WO2020113521A1 - 免疫检测中消除阿霉素干扰的方法及免疫检测试剂盒 - Google Patents

免疫检测中消除阿霉素干扰的方法及免疫检测试剂盒 Download PDF

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WO2020113521A1
WO2020113521A1 PCT/CN2018/119586 CN2018119586W WO2020113521A1 WO 2020113521 A1 WO2020113521 A1 WO 2020113521A1 CN 2018119586 W CN2018119586 W CN 2018119586W WO 2020113521 A1 WO2020113521 A1 WO 2020113521A1
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doxorubicin
immunoassay
kit
immunodetection
interfering agent
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PCT/CN2018/119586
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English (en)
French (fr)
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李可
张裕平
杨友
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深圳迈瑞生物医疗电子股份有限公司
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Priority to PCT/CN2018/119586 priority Critical patent/WO2020113521A1/zh
Priority to CN201880098379.0A priority patent/CN112888945B/zh
Publication of WO2020113521A1 publication Critical patent/WO2020113521A1/zh

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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/543—Immunoassay; Biospecific binding assay; Materials therefor with an insoluble carrier for immobilising immunochemicals

Definitions

  • the present invention relates to the field of immune detection, and in particular to a detection method for patients undergoing cancer chemotherapy to eliminate the effects of chemotherapy drugs on immune detection.
  • Chemotherapy is an important means of anti-tumor therapy.
  • the metabolism in the body will have a certain half-life. Therefore, within a certain period after taking the medicine, the patient's blood will still contain a certain amount of medicine.
  • clinical immunoassay if there is a certain concentration of drug or metabolite in the blood of the subject, it will interfere with the accuracy of the immunoassay results, and then affect the clinical judgment.
  • dynamic monitoring of tumor markers in patients who have been diagnosed with malignant tumors can be used to assist in determining the course of the disease or the therapeutic effect.
  • the drug or its metabolites in the blood will misjudge the course of the disease or the treatment effect, and ultimately lead to an unreasonable treatment plan.
  • the present invention provides a method for anti-doxorubicin interference in immunodetection and an immunodetection kit for anti-doxorubicin interference.
  • a method of eliminating doxorubicin interference in the immunoassay of a sample comprising: performing an immunodetection reaction in the presence of an anti-doxorubicin interfering agent, wherein the anti The final concentration of the doxorubicin interfering agent is 0.1 mg/mL to 100 mg/mL and is selected from 6-mercaptopurine, 6-mercaptoguanine, 8-azaazaguanine, hypoxanthine, adenine, purine, 2,6 , At least one of the group consisting of 8-trioxypurine, adenine nucleotide and adenosine.
  • the final concentration of the anti-doxorubicin interfering agent is 5 mg/mL to 80 mg/mL, preferably 10 mg/mL to 80 mg/mL, and more preferably 50 mg/mL to 80 mg/mL.
  • the anti-doxorubicin interfering agent in the present invention may be at least one selected from the group consisting of 6-mercaptoguanine, hypoxanthine, purine, and adenosine.
  • the method of the present invention can be used in various immunoassays, especially chemiluminescence immunoassays, electrochemiluminescence immunoassays, or enzyme-linked immunoassays.
  • the method of the invention involves immunodetection against tumor markers. More specifically, the immunoassay using the solid phase method.
  • the anti-doxorubicin interfering agent may be added to the immunodetection reaction system in the form of a separate reagent, for example, in the form of a sample pretreatment solution before adding the immunodetection reagent to the sample to be tested.
  • the anti-doxorubicin interfering agent of the present invention is added to the immunodetection reaction system in combination with one or more reagents.
  • one or more reagents that may be exemplified include, but are not limited to: substrates, labels, solid phases coated with immunodetection reagents, sample processing solutions, buffers, and ionic strength modifiers , Surfactants, preservatives and cleaning agents.
  • the anti-doxorubicin interfering agent of the present invention may be added before adding the substrate, preferably before adding the solid phase coated with the immunodetection reagent or before adding the label, and more preferably may be added in the sample Added in the pre-processing step.
  • the sample is a blood sample, more specifically a serum or plasma sample.
  • an immunodetection kit includes an anti-doxorubicin interfering agent with a final concentration of 0.1 mg/mL to 100 mg/mL.
  • the doxorubicin anti-interfering agent is selected from the group consisting of 6 -At least at least one of the group consisting of mercaptopurine, 6-mercaptoguanine, 8-azaazaguanine, hypoxanthine, adenine, purine, 2,6,8-trioxypurine, adenine nucleotide and adenosine One kind.
  • the immunodetection kit includes anti-doxorubicin interference with a final concentration of 5 mg/mL to 80 mg/mL, preferably 10 mg/mL to 80 mg/mL, and more preferably 50 mg/mL to 80 mg/mL. Agent.
  • the anti-doxorubicin interfering agent in the kit of the present invention is at least one selected from the group consisting of 6-mercaptoguanine, hypoxanthine, purine and adenosine.
  • the immunodetection kit of the present invention may be any kit for immunodetection, especially a chemiluminescence immunodetection kit, an electrochemiluminescence immunodetection kit or an enzyme-linked immunoassay kit.
  • the immunodetection kit of the present invention is an immunodetection kit for tumor markers.
  • the anti-doxorubicin interfering agent may be combined with one or more reagents in the kit, or may be provided in the form of a separate reagent Kit.
  • the immunodetection kit according to the present invention also includes necessary reagents for immunodetection. According to the needs of the detection object and the detection method, the immunodetection kit of the present invention accordingly includes different reagents. The reagents specifically contained in different immunodetection kits are already mastered by those skilled in the art.
  • substrates, labels, and immunodetection reagents especially immunodetection reagents coated on a solid phase (such as antigen, antibody, streptavidin, etc.).
  • the solid phase can be magnetic beads, plastic beads or ELISA plates or strips.
  • the kit may further include a sample processing solution, a buffer solution, an ionic strength regulator, a surfactant, and/or a preservative, etc., but it is not limited thereto.
  • the immunodetection kit of the present invention is used to detect blood samples.
  • the blood sample may be a serum or plasma sample.
  • an immunodetection method that eliminates doxorubicin interference is also provided.
  • the immunodetection method has the features defined above and/or includes the steps defined above.
  • an anti-doxorubicin interfering agent for eliminating the interference of doxorubicin in the immunodetection of blood samples.
  • the anti-doxorubicin interfering agent is selected from 6-mercaptopurine and 6-mercapto At least one of the group consisting of guanine, 8-azaaza, hypoxanthine, adenine, purine, 2,6,8-trioxypurine, adenine nucleotide, and adenosine.
  • the method and the kit of the present invention can significantly reduce or even eliminate the interference caused by doxorubicin or its metabolites during the immunoassay of subjects undergoing doxorubicin treatment, and obtain a more accurate result that is not interfered by doxorubicin Immunoassay results provide a reliable basis for clinical diagnosis and treatment.
  • the method of the invention is simple and does not interfere with the original immunodetection method.
  • doxorubicin hydrochloride doxorubicin hydrochloride
  • liposomal doxorubicin liposomal doxorubicin
  • Doxorubicin is a broad-spectrum anticancer drug, suitable for acute leukemia (lymphocytic and granulocytic), malignant lymphoma, breast cancer, bronchial lung cancer (undifferentiated small cell and non-small cell) , Ovarian cancer, soft tissue sarcoma, osteosarcoma, rhabdomyosarcoma, Ewing's sarcoma, blastoma, neuroblastoma, bladder cancer, thyroid cancer, prostate cancer, head and neck squamous cell carcinoma, testicular cancer, gastric cancer, liver cancer, etc. cancer. After intravenous injection of doxorubicin, it quickly distributed to the heart, kidney, spleen, lung and other organs.
  • acute leukemia lymphocytic and granulocytic
  • malignant lymphoma breast cancer
  • bronchial lung cancer undifferentiated small cell and non-small cell
  • Ovarian cancer soft tissue sarcoma
  • the method of the present invention aims to provide a method for eliminating the interference of doxorubicin when performing immunoassays on subjects who are undergoing or recently undergoing doxorubicin treatment.
  • anti-doxorubicin interference or “elimination of doxorubicin interference” refers to the reduction or even elimination of the interference of doxorubicin product or its metabolites (such as doxorubicin alcohol, etc.) to immune detection.
  • the "subject" referred to herein refers to a subject in need of immunoassay who is undergoing doxorubicin administration, or has recently administered doxorubicin. For example, doxorubicin has been administered within 6 months, or doxorubicin has been administered within 4 months, 3 months, 2 months, or 1 month.
  • sample refers to a blood sample taken from a subject for immunodetection. It is specifically a serum or plasma sample, especially a serum sample.
  • immunoassay refers to a method for determining the content of the test substance in the sample by using the test principle as an antigen or antibody.
  • the immunodetection method that can be used in the present invention refers to a detection method based on the principle of immune reaction, including, but not limited to: enzyme-linked immunoassay, radioimmunoassay, fluorescent immunoassay, chemiluminescence immunoassay, electrochemiluminescence immunoassay, etc. Especially suitable for enzyme-linked immunoassay, chemiluminescence immunoassay and electrochemiluminescence immunoassay methods and kits.
  • Enumerated labels include antibodies (or antigens) labeled with enzymes (such as alkaline phosphatase, horseradish peroxidase), luminescent compounds (such as acridinium esters, luminol, isoluminol, ruthenium terpyridine, etc.) ) Labeled antibody (or antigen, or immunoassay analyte), etc., but not limited thereto.
  • enzymes such as alkaline phosphatase, horseradish peroxidase
  • luminescent compounds such as acridinium esters, luminol, isoluminol, ruthenium terpyridine, etc.
  • the method of the present invention is more suitable for solid phase immunoassay.
  • the solid phase used in the solid phase immunodetection of the present invention may be magnetic beads, plastic beads, immunoplates (or strips) coated with immunodetection reagents, and the like.
  • the immunodetection reagent coated on the solid phase varies according to the method, and may include, for example, antigen, antibody, streptavidin and the like.
  • the immunodetection method for eliminating doxorubicin interference of the present invention is particularly suitable for immunoassay of tumor markers.
  • Tumor markers are substances that exist in or are produced by cancer cells or the body reacts to cancer cells, and can reflect the presence, absence, and development of tumors. Therefore, the detection of tumor markers in serum can be used for tumor diagnosis, disease course analysis, treatment planning, monitoring recurrence or metastasis, etc.
  • tumor markers including carbohydrate antigens, embryonic antigens, cytokeratins, tumor-related enzymes, hormones, and other proteins.
  • Common tumor markers include: alpha-fetoprotein (AFP), carcinoembryonic antigen (CEA), carbohydrate antigen 125 (CA125), carbohydrate antigen 153 (CA153), carbohydrate antigen 199 (CA199), carbohydrate Antigen 724 (CA724), carbohydrate antigen 242 (CA242), carbohydrate antigen 50 (CA50), CYFRA21-1 (Cy211), neuron-specific enolase (NSE), prostate-specific antigen (PSA), human villi Membrane gonadotropin (HCG), thyroglobulin (TG), ferritin (SF), ⁇ 2-microglobulin ( ⁇ 2-MG), squamous cell antigen (SCC), etc., but not limited thereto.
  • AFP alpha-fetoprotein
  • CEA carcinoembryonic antigen
  • CA125 carbohydrate antigen 125
  • carbohydrate antigen 153 CA153
  • carbohydrate antigen 199 CA199
  • purine compounds and their derivatives can reduce or even eliminate the interference of doxorubicin or its metabolites in the immunoassay.
  • Purine compounds and derivatives thereof that can be used in the present invention are 6-mercaptopurine, 6-mercaptoguanine, 8-azaazaguanine, hypoxanthine, adenine, purine, 2,6,8-trioxypurine, adenine Purine nucleotides and adenosine.
  • 6-mercaptoguanine, hypoxanthine, purine and adenosine have better effects.
  • the final concentration of the anti-doxorubicin interfering agent is 0.1 mg/mL to 100 mg/mL.
  • Specific examples of the final concentration of the anti-doxorubicin interfering agent may be 2 mg/mL, 3 mg/mL, 4 mg/mL, 5 mg/mL, 10 mg/mL, 15 mg/mL, 20 mg/mL, 30 mg/mL, 40 mg/mL, 50 mg/ mL, 60mg/mL, 70mg/mL or 80mg/mL.
  • the final concentration of the anti-doxorubicin interfering agent is 5 mg/mL to 80 mg/mL, preferably 10 mg/mL to 80 mg/mL, and more preferably 50 mg/mL to 80 mg/mL.
  • the anti-doxorubicin interfering agent may be present as a separate reagent in the immunodetection kit of the present invention or added to the immunodetection reaction system, or may be present in combination with one or more other reagents Invented immunodetection kit or added to immunodetection reaction system. Therefore, the concentration of the anti-doxorubicin interfering agent of the present invention before it is added to the immunodetection reaction system depends on the manner of its existence. To make the context clear and consistent, the "final concentration” referred to herein refers to the concentration in the immunoassay reaction system, especially the concentration of the anti-doxorubicin interfering agent in the final immunoassay reaction system.
  • the anti-doxorubicin interfering agent is present as a separate agent.
  • the anti-doxorubicin interfering agent is dissolved in an appropriate solvent to prepare a solution.
  • the anti-doxorubicin interfering agent as a separate reagent can be used as a sample pretreatment agent, and can be added to the sample to be tested successively or simultaneously with other sample treatment solutions.
  • Anti-doxorubicin interfering agents can also be added during the detection reaction. For example, it is added to the reaction system before the substrate is added, especially before the solid phase or label coated with the immunodetection reagent is added.
  • the anti-doxorubicin interfering agent is added to the immunodetection reaction system in combination (eg, mixing) with other immunodetection reagents.
  • the anti-doxorubicin interfering agent may be added to the reagent containing the marker, the reagent containing the substrate, or the solid phase reagent.
  • anti-doxorubicin interfering agents can also be added to auxiliary reagents, such as other sample processing agents, buffers, ionic strength modifiers, surfactants, preservatives, or cleaning agents.
  • those skilled in the art can add anti-doxorubicin interfering agents to reagents that are convenient to operate and have no adverse effects according to specific needs, so as to add anti-doxorubicin interfering agents to the immune detection reaction system at an appropriate time, This ensures that during the immunoassay reaction, doxorubicin or its metabolites do not interfere with the immunoassay reaction.
  • the present invention further provides an immunodetection kit including the anti-doxorubicin interfering agent of the present invention, so as to conveniently implement the method of the present invention.
  • the anti-doxorubicin interfering agent contained in the kit of the present invention is as defined above.
  • the kit of the present invention may be any kit for immunoassay to be performed by a subject, and is not particularly limited.
  • the kit of the present invention is especially an enzyme-linked immunoassay kit, a chemiluminescence immunoassay kit or an electrochemiluminescence immunoassay kit.
  • the immunodetection kit of the present invention is a kit for detecting tumor markers. And it is more preferably a kit using a solid-phase detection method.
  • the anti-doxorubicin interfering agent may exist in the form of a separate reagent, or may be combined with (eg, mixed with) one or more other reagents required for the immunoassay reaction. Form exists.
  • the gastrin releasing peptide precursor chemiluminescence immunoassay kit was used to test the interference sample and the control sample twice.
  • the mean value of the test result of the interferer sample is recorded as M
  • the mean value of the test result of the control sample is recorded as T.
  • the interference deviation B is calculated according to the following formula:
  • the kit for performing the detection of the gastrin releasing peptide precursor is a commercially available kit and a kit in which an anti-doxorubicin interfering agent is added to the commercially available kit according to the present invention .
  • the commercially available kits include the following components:
  • Magnetic particle reagent superparamagnetic particles coated with anti-gastrin releasing peptide precursor antibody suspended in Tris buffer;
  • Labeling reagent anti-gastrin releasing peptide precursor antibody-alkaline phosphatase label dissolved in MES buffer;
  • Chemiluminescent substrate 3-(2-helixadamantane)-4-methoxy-4-(3-phosphoryl)-phenyl-1,2-dioxane, AMPPD.
  • the anti-doxorubicin interfering agents are: 6-mercapto Purine, 6-mercaptoguanine, 8-azaazaguanine, hypoxanthine, adenine, purine (C 5 H 4 N 4 ), 2,6,8-trioxypurine, adenine nucleotide and adenosine ( 9- ⁇ -D-ribofuranosyl adenine).
  • the magnetic particle reagent and the labeling reagent in the above kit can be coated with magnetic particles and labeled with alkaline phosphatase by conventional antibody coating methods and labeling techniques.
  • Step 1 Add 20 ⁇ L of sample, 50 ⁇ L of magnetic particle reagent and 50 ⁇ L of label reagent to the reaction tube, and incubate at 37°C for 10 minutes. After the reaction is completed, a sandwich complex is formed, the magnetic beads are attracted under a magnetic field, and unbound substances are washed away.
  • Step 2 Add chemiluminescent substrate (AMPPD) to the reaction tube and incubate at 37°C for 6 minutes.
  • APPD chemiluminescent substrate
  • the alkaline phosphatase bound to the sandwich complex on the magnetic particles catalyzes the luminescence of the substrate.
  • the number of photons produced is proportional to the concentration of gastrin-releasing peptide precursor in the sample, and the luminescence reading is recorded.
  • the amount of gastrin releasing peptide precursor in the sample is calculated from the calibration curve.
  • the above kits containing different anti-doxorubicin interfering agents and kits containing no anti-doxorubicin interfering agents were used for detection.
  • the interference deviation B obtained is shown in the following table.
  • the interference deviation can be reduced to an acceptable range (within ⁇ 10%), effectively reducing The interference of doxorubicin to the test results was discussed.
  • Example 2 the anti-doxorubicin interference ability of the anti-doxorubicin interfering agent at different final concentrations was evaluated in substantially the same manner as in Example 1.
  • the final concentrations of 1 ⁇ g/mL, 0.1 mg/mL, 1 mg/mL, 5 mg/mL, 10 mg/mL were added to the marker reagent of the gastrin releasing peptide precursor chemiluminescence immunoassay kit, 20mg/mL, 50mg/mL, 80mg/mL, 100mg/mL adenosine, and then the concentration of gastrin releasing peptide precursor (ProGRP) was (40.00 ⁇ 10.00) pg/mL in the same way as in Example 1 , (600.00 ⁇ 120.00) pg/mL serum samples containing 72 ⁇ g/mL doxorubicin interference or without any interference were measured, and the interference deviation B was calculated. The results are shown in the table below.
  • the absolute value of the deviation of anti-doxorubicin interference further decreases.
  • the final concentration of adenosine reaches 20 mg/mL, as the concentration of adenosine increases, the influence on the deviation of the detection result relatively decreases.

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Abstract

一种免疫检测中消除阿霉素干扰的方法及免疫检测试剂盒。该方法包括：在抗阿霉素干扰剂的存在下进行免疫检测反应，其中该抗阿霉素干扰剂的终浓度为0.1mg/mL～100mg/mL，且选自由6-巯基嘌呤、6-巯基鸟嘌呤、8-杂氮鸟嘌呤、次黄嘌呤、腺嘌呤、嘌呤、2,6,8-三氧嘌呤、腺嘌呤核苷酸和腺苷所组成的组中的至少一种。该方法及试剂盒能有效消除阿霉素对免疫检测结果的干扰。

Description

免疫检测中消除阿霉素干扰的方法及免疫检测试剂盒 技术领域
本发明涉及免疫检测领域，特别涉及针对经历癌症化疗患者消除化疗药物对免疫检测影响的检测方法。
背景技术
化疗是抗肿瘤治疗的一种重要手段。当化疗药物被患者服用后，在体内的代谢会有一定时间的半衰期。因此，在服药后的一定时期内，患者的血液中仍会含有一定量的药物。在临床免疫检测中，如果受试者的血液中存在一定浓度的药物或其代谢物时，会干扰免疫测定结果的准确性，并进而影响临床判断。例如对已确诊恶性肿瘤的患者进行肿瘤标志物动态监测可用于辅助判断疾病的进程或治疗效果。当血液中的药物或其代谢物将对病程或治疗效果产生误判，并最终导致不合理的治疗方案。
因此，需要一种能够消除抗肿瘤药物对受试者免疫测定干扰的方法。
发明内容
为此，本发明提供了一种在免疫检测中抗阿霉素干扰的方法以及抗阿霉素干扰的免疫检测试剂盒。
根据本发明的第一方面，提供一种在对样本的免疫检测中消除阿霉素干扰的方法，所述方法包括：在抗阿霉素干扰剂的存在下进行免疫检测反应，其中所述抗阿霉素干扰剂的终浓度为0.1mg/mL～100mg/mL，且选自由6-巯基嘌呤、6-巯基鸟嘌呤、8-杂氮鸟、次黄嘌呤、腺嘌呤、嘌呤、2,6,8-三氧嘌呤、腺嘌呤核苷酸和腺苷所组成的组中的至少一种。
根据进一步的实施方式，所述抗阿霉素干扰剂的终浓度为5mg/mL～80 mg/mL、优选为10mg/mL～80mg/mL、更优选为50mg/mL～80mg/mL。
根据更进一步的实施方式，本发明中所述抗阿霉素干扰剂可为选自由6-巯基鸟嘌呤、次黄嘌呤、嘌呤和腺苷所组成的组中的至少一种。
本发明的方法可用于各种免疫检测中，尤其是化学发光免疫检测、电化学发光免疫检测或酶联免疫检测。
具体地，本发明的方法涉及针对肿瘤标志物的免疫检测。更具体地为采用固相法进行的免疫检测。
根据一种实施方式，本发明中，抗阿霉素干扰剂可以以单独的试剂形式加入免疫检测反应体系中，例如以样本前处理液的形式预先在加入免疫检测试剂之前加入待测样本中。
根据另一种实施方式，本发明的抗阿霉素干扰剂以与一种或多种试剂组合的形式加入所述免疫检测反应体系中。在本发明的方法中，可列举的一种或多种试剂包括，但不限于：底物、标记物、包被有免疫检测反应物的固相、样本处理液、缓冲液、离子强度调节剂、表面活性剂、防腐剂和清洗剂等。
根据具体实施方式，本发明的抗阿霉素干扰剂可在加入底物之前加入，优选可在加入包被有免疫检测反应物的固相之前或加入标记物之前加入，更优选地可在样本前处理步骤中加入。
本发明的方法中，所述样本为血液样本，更具体地为血清或血浆样本。
本发明的第二方面，提供一种免疫检测试剂盒，所述试剂盒包括终浓度为0.1mg/mL～100mg/mL的抗阿霉素干扰剂，所述阿霉素抗干扰剂选自由6-巯基嘌呤、6-巯基鸟嘌呤、8-杂氮鸟、次黄嘌呤、腺嘌呤、嘌呤、2,6,8-三氧嘌呤、腺嘌呤核苷酸和腺苷所组成的组中的至少一种。
根据一种实施方式，所述免疫检测试剂盒包括终浓度为5mg/mL～80mg/mL、优选为10mg/mL～80mg/mL、更优选为50mg/mL～80mg/mL的抗 阿霉素干扰剂。
根据进一步的实施方式，本发明的试剂盒中的抗阿霉素干扰剂为选自由6-巯基鸟嘌呤、次黄嘌呤、嘌呤和腺苷所组成的组中的至少一种。
本发明的免疫检测试剂盒可以是任何用于免疫检测的试剂盒，尤其是是化学发光免疫检测试剂盒、电化学发光免疫检测试剂盒或酶联免疫检测试剂盒。
根据具体实施方式，本发明的免疫检测试剂盒是针对肿瘤标志物的免疫检测试剂盒。
在本发明的免疫检测试剂盒中，所述抗阿霉素干扰剂可以为与所述试剂盒中的一种或多种试剂组合的形式，或者也可以是以单独试剂的形式提供在所述试剂盒中。
根据本发明的免疫检测试剂盒还包括用于免疫检测的必要试剂。根据检测对象及检测方法的需要，本发明的免疫检测试剂盒相应地包括不同试剂。不同的免疫检测试剂盒中具体包含的试剂是本领域技术人员已经掌握的。
例如，对于常见的酶联免疫试剂盒及化学发光免疫检测试剂盒，通常来说，还可包括底物、标记物和免疫检测反应物，尤其是包被在固相上的免疫检测反应物(如抗原、抗体、链酶亲和素等)。用作固相的可以是磁珠、塑料珠或者酶联免疫的板或条。
根据不同需要，所述试剂盒中还可包括样本处理液、缓冲液、离子强度调节剂、表面活性剂和/或防腐剂等，但不限于此。
本发明的免疫检测试剂盒用于对血液样本的检测。所述血液样本可以是血清或血浆样本。
本发明的另一方面，还提供一种消除阿霉素干扰的免疫检测方法。所述免疫检测方法具有以上定义的特征和/或包括以上定义的步骤。
本发明的再一方面，提供一种抗阿霉素干扰剂在对血液样本的免疫检测中消除阿霉素干扰的用途，所述抗阿霉素干扰剂选自由6-巯基嘌呤、6-巯基鸟嘌呤、8-杂氮鸟、次黄嘌呤、腺嘌呤、嘌呤、2,6,8-三氧嘌呤、腺嘌呤核苷酸和腺苷所组成的组中的至少一种。
本发明的方法和试剂盒能显著降低、甚至消除进行阿霉素治疗的受试者在进行免疫检测中由阿霉素或其代谢产物引起的干扰，得到不受阿霉素干扰的较准确的免疫测定结果，为临床诊治提供可靠的判断依据。本发明的方法简单，对原免疫检测方法不产生干扰。
具体实施方式
下面将结合本发明具体实施方式和实施例，对本发明实施方式中的技术方案进行清楚、完整地描述，显然，所描述的具有实施方式仅仅是本发明的一部分实施方式，而不是全部的实施方式。基于本发明中的实施方式，本领域普通技术人员在没有作出创造性劳动前提下所获得的所有其他实施方式，都属于本发明保护的范围。
在整个说明书中，除非另有特别说明，本文使用的术语应理解为如本领域中通常所使用的含义。因此，除非另有定义，本文使用的所有技术和科学术语具有与本发明所属领域技术人员的一般理解相同的含义。若存在矛盾，本说明书优先。
在文中，术语“包括”、“包含”或者其任何其他变体意在涵盖非排他性的包含，从而使得包括一系列要素的方法或者产品不仅包括所明确记载的要素，而且还包括没有明确列出的其他要素，或者还包括为实施所述方法或者产品所固有的要素。
除非另有说明，否则如在本文件所使用的单数形式“一个/种(a/an)”和“该/所述”包括所指名词的复数。
本文所述“阿霉素”，除非另有说明，包括其所有药用形式，例如其 可药用的盐的形式(如盐酸阿霉素)和脂质体阿霉素等。
阿霉素(doxorubicin)是一种广谱抗癌药物，适用于急性白血病(淋巴细胞性和粒细胞性)、恶性淋巴瘤、乳腺癌、支气管肺癌(未分化小细胞性和非小细胞性)、卵巢癌、软组织肉瘤、成骨肉瘤、横纹肌肉瘤、尤文肉瘤、母细胞瘤、神经母细胞瘤、膀胱癌、甲状腺癌、前列腺癌、头颈部鳞癌、睾丸癌、胃癌、肝癌等多种癌症。静脉注射阿霉素后迅速分布至心、肾、脾、肺等器官中。
本发明的方法旨在为正在或近期进行阿霉素治疗的受试者进行免疫检测时，提供消除阿霉素的干扰的方法。
本文所述的“抗阿霉素干扰”或“消除阿霉素干扰”是指降低、甚至消除阿霉素本品或其代谢产物(如阿霉素醇等)对免疫检测的干扰。
本文所称“受试者”是指有需要进行免疫检测的受试者，其正在经历阿霉素的给药，或者近期曾经进行过阿霉素的给药。例如，在6个月内施用过阿霉素，或者在4个月、3个月、2个月、或1个月内施用过阿霉素。
本文所述“样本”指用于进行免疫检测的采自受试者的血液样本。具体为血清或血浆样本，特别是血清样本。
本文所述“免疫检测”，如无特别说明，是指利用免疫学原理，以待测物作为抗原或抗体从而测定样本中待测物质含量的方法。
可用于本发明的免疫检测方法是指基于免疫反应原理的检测方法，包括，但不限于：酶联免疫法、放射免疫法、荧光免疫法、化学发光免疫法、电化学发光免疫法等。特别适用于酶联免疫检测、化学发光免疫检测和电化学发光免疫检测的方法和试剂盒。
标记物根据具体方法不同而不同，本发明对此并无特别限制。可列举的标记物包括酶(如碱性磷酸酶、辣根过氧化物酶)标记的抗体(或抗原)， 发光化合物(如吖啶酯、鲁米诺、异鲁米诺、三联吡啶钌等)标记的抗体(或抗原、或免疫测定被分析物)等，但不限于此。
本发明的方法更适用于固相免疫检测法。用于本发明固相免疫检测的固相可以是包被有免疫检测反应物的磁珠、塑料珠、免疫板(或条)等。包被在固相上的免疫检测反应物根据方法的不同而不同，例如可以包括抗原、抗体、链酶亲和素等。
本发明的消除阿霉素干扰的免疫检测方法尤其适用于肿瘤标志物的免疫测定。
肿瘤标志物是存在于癌细胞中的、或由癌细胞产生的、或机体对癌细胞反应而产生的物质，能反映肿瘤的有、无、发展。因此，对血清中肿瘤标志物的检测可用于肿瘤诊断、病程分析、制定治疗方案、监测复发或转移等。已知的肿瘤标志物有很多，包括糖类抗原、胚胎性抗原、细胞角蛋白、肿瘤相关的酶、激素类以及其他蛋白类。常见的肿瘤标志物可列举的有：甲胎蛋白(AFP)、癌胚抗原(CEA)、糖类抗原125(CA125)、糖类抗原153(CA153)、糖类抗原199(CA199)、糖类抗原724(CA724)、糖类抗原242(CA242)、糖类抗原50(CA50)、CYFRA21-1(Cy211)、神经元特异性烯醇化酶(NSE)、前列腺特异性抗原(PSA)、人绒毛膜促性腺激素(HCG)、甲状腺球蛋白(TG)、铁蛋白(SF)、β2-微球蛋白(β2-MG)、鳞状细胞抗原(SCC)等，但不限于此。
本发明人发现，很多嘌呤类化合物及其衍生物可以降低、甚至消除免疫检测中阿霉素或其代谢物对免疫检测的干扰。可用于本发明的嘌呤类化合物及其衍生物有6-巯基嘌呤、6-巯基鸟嘌呤、8-杂氮鸟、次黄嘌呤、腺嘌呤、嘌呤、2,6,8-三氧嘌呤、腺嘌呤核苷酸和腺苷。其中，6-巯基鸟嘌呤、次黄嘌呤、嘌呤和腺苷具有更优的效果。
本发明中，抗阿霉素干扰剂的终浓度为0.1mg/mL～100mg/mL。抗阿 霉素干扰剂终浓度具体实例可为2mg/mL、3mg/mL、4mg/mL、5mg/mL、10mg/mL、15mg/mL、20mg/mL、30mg/mL、40mg/mL、50mg/mL、60mg/mL、70mg/mL或80mg/mL。
在较佳的实施方式中，抗阿霉素干扰剂的终浓度为5mg/mL～80mg/mL、优选为10mg/mL～80mg/mL、更优选为50mg/mL～80mg/mL。
根据本发明，所述抗阿霉素干扰剂可作为单独的试剂存在于本发明的免疫检测试剂盒中或者添加至免疫检测反应体系中，也可以与其他一种或多种试剂组合存在于本发明的免疫检测试剂盒中或者添加至免疫检测反应体系中。因此，本发明的抗阿霉素干扰剂在添加到免疫检测反应体系中之前的浓度取决于其存在方式。为使上下文清楚、一致，本文所说的“终浓度”是指在免疫检测反应体系中的浓度，尤其是抗阿霉素干扰剂在最终免疫检测反应体系中的浓度。
根据本发明的一种实施方式，抗阿霉素干扰剂是以单独的试剂形式存在。具体地，将抗阿霉素干扰剂溶解在适当的溶剂中，制成溶液。作为单独的试剂的抗阿霉素干扰剂可以作为样本前处理剂，与其他样本处理液先后或同时加入待测样本中。也可以在检测反应过程中加入抗阿霉素干扰剂。例如，在加入所述底物之前、尤其是在加入包被有免疫检测反应物的固相或标记物之前加入反应体系中。
根据本发明的另一种实施方式，抗阿霉素干扰剂是以与其他免疫检测用试剂组合(如混合)的形式被加入到免疫检测反应体系中。例如，抗阿霉素干扰剂可添加在含标记物的试剂中、含底物的试剂中，或者添加在固相试剂中。此外，抗阿霉素干扰剂也可添加在辅助试剂中，例如添加在其他样本处理剂中、添加在缓冲液、离子强度调节剂、表面活性剂、防腐剂或清洗剂中。总之，本领域技术人员可以根据具体需要，将抗阿霉素干扰剂添加在方便操作且无不良作用的试剂中，以便在适当的时机将抗阿霉素 干扰剂添加到免疫检测反应体系中，从而确保免疫检测反应过程中，阿霉素或其代谢产物不对免疫检测反应产生干扰。
本发明进一步提供一种包括本发明的抗阿霉素干扰剂的免疫检测试剂盒，以便方便地实施本发明的方法。
本发明的试剂盒中包含的抗阿霉素干扰剂如上文定义。
同样的，本发明的试剂盒可以是受试者需要进行的任何免疫检测的试剂盒，并无特别限制。但是，本发明的试剂盒尤其为酶联免疫检测试剂盒、化学发光免疫检测试剂盒或电化学发光免疫检测试剂盒。
更具体地，本发明的免疫检测试剂盒是针对肿瘤标志物的检测试剂盒。并且更优选为采用固相检测法的试剂盒。
同样的，在本发明的免疫检测试剂盒中，抗阿霉素干扰剂可以以单独的试剂形式存在，也可以以与其他一种或多种免疫检测反应所需要的试剂组合(如混合)的形式存在。
以下实施例用于进一步说明本发明的效果。
实施例1
在该实施例1中，对上述抗阿霉素干扰剂的抗阿霉素干扰能力进行评估。
首先准备胃泌素释放肽前体(ProGRP)浓度分别为(40.00±10.00)pg/mL、(600.00±120.00)pg/mL的两组血清样本，每组各两份；向其中一份样本中添加一定体积的高浓度阿霉素溶液(使用无水乙醇溶解，添加体积不超过添加后总体积的1/20)，配制得到阿霉素浓度为72μg/mL的干扰样本；向另一份样本中添加等体积无水乙醇(添加体积与前述干扰样本添加体积一致，不超过添加后总体积的1/20)，配制得到不含干扰物的对照样本。
在此使用胃泌素释放肽前体化学发光免疫分析试剂盒对干扰样本和对 照样本分别测试2次。干扰物样本的测试结果均值记为M，对照样本的测试结果均值记为T，按以下公式计算干扰偏差B：
B(％)＝(M-T)/T×100％。
在本实施例1中，用于进行检测的胃泌素释放肽前体测定的试剂盒为商购试剂盒以及按照本发明的在商购试剂盒中加入了抗阿霉素干扰剂的试剂盒。其中，商购试剂盒包括以下组分：
磁性微粒试剂：悬浮于Tris缓冲液中的包被着抗胃泌素释放肽前体抗体的超顺磁性微粒；
标记物试剂：抗胃泌素释放肽前体抗体-碱性磷酸酶标记物溶于MES缓冲液；和
化学发光底物：3-(2-螺旋金刚烷)-4-甲氧基-4-(3-磷氧酰)-苯基-1,2-二氧环乙烷，AMPPD。
在所述标记物试剂中加入终浓度为10mg/mL的本发明的抗阿霉素干扰剂，以制备按照本发明的免疫检测试剂盒，所述抗阿霉素干扰剂分别为：6-巯基嘌呤、6-巯基鸟嘌呤、8-杂氮鸟、次黄嘌呤、腺嘌呤、嘌呤(C 5H 4N 4)、2,6,8-三氧嘌呤、腺嘌呤核苷酸和腺苷(9-β-D-呋喃核糖基腺嘌呤)。
上述试剂盒中的磁微粒试剂和标记物试剂可以用常规的抗体包被方法和标记技术，将抗体包被到磁微粒和将抗体与碱性磷酸酶结合标记。
分别用含有不同的抗阿霉素干扰剂的试剂盒进行胃泌素释放肽前体的检测，检测步骤如下：
第一步：将20μL样本与50μL磁性微粒试剂和50μL标记物试剂添加到反应管中，37℃孵育10分钟。反应完成后，形成夹心复合物，在磁场下吸住磁珠，洗去未结合的物质。
第二步：将化学发光底物(AMPPD)添加到反应管内，37℃孵育6分钟。结合到磁性微粒上的夹心复合物上的碱性磷酸酶催化底物发光，所产 生光子数与样本内胃泌素释放肽前体的浓度成正比，记录发光读数。样本内胃泌素释放肽前体的量由校准曲线来计算得到。
采用上述含有不同抗阿霉素干扰剂的试剂盒以及不含有抗阿霉素干扰剂的试剂盒进行检测，得到的干扰偏差B如下表所示。
Figure PCTCN2018119586-appb-000001
从上表中结果可以看出，当样本中干扰物阿霉素浓度达72μg/mL时，采用不添加本发明的抗阿霉素干扰剂的胃泌素释放肽前体试剂盒进行检测的干扰偏差较大(低值样本-22.04％，高值样本-27.86％)，表明样本中的阿霉素严重干扰了试剂盒的检测结果。
当在试剂盒中添加一定终浓度(在该实施例中为10mg/mL)的上述抗阿霉素干扰剂后，能够将干扰偏差降低至可接受范围内(±10％范围内)，有效降低了阿霉素对检测结果的干扰。
实施例2
在该实施例2中，按照与实施例1基本相同的方法对不同终浓度的抗阿霉素干扰剂的抗阿霉素干扰能力进行评估。
本实施例中，向胃泌素释放肽前体化学发光免疫分析试剂盒的标记物试剂中添加终浓度分别为1μg/mL、0.1mg/mL、1mg/mL、5mg/mL、10mg/mL、20mg/mL、50mg/mL、80mg/mL、100mg/mL的腺苷，然后按照与实施例1 相同的方法对胃泌素释放肽前体(ProGRP)浓度分别为(40.00±10.00)pg/mL、(600.00±120.00)pg/mL的、含有72μg/mL阿霉素干扰或不含任何干扰的血清样本进行测定，并计算干扰偏差B，结果如下表所示。
Figure PCTCN2018119586-appb-000002
从上表中结果可以看出，不同终浓度的腺苷能够不同程度地降低、甚至消除免疫测定中由阿霉素引起的干扰。随着胃泌素释放肽前体试剂盒中腺苷的添加浓度依次升高，测定含72μg/mL阿霉素浓度干扰样本的干扰偏差依次降低；当腺苷的添加浓度升高至终浓度大约为0.1mg/mL时，能够将干扰偏差降低至可接受范围内(±10％范围内)，即显著地降低了阿霉素对检测结果的干扰。随腺苷的终浓度进一步增加，抗阿霉素干扰的偏差绝对值进一步降低。当腺苷的终浓度达到20mg/mL之后，随腺苷浓度的增大，对检测结果的偏差的影响相对减小。

Claims (15)

  1. 一种在对样本的免疫检测中消除阿霉素干扰的方法，所述方法包括：在抗阿霉素干扰剂的存在下进行免疫检测反应，其中所述抗阿霉素干扰剂的终浓度为0.1mg/mL～100mg/mL，且选自由6-巯基嘌呤、6-巯基鸟嘌呤、8-杂氮鸟、次黄嘌呤、腺嘌呤、嘌呤、2,6,8-三氧嘌呤、腺嘌呤核苷酸和腺苷所组成的组中的至少一种。
  2. 根据权利要1中所述的方法，其中，所述抗阿霉素干扰剂的终浓度为5mg/mL～80mg/mL、优选为10mg/mL～80mg/mL、更优选为50mg/mL～80mg/mL。
  3. 根据权利要求1或2所述的方法，其中，所述抗阿霉素干扰剂为选自由6-巯基鸟嘌呤、次黄嘌呤、嘌呤和腺苷所组成的组中的至少一种。
  4. 根据权利要求1～3中任一项所述的方法，其中，所述免疫检测为化学发光免疫检测、电化学发光免疫检测或酶联免疫检测，优选为针对肿瘤标志物的免疫检测，更优选为固相法免疫检测。
  5. 根据权利要求1～4所述的方法，其中，所述抗阿霉素干扰剂以单独的试剂形式，优选以样本处理液的形式加入免疫检测反应体系中，或者以与一种或多种试剂组合的形式加入所述免疫检测反应体系中，优选，所述一种或多种试剂选自由底物、标记物、包被有免疫检测反应物的固相、样本处理液、缓冲液、离子强度调节剂、表面活性剂、防腐剂和清洗剂中的一种或多种。
  6. 根据权利要求5所述的方法，其中，所述抗阿霉素干扰剂在加入底物之前加入，优选在加入包被有免疫检测反应物的固相之前或加入标记物之前加入，更优选在样本前处理步骤中加入。
  7. 根据权利要求1～6中任一项所述的方法，其中，所述样本为血液样本，例如血清样本或血浆样本。
  8. 一种免疫检测试剂盒，所述试剂盒包括终浓度为0.1mg/mL～100mg/mL的抗阿霉素干扰剂，所述阿霉素抗干扰剂选自由6-巯基嘌呤、6-巯基鸟嘌呤、8-杂氮鸟、次黄嘌呤、腺嘌呤、嘌呤、2,6,8-三氧嘌呤、腺嘌呤核苷酸和腺苷所组成的组中的至少一种。
  9. 根据权利要求8所述的免疫检测试剂盒，其中，所述免疫检测试剂盒包括终浓度为5mg/mL～80mg/mL、优选为10mg/mL～80mg/mL、更优选为50mg/mL～80mg/mL的抗阿霉素干扰剂。
  10. 根据权利要求8或9所述的免疫检测试剂盒，其中，所述抗阿霉素干扰剂为选自由6-巯基鸟嘌呤、次黄嘌呤、嘌呤和腺苷所组成的组中的至少一种。
  11. 根据权利要求8～10中任一项所述的免疫检测试剂盒，其中，所述免疫检测试剂盒是化学发光免疫检测试剂盒、电化学发光免疫检测试剂盒或酶联免疫检测试剂盒，优选是肿瘤标志物免疫检测试剂盒。
  12. 根据权利要求8～11中任一项所述的免疫检测试剂盒，其中，所述抗阿霉素干扰剂以与所述试剂盒中的一种或多种试剂组合的形式，或者以单独试剂的形式包含在所述免疫检测试剂盒中。
  13. 根据权利要求11或12所述的免疫检测试剂盒，其中，所述免疫检测试剂盒还包括底物、标记物和包被有免疫检测反应物的固相，以及可选的选自由样本处理液、缓冲液、离子强度调节剂、表面活性剂和防腐剂所组成的组中的一种或多种。
  14. 根据权利要求8～13中任一项所述的免疫检测试剂盒，其中，所述免疫检测试剂盒用于对血液样本、例如血清样本或血浆样本的检测。
  15. 一种抗阿霉素干扰剂在对血液样本的免疫检测中消除阿霉素干扰的用途，所述抗阿霉素干扰剂选自由6-巯基嘌呤、6-巯基鸟嘌呤、8-杂氮鸟、次黄嘌呤、腺嘌呤、嘌呤、2,6,8-三氧嘌呤、腺嘌呤核苷酸和腺苷所组成的 组中的至少一种。
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