker and / or solid phase carrier.

[0067] The connection includes physical connection and / or chemical connection, for example, it can be but not limited to connecting the anti-quetiapine antibody or antigen-binding fragment thereof described in the first aspect with the tracer marker and / or solid phase carrier through chemical bonds or adsorption.

[0068] In an optional embodiment, the tracer marker includes but is not limited to one or more of enzymes, fluorescent molecule markers, fluorescent microspheres, colored microspheres, latex microspheres, colloidal gold, colloidal selenium, colloidal silver, colloidal carbon, quantum dots, biotin, streptavidin, radionuclides, radiocontrast agents, paramagnetic ions, metals and photosensitizers.

[0069] In an optional embodiment, the solid phase carrier includes but is not limited to microtubes, columns, microparticles, nitrocellulose membranes, chromatography matrices or lateral flow devices; more specifically, for example, it can be but is not limited to enzyme-labeled wells, immunochromatographic test strips or magnetic beads.

[0070] In a fourth aspect, a conjugate containing an antibody is also provided, wherein the conjugate comprises the anti-quetiapine antibody or its antigen-binding fragment as described in the first aspect and a functional molecule, wherein the functional molecule is covalently linked to the antibody or its antigen-binding fragment, and the functional molecule comprises one or more of sugars, proteins, polypeptides, lipids, nucleic acids and small molecule compounds.

[0071] In the fifth aspect, there is provided the use of the anti-quetiapine antibody or antigen-binding fragment thereof described in the first aspect, or the biological material described in the second aspect, or the antibody-containing composition described in the third aspect, or the antibody-containing conjugate described in the fourth aspect in detecting quetiapine for non-diagnostic and therapeutic purposes, or in preparing a product for detecting quetiapine.

[0072] In the sixth aspect, a kit for detecting quetiapine is also provided, the kit comprising the anti-quetiapine antibody or antigen-binding fragment thereof of the first aspect, or the antibody-containing composition of the third aspect, or the antibody-containing conjugate of the fourth aspect. The kit comprises one or more reagents, and when the kit comprises one reagent, the kit may be equivalent to the reagent.

[0073] In an optional embodiment, the kit includes an immunochromatographic detection kit, an ELISA detection kit, an immunomagnetic particle detection kit, an immunofluorescence detection kit or an immunoblot detection kit.

[0074] In an optional embodiment, the kit further contains reagents and / or consumables for detection, including but not limited to one or more of primers, probes, buffers, dyes, diluents, washing solutions, color developing solutions, lysates, negative controls, positive controls, and blank controls; consumables include but are not limited to solid phase carriers, such as magnetic beads, enzyme-labeled wells, or nitrocellulose membranes, etc. Those skilled in the art can select the reagent composition of the kit according to the specific detection method, and the present invention does not limit this.

[0075] In an optional embodiment, the kit includes an immunochromatographic test paper, which is a competitive immunochromatographic test paper. The competitive immunochromatographic test paper is coated with the antibody or antigen-binding fragment thereof in any of the above embodiments, and is used to capture quetiapine in the sample to be tested.

[0076] In an optional embodiment, the detection line of the immunochromatographic test paper is coated with quetiapine coupled to a protein carrier, and the conjugate pad is coated with the anti-quetiapine antibody or its antigen-binding fragment labeled with a tracer marker. It is understandable that the immunochromatographic test paper has a conventional immunochromatographic test paper structure known in the art, and an exemplary immunochromatographic test paper structure includes a sample pad, a conjugate pad and a detection pad along the sample flow direction, and the detection pad is provided with a detection line and a quality control line. The quality control line is coated with an antibody that specifically binds to the anti-quetiapine antibody or its antigen-binding fragment; when the sample contains a quetiapine small molecule, the quetiapine in the sample and the quetiapine antigen coated on the detection line are simultaneously competitively bound to the anti-quetiapine antibody or its antigen-binding fragment on the conjugate pad, and the quetiapine in the sample will preferentially compete with the anti-quetiapine antibody or its antigen-binding fragment on the conjugate pad. The higher the quetiapine content in the sample, the fewer anti-quetiapine antibodies or their antigen-binding fragments that can bind to the quetiapine antigen are left on the detection line when chromatographed to the detection line, and therefore the less detectable signal is on the detection line. The anti-quetiapine antibody or antigen-binding fragment thereof labeled with a tracer marker flows through the quality control line and is captured by the antibody coated on the quality control line, and a measurable signal appears, indicating that the immunochromatographic test paper is usable.

[0077] In an optional embodiment, the immunochromatographic test paper is coated with an antibody that binds to quetiapine and is labeled with a tracer marker, and the heavy chain variable region amino acid sequence of the antibody that binds to quetiapine is shown in SEQ ID NO.1, and the light chain variable region amino acid sequence is shown in SEQ ID NO.2.

[0078] In an alternative embodiment, the anti-quetiapine antibody or antigen-binding fragment thereof coated on the conjugate pad is labeled with colloidal gold.

[0079] In an optional embodiment, the protein carrier to which quetiapine is coupled includes but is not limited to bovine gamma globulin, bovine serum albumin, ovalbumin, scutellaria hemocyanin, human serum albumin, thyroglobulin, tetanus toxoid, synthetic polylysine or purified protein derivatives, preferably bovine gamma globulin.

[0080] The present invention is further described below by means of specific examples. However, it should be understood that these examples are only used for more detailed description and should not be construed as limiting the present invention in any form.

[0081] Example 1 Preparation of Quetiapine-BGG Antigen

[0082] Table 3 Preparation of quetiapine-BGG antigen

[0083] Antigen source Antigen name batch number concentration Total use Self-produced antigens Quetiapine-BGG #D22092801 5.34mg / ml 5.0mg For immunization and screening

[0084] The chemically synthesized quetiapine antigen Quetiapine-BGG was used to perform phased immunization on experimental mice.

[0085] Example 2 Preparation of monoclonal antibody anti-Quetiapine-mab1

[0086] 1. Preparation of monoclonal antibody anti-Quetiapine-mab1:

[0087] Healthy female Balb / c mice aged 6 to 8 weeks were selected and immunized according to a pre-specified immunization protocol. As an immunogen, BALB / c mice were immunized, spleen lymphocytes of successfully immunized mice were extracted, and lymphocytes were fused with mouse myeloma cells SP2 / 0 by cell fusion technology. After two rounds of subclone screening, hybridoma cell lines that stably secreted monoclonal antibodies against quetiapine were obtained, thereby obtaining monoclonal antibodies against quetiapine.

[0088] The quetiapine antigen prepared in Example 1 was used to perform phased immunization on experimental mice.

[0089] The specific steps of animal immunization experiments include:

[0090] 1. Balb / c mice with the same mean body weight and age were randomly divided into two groups: the group with aluminum adjuvant (aluminum hydroxide adjuvant) and the group without aluminum adjuvant.

[0091] 2. Before the experiment, the pre-immune serum of each mouse was collected (pre-immune serum was collected on the fifth day, blood was collected through the eyeball, and an appropriate amount of blood was collected to ensure the normal state of the mice), and the collected serum was stored at -80°C.

[0092] 3. Preparation of the aluminum adjuvant (aluminum hydroxide adjuvant) group: Before immunization, each antigen was diluted to the corresponding dose (75 μg / mouse) in 75 μL PBS, and mixed with alum adjuvant (1 mg / mouse), according to the volume of antigen: adjuvant = 3:1 (i.e., 25 μL adjuvant was added to 75 μL immunogen diluent); the adjuvant was shaken before use, and the injection adjuvant (25 μL) was slowly added to the immunogen solution; after the adjuvant and the immunogen diluent were fully mixed, the two were fully mixed for 30 minutes. The adjuvant effectively adsorbed the antigen; the subsequent operation was carried out according to the immunization animal experiment.

[0093] 4. Group without aluminum adjuvant: The antigens were diluted in 100 μL PBS to the corresponding doses in the above table (75 μg / mouse), and 100 μL of immunogen was added. The subsequent operation was carried out according to the animal immunization experiment.

[0094] 5. Subcutaneous injection at intervals of 2 weeks: The experiment was designed as three immunizations, but blood was collected from the eyeballs 7 days after each immunization, and part of the mouse supernatant was obtained by centrifugation. The serum titer was first tested. 7 days after the last immunization, blood was collected from the heart to obtain the maximum amount of blood, which was centrifuged to obtain the supernatant and stored at -80°C.

[0095] 6. Detect serum titer.

[0096] (1) Four mice were immunized, and the mice were numbered A0, A1, A2 and A3. After three immunizations, the serum titer was tested. The test data are shown in Table 4 below, and the test method is as follows:

[0097] The quetiapine standard was used for antigen competition detection, and the quetiapine-BGG antigen was used as the coating antigen for indirect ELISA and competitive ELISA to detect the titer of immune mouse serum. 50 μL of the coating antigen diluted with the coating solution was added to each well of the indirect ELISA enzyme-labeled plate at 1 μg / ml. After coating overnight at 4°C, the plate was washed 3 times with a washing solution (PBST) (the same below). 200 μL of blocking solution (5% skim milk powder) was added to each well, and placed in a 37°C incubator for 2 hours. After washing, 50 μL of diluted serum was added to each well, and then reacted in a 37°C incubator for 30 minutes. After washing, 50 μL of goat anti-mouse IgG-HRP solution was added, and reacted in a 37°C incubator for 30 minutes. After washing, 100 μL of substrate solution was added, and color was developed in a 37°C incubator in the dark for 10 minutes. Finally, 2 mol / L H2SO4, 50 μL, was added to terminate the reaction, and the A450 value was read on an enzyme-labeled instrument. The titers of orbital blood of 3 mice after three immunizations were all >62500.

[0098] The process of indirect competitive ELISA is mostly the same as that of indirect ELISA, except that the plate is blocked with blocking solution, 50 μL of diluted 50 ng / mL and 300 ng / mL small molecule quetiapine standard solution is added after washing, and then 50 μL of diluted serum antibody is added. The rest of the steps are the same. For the competition test of 50 ng / mL and 300 ng / mL small molecule quetiapine, 4 mice can reach more than 50% at 1:12500, and fusion can be arranged.

[0099] Table 4: Serum titer test data

[0100]

[0101]

[0102] The immune spleen cells were fused with myeloma cell line SP2 / 0 cells, and the fused cells were screened by HAT selection medium (HAT selection medium contains hypoxanthine, aminopterin and thymidine), and the fused cells were subjected to ELISA positive screening and subcloning; the screened positive monoclonal antibody was purified from ascites using ProteinA / G antibody purification column, and the ELISA titer of the purified antibody was >1:128,000, and the purity was >90%.

[0103] 2. Enzyme-linked immunosorbent assay (ELISA) was used to detect the binding activity of quetiapine.

[0104] IgG antibody titer detection method

[0105] 1. Bottom plate coating: dilute the antigen to 3 μg / ml with coating diluent, add 100 μL of the prepared coating solution to each well, and place in a 4°C refrigerator for 24 hours.

[0106] 2. After 24 hours, take out the wells from the refrigerator and equilibrate at 37°C for 30 minutes, then discard the liquid in the wells; wash the wells three times with washing solution, each time for 3 minutes.

[0107] 3. Block the enzyme-labeled reaction wells: add 200 μL of 5% calf serum to each well and block at 37°C for 90 min. After blocking, wash the wells three times with washing solution, each time for 3 min.

[0108] 4. Add the sample to be tested: dilute the sample according to the required ratio, add the diluted sample to the enzyme-labeled reaction well, 100 μL per well, incubate at 37°C for 90 min; wash the well three times with washing solution, 3 min each time.

[0109] 5. Add enzyme-labeled antibody: Add secondary antibody of appropriate concentration according to the instructions; incubate at 37°C for 90 min, add 100 μL per well and wash as before.

[0110] 6. Add substrate solution: 100 μL of substrate is added to each well and placed at 37°C away from light for 15 to 30 minutes.

[0111] 7. Stop reaction: Add 50 μL of stop solution to each well to stop the reaction and measure the experimental results within 20 minutes.

[0112] 3. Detect the binding activity of monoclonal antibodies to quetiapine.

[0113] 1. Cell fusion and clone screening data

[0114] The mice were numbered A0, A1, A2 and A3 and four rounds of fusion were completed.

[0115] Twelve positive wells of mouse A0 were selected for subcloning, but no clones were found.

[0116] A1 mouse was used to select 51 positive wells for subcloning. After fusion screening, 30 positive wells with OD450 values ​​> 2.1 were selected for titer detection by serial dilution. The second and third subclone screenings were then performed, and finally 4 cell lines were obtained, which were named A1-1, A1-2, A1-3, and A1-4.

[0117] A2 mice were screened for 51 positive wells for subcloning. After fusion screening, 20 positive wells with OD450 values ​​> 2.1 were selected for titer detection by serial dilution. The second and third subclone screenings were then performed, and finally three cell lines were obtained, which were named A2-1, A2-2, and A2-3.

[0118] 70 positive wells of mouse A3 were selected for subcloning. After fusion screening, 30 positive wells with OD450 values ​​>2.1 were selected for titer detection by serial dilution. The second and third subclone screenings were then performed, and finally three cell lines were obtained, which were named A3-1, A3-2, and A3-3.

[0119] A total of 10 cell lines were obtained after four cell fusions.

[0120] 2. Ascites preparation and testing data

[0121] Three F1 mice were injected into each complete cell line, and a total of 10 ascites were prepared. The titer data of all ascites tests are shown in the following table:

[0122] Table 5

[0123]

[0124]

[0125] 3. Antibody purification conditions exploration and test data

[0126] The above ascites was purified by 3.3% n-octanoic acid-thiamine precipitation method, and a total of 10 antibodies were obtained. The titer test data of all antibodies are shown in the following table:

[0127] Table 6

[0128]

[0129] The above data show that the monoclonal antibodies of the 10 cell lines have good specific binding ability to quetiapine antigen. The quetiapine colloidal gold product detects urine samples, so the standard quetiapine is used for competition experiments. The results show that 10 antibodies including A1-1A1-2, A1-3, A1-4, A2-1, A2-2, A2-3, A3-1, A3-2 and A3-3 have competitive effects on small molecule quetiapine. Therefore, antibodies A1-1 and A3-1 are selected for the test of quetiapine colloidal gold products.

[0130] Example 3 Application of monoclonal antibody anti-Quetiapine-mab1 in products

[0131] The quetiapine antibodies A1-1 and A3-1 were verified by the immunocolloidal gold platform. The immunocolloidal gold platform is an immunochromatographic test paper, which includes a sample pad, a conjugation pad and a detection pad according to the chromatography direction, and the detection pad is provided with a detection line and a quality control line. The conjugation pad is coated with the screened monoclonal antibody labeled with colloidal gold, and the detection line is coated with the quetiapine-BGG antigen of Example 1.

[0132] Specifically, the experimental group used the quetiapine antibodies A1-1 and A3-1 obtained in the above experiment to test the quetiapine standard of Hangzhou Anxu Biotechnology Co., Ltd. The negative control was a urine sample. The above reagents were added, and then the results were tested using the POCT detection instrument ACG1000 (ID-A003) of Hangzhou Anxu Biotechnology Co., Ltd. The experimental data results are shown in Table 7.

[0133] Table 7 Preliminary evaluation results of 2 antibodies

[0134]

[0135] Note: G4-G8 indicates the color depth of the test strip. The higher the value, the darker the color. + / - indicates that the color is slightly darker or lighter than that level. Figure 1 The lower value after adding quetiapine standard indicates that the small molecule has a competitive effect and the antibody can bind to the quetiapine standard.

[0136] The results showed that the gradients of antibodies A1-1 and A3-1 were good and could be used in quetiapine products. The cut-off value was 1000ng / ml. The stability of antibody A3-1 was then evaluated. Three batches of antibody samples were prepared. The evaluation results are shown in the following table and Figure 1 As shown:

[0137] Table 8 Evaluation results of three batches of stability A0-3 samples

[0138] Antibody lot number Negative Quetiapine 500ng / ml Quetiapine 750ng / ml A3-1-(1) G9+ G5 G3.5 A3-1-(2) G9 G4+ G3.5 A3-1-(3) G9- G4 G3.5

[0139] Based on the product evaluation results, antibody A3-1 was named anti-Quetiapine-mab1, which can be used for the quetiapine antigen detection kit.

[0140] Example 4 Sequence analysis of the heavy chain V region (VH) and light chain V region (VL) of the monoclonal antibody anti-Quetiapine-mab1.

[0141] 1. Design primers for amplifying the heavy chain V region (VH) and light chain V region (VL) genes.

[0142] The primers are as follows:

[0143] Heavy chain variable region forward primer (VH-FOR):

[0144] GGGAATTCGAGGTGCAGCTGCAGGAGTCTGG (SEQ ID NO. 25);

[0145] Heavy chain variable region reverse primer (VH-BACK):

[0146] GGAAGGTGTGCACACCGCTGGAC (SEQ ID NO. 26);

[0147] Light chain variable region forward primer (VL-FOR):

[0148] CACGCTAGGGGCGGCCACTGTGGATCCGGATACAGTTGGTGCAGCATC (SEQ ID NO. 27);

[0149] Light chain variable region reverse primer (VL-BACK):

[0150] GGCTGAGCGGGGCTAGATGCCTCGAGGATATTGTGATAACCCAG (SEQ ID NO. 28).

[0151] 2. Take the hybridoma cell line of anti-Quetiapine-mab1 in the logarithmic growth phase (about 10 7 The total RNA of the cells was extracted according to the instruction of Trizol RNA extraction kit, the first chain of cDNA was synthesized by reverse transcription using the total RNA as a template, and the VH / VL gene of the antibody was amplified by PCR using the above amplified product as a template.

[0152] 3. Recover the heavy chain VH (about 360bp) and light chain VL (about 300bp) fragments of anti-Quetiapine-mab1 and send them to the company for sequencing.

[0153] 4. Then analyze the VH / VL gene sequence, and the resulting sequence is as follows:

[0154] Nucleotide sequence of the variable region of the heavy chain: anti-Quetiapine-mab1-VH: 354 bp

[0155] GTGCAACTGCAGCAGTCAGGGTCTGAACTGGTGAAACCTGGGGCTTCAGTGACGTTGTCC

[0156] TGCAAGGCTACTGGCTACACCTCCACCCGCTACTATGTATACTGGGTGAAACAGAGGCCTGGAC

[0157] AAGGCCTTGAGTGGATTGGAGAGATTAATCCTACCAATGGTGGAACTAAATTGAATGAGAAGTT

[0158] CAAGAGCAAGGCCACAATGACTCTGGACAAATCCTCCAGCACATCATACCTGCGACTCAACAG

[0159] TCTGACATCTGAGGACTCTGCGGTCTATTACTGTACAAGATATGATTACGACGTCTGGCTTGCTT

[0160] ACTGGGGCCAAGGGACTCTGGTCACTGTCTCTGCAGCC(SEQ ID NO.3)

[0161] Variable region amino acid sequence of the heavy chain: anti-Quetiapine-mab1-VH protein: 118aa

[0162] VQLQQSGSELVKPGASVTLSCKATGYTSTRYYVYWVKQRPGQGLEWIGEINPTNGGTKLNEK FKSKAMTLDKSSSTSYLRLNSLTSEDSAVYYCTRYDYDVWLAYWGQGTLVTVSAA(SEQ ID NO.1)

[0163] The results of heavy chain variable region CDR analysis are shown in Table 1:

[0164] Table 1

[0165]

[0166]

[0167] Variable region nucleotide sequence of light chain: anti-Quetiapine-mab1-LVκ: 309 bp

[0168] GACATTTGTGATGACCCAGTCTCACAAATTCATGTCCACATCAGTAGGAGACAGGGTCAGCATCACCTGCAAGGCCAGTCAGGATGTGGGGTACTGCTGTTGCCTGGTATCACCAGAAACCAGGACAATCTCCTAAATTACTGATTTACTGGGCATCC ACCCGGCACAGTGGAGTCCCTGATCGCTTCACAGGCAGTGGTTCTGGGACAGATTTCACTCTCACCATTAGCAATGTGCAGTCTGAAGACTTGGCAGATTTTTTCTGTCAGCAATATAGCAGCTATCCGTACACGTTCGGAGGGGGGACCAAG(SEQ ID NO.4)

[0169] The amino acid sequence of the variable region of the light chain: anti-Quetiapine-mab1-LVκprotein: 103aa

[0170] DIVMTQSHKFMSTSVGDRVSITCKASQDVGTAVAWYHQKPGQSPKLLIYWASTRHSGVPDRF TGSGSGTDFTLTISNVQSEDLADFFCQQYSSYPYTFGGGTK(SEQ ID NO.2)

[0171] The results of light chain variable region CDR analysis are shown in Table 2:

[0172] Table 2

[0173]

[0174] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit it. Although the present invention has been described in detail with reference to the aforementioned embodiments, those skilled in the art should understand that they can still modify the technical solutions described in the aforementioned embodiments, or replace some or all of the technical features therein with equivalents. However, these modifications or replacements do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of the present invention.

Claims

1. An anti-quetiapine antibody or an antigen-binding fragment thereof, characterized in that: The antibody or antigen-binding fragment thereof contains the complementarity determining regions HCDR1, HCDR2 and HCDR3 of the heavy chain variable region, and the complementarity determining regions LCDR1, LCDR2 and LCDR3 of the light chain variable region; The HCDR1, HCDR2 and HCDR3 include amino acid sequences consistent with HCDR1, HCDR2 and HCDR3 of the heavy chain variable region shown in SEQ ID NO.1; the LCDR1, LCDR2 and LCDR3 include amino acid sequences consistent with LCDR1, LCDR2 and LCDR3 of the light chain variable region shown in SEQ ID NO.

2.

2. The antibody or antigen-binding fragment thereof according to claim 1, characterized in that: The HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 or LCDR3 of the anti-quetiapine antibody or antigen-binding fragment thereof is defined by any one of the Kabat, Chothia, IMGT, ABM or Contact systems or a combination of multiple definition systems; Optionally, according to the IMGT definition: the amino acid sequence of the HCDR1 is shown as SEQ ID NO.9, the amino acid sequence of the HCDR2 is shown as SEQ ID NO.14, and the amino acid sequence of the HCDR3 is shown as SEQ ID NO.17; the amino acid sequence of the LCDR1 is shown as SEQ ID NO.20, the amino acid sequence of the LCDR2 is WAS, and the amino acid sequence of the LCDR3 is shown as SEQ ID NO.

23.

3. The antibody or antigen-binding fragment thereof according to claim 1, characterized in that: The heavy chain variable region further comprises at least one framework region, and / or the light chain variable region further comprises at least one framework region; Optionally, the antigen-binding fragment is one of F(ab')2, Fab', Fab, Fv, scFv, dsFv, bispecific antibody and antibody minimum recognition unit; Optionally, the antibody is freed of CDR regions, and the remaining sequences are from species including one or more of mice, rats, guinea pigs, hamsters, rabbits, ferrets, cats, dogs, goats, sheep, cows, pigs, horses, monkeys and humans.

4. The antibody or antigen-binding fragment thereof according to any one of claims 1 to 3, characterized in that: The heavy chain variable region of the antibody or antigen-binding fragment thereof is shown in SEQ ID NO.1, and the light chain variable region is shown in SEQ ID NO.2; Optionally, the antibody or antigen-binding fragment thereof further contains part or all of a constant region; Optionally, the constant region sequence is selected from the sequence of a portion or all of the constant region of any one of IgG1, IgG2, IgG3, IgG4, IgA, IgM, IgE or IgD; Optionally, the antibody further comprises a heavy chain constant region and a light chain constant region, the light chain of the antibody is a κ chain, and the antibody is an IgG antibody.

5. Biomaterial, characterized in that The biological material is selected from any one of (i) to (iii): (i) a polynucleotide comprising a nucleotide sequence encoding the anti-quetiapine antibody or antigen-binding fragment thereof according to any one of claims 1 to 4; (ii) a vector carrying the polynucleotide described in (i). (iii) a cell, wherein the cell carries the polynucleotide described in (i), or contains the vector described in (ii), or expresses the anti-quetiapine antibody or its antigen-binding fragment; Optionally, the polynucleotide contains a fragment of the nucleotide sequence as shown in SEQ ID NO.3; Optionally, the polynucleotide contains a fragment of the nucleotide sequence shown in SEQ ID NO.

4.

6. A composition containing an antibody, characterized in that Contains the following (I) and (II) connected or separately packaged: (I) the anti-quetiapine antibody or antigen-binding fragment thereof according to any one of claims 1 to 4; (II) Tracing marker and / or solid phase carrier.

7. A conjugate containing an antibody, characterized in that The invention comprises the anti-quetiapine antibody or antigen-binding fragment thereof and a functional molecule according to any one of claims 1 to 4, wherein the functional molecule is covalently linked to the antibody or antigen-binding fragment thereof, and the functional molecule comprises one or more of sugars, proteins, polypeptides, lipids, nucleic acids and small molecule compounds.

8. Use of the anti-quetiapine antibody or antigen-binding fragment thereof according to any one of claims 1 to 4, or the biomaterial according to claim 5, or the antibody-containing composition according to claim 6, or the antibody-containing conjugate according to claim 7 in detecting quetiapine for non-diagnostic and therapeutic purposes, or in preparing a product for detecting quetiapine.

9. A kit for detecting quetiapine, characterized in that: A composition comprising the anti-quetiapine antibody or antigen-binding fragment thereof according to any one of claims 1 to 4, or the antibody-containing composition according to claim 6, or the antibody-containing conjugate according to claim 7.

10. The kit according to claim 9, characterized in that The kit includes a kit for immunoassay; Optionally, the kit includes an immunochromatographic detection kit, an ELISA detection kit, an immunomagnetic microparticle detection kit, an immunofluorescence detection kit or an immunoblot detection kit; Optionally, the kit includes an immunochromatographic test paper, and the immunochromatographic test paper is a competitive immunochromatographic test paper; Optionally, the detection line of the immunochromatographic test paper is coated with quetiapine coupled to a protein carrier, and the conjugate pad is coated with the anti-quetiapine antibody or antigen-binding fragment thereof labeled with a tracer marker; Optionally, the protein carrier includes bovine gamma globulin, bovine serum albumin, ovalbumin, spikelet hemocyanin, human serum albumin, thyroglobulin, tetanus toxoid, artificially synthesized poly-lysine or purified protein derivatives.

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