WO2021164713A1 - Biomarqueur se rapportant à l'effet d'une immunothérapie antitumorale et son application - Google Patents

Biomarqueur se rapportant à l'effet d'une immunothérapie antitumorale et son application Download PDF

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WO2021164713A1
WO2021164713A1 PCT/CN2021/076771 CN2021076771W WO2021164713A1 WO 2021164713 A1 WO2021164713 A1 WO 2021164713A1 CN 2021076771 W CN2021076771 W CN 2021076771W WO 2021164713 A1 WO2021164713 A1 WO 2021164713A1
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tumor
autoantibodies
combination
immunotherapy
trim21
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PCT/CN2021/076771
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English (en)
Chinese (zh)
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孙苏彭
杨盼盼
隗啸南
周静
康美华
孙立平
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杭州凯保罗生物科技有限公司
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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
    • G01N33/574—Immunoassay; Biospecific binding assay; Materials therefor for cancer
    • G01N33/57484—Immunoassay; Biospecific binding assay; Materials therefor for cancer involving compounds serving as markers for tumor, cancer, neoplasia, e.g. cellular determinants, receptors, heat shock/stress proteins, A-protein, oligosaccharides, metabolites
    • G01N33/57488—Immunoassay; Biospecific binding assay; Materials therefor for cancer involving compounds serving as markers for tumor, cancer, neoplasia, e.g. cellular determinants, receptors, heat shock/stress proteins, A-protein, oligosaccharides, metabolites involving compounds identifable in body fluids
    • 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
    • G01N33/574—Immunoassay; Biospecific binding assay; Materials therefor for cancer
    • G01N33/57407—Specifically defined cancers
    • G01N33/57423—Specifically defined cancers of lung

Definitions

  • the present invention relates to the field of biotechnology. Specifically, the present invention relates to a biomarker related to the effect of tumor immunotherapy, a protein combination for detecting the biomarker, and the corresponding application in predicting the effect of tumor immunotherapy.
  • Immunotherapy is currently the most promising research direction in the field of cancer treatment.
  • One of the hot spots is the use of immune checkpoint inhibitors (immune checkpoint inhibitor, ICI) immune blocking therapy, such as blocking programmed death factor-1 (programmed death factor-1). death-1, PD-1)/programmed death ligand-1 (PD-L1) immune checkpoint pathway therapy.
  • immune checkpoint inhibitors immune checkpoint inhibitor, ICI
  • ICI immune checkpoint inhibitors
  • PD-1/PD-L1 immune checkpoint pathway blocking therapy usually refers to injecting specific antibodies against PD-1 or PD-L1 into the tumor patient so that the tumor no longer has the ability to evade the immune system. Thereby promoting the body's immune system to eliminate tumor cells.
  • This therapy has achieved a significant effect of inhibiting tumor growth and removing tumors in some patients, and has been approved for melanoma, Hodgkin’s lymphoma, lung cancer, head and neck squamous cell carcinoma, liver cancer, esophageal cancer, breast cancer, Various indications for gastric cancer, nasopharyngeal cancer, lymphoma, etc.
  • PD-L1 is highly expressed (the expression level of PD-L1 is 50% or higher), and the response rate of immune checkpoint molecular inhibitor drugs is only between 30% and 40%; but in addition, it is found that 10% of PD -L1 low expression (PD-L1 expression ⁇ 50%) or PD-L1 negative cases are response cases, and even many patients whose PD-L1 expression is so low that it is undetectable have obtained lasting clinical benefit from ICI treatment .
  • the use of PD-L1 expression as a predictor of ICI curative effect has the following drawbacks: a considerable proportion of patients with advanced tumors cannot provide enough tumor tissue for the detection of PD-L1 expression; PD-L1 expression varies in different stages of tumor development.
  • ICI efficacy include tumor mutation burden (tumor mutation burden, TMB), neoantigen burden, mismatch repair (MMR)/microsatellite instability (microsatellite instability).
  • Tumor antigen expression is also related to the cellular activity of tumor infiltrating immune cells. Therefore, autoantibodies against tumor-associated antigens may also become targets or predictive markers for highly specific immunotherapy.
  • There have been related research reports, including Sachet a. Shukla has identified a subclass of tumor testis antigen MAGE-A, which is located in a narrow 75kb region of Xq28 chromosome, which can be used to predict the efficacy of anti-CTLA-4 antibodies .
  • Other studies have shown that serum antibodies against NY-ESO-1 and/or XAGE1 tumor testis antigen can be used to predict the ICI efficacy and patient survival of initial and subsequent non-small cell lung cancer (NSCLC).
  • NSCLC non-small cell lung cancer
  • Immune checkpoint inhibitors are very expensive drugs. Unlike conventional chemotherapy, although immune checkpoint inhibitor drugs are effective for some patients, they may also cause serious adverse reactions, especially the development of systemic autoimmune diseases. Therefore, there is still a need to identify new autoantibody biomarkers that can be used to predict the efficacy of ICI, and to develop detection antigens for the autoantibody biomarkers, especially antigen combinations, in order to provide new predictive methods for tumor immunotherapy effects .
  • the present invention detects autoantibodies against different antigen targets in the blood of lung cancer patients, and finally identifies a group of immune checkpoint inhibitors (ICI) that can be used to predict or judge the therapeutic effect of tumors, especially lung cancer.
  • ICI immune checkpoint inhibitors
  • an object of the present invention is to provide a combination of autoantibody biomarkers for predicting or judging the effect of tumor immunotherapy.
  • another object of the present invention is to provide reagents for detecting the autoantibody markers, such as an antigen protein combination, which can be used to detect the self in a tumor patient sample (such as blood) Whether the antibody biomarker is positive, so as to predict or judge the immunotherapy effect of tumor patients; and provide a kit containing the detection reagent, which can be used for corresponding detection.
  • the autoantibody markers such as an antigen protein combination
  • Another object of the present invention is to provide the use of the autoantibody biomarker combination or antigen protein combination in the preparation of products for predicting or judging the effect of tumor immunotherapy.
  • Another object of the present invention is to provide a method for predicting or judging the effect of immunotherapy of tumor patients or a method for treating tumors.
  • the present invention provides a biomarker for predicting or judging the effect of tumor immunotherapy in a subject.
  • the biomarker is a combination of autoantibodies, and the combination of autoantibodies includes anti-tumor-related antigens selected from the group consisting of: At least one of autoantibodies: Trim21, BRCA2, Annexin 1, HUD, NY-ESO-1, P53, IMP2, HSP105, MAGE-A3, AKAP4, PRAME.
  • the autoantibody combination may include at least one selected from the group consisting of autoantibodies against the following tumor-associated antigens: Trim21, BRCA2, Annexin 1, HUD, NY -ESO-1, P53, IMP2.
  • the biomarker can be used to predict or judge: the subject's good tumor treatment effect; the subject benefits from tumor immunotherapy; the treatment is effective; or, the subject's tumor is sensitive to immunotherapy.
  • the autoantibody combination includes two, three or four autoantibodies selected from the following tumor-associated antigens: Trim21, BRCA2, Annexin 1, HUD; more preferably, the autoantibody combination includes anti- Tumor-associated antigen autoantibodies: Trim21 and BRCA2; further preferably, the autoantibody combination also includes one or two of the following autoantibodies against the following tumor-associated antigens: Annexin 1, HUD.
  • the autoantibody combination includes autoantibodies against the following tumor-associated antigens:
  • the present invention provides a biomarker for predicting or judging the effect of tumor immunotherapy in a subject
  • the biomarker is a combination of autoantibodies
  • the combination of autoantibodies includes anti-tumor-associated antigen Trim21, BRCA2 , Annexin 1, HUD autoantibodies, namely anti-Trim21 autoantibody, anti-BRACA2 autoantibody, anti-Annexin 1 autoantibody and anti-HUD autoantibody.
  • the autoantibody combination may include at least one selected from the group consisting of autoantibodies against the following tumor-associated antigens: HSP105, MAGE-A3, AKAP4, PRAME.
  • the biomarkers can be used to predict or judge: the subject's poor tumor treatment effect; the subject does not benefit from tumor immunotherapy; the treatment is ineffective; or the subject's tumor is not sensitive to immunotherapy.
  • the autoantibody combination includes autoantibodies against the following tumor-associated antigens: HSP105, or HSP105 and AKAP4.
  • the autoantibody combination includes autoantibodies against the following tumor-associated antigens:
  • the present invention provides a biomarker for predicting or judging a subject's immune tumor treatment effect
  • the biomarker is a combination of autoantibodies
  • the combination of autoantibodies includes anti-tumor-associated antigens HSP105, AKAP4 Anti-HSP105 autoantibodies and anti-AKAP4 autoantibodies.
  • the autoantibody is the autoantibody in serum, plasma, interstitial fluid, cerebrospinal fluid or urine before the subject receives tumor immunotherapy; preferably, the autoantibody is IgA (for example, IgA1, IgA2), IgM or IgG (e.g. IgG1, IgG2, IgG3, IgG4).
  • IgA for example, IgA1, IgA2
  • IgM for example, IgA2, IgG3, IgG4
  • the subject is a mammal, preferably a primate mammal, more preferably a human.
  • the tumor is kidney cancer, liver cancer, ovarian cancer, cervical cancer, head and neck squamous cell carcinoma, nasopharyngeal cancer, urothelial cancer, laryngeal cancer, gastric cancer, melanoma, prostate cancer, Hodge King’s lymphoma, bladder cancer, colorectal cancer, lung cancer, especially lung cancer, such as small cell lung cancer, non-small cell lung cancer, lung squamous cell carcinoma, lung adenocarcinoma and other subtypes of lung cancer.
  • the immunotherapy includes treatment with immune checkpoint inhibitors; preferably, the immunotherapy is the treatment of immune checkpoint inhibitors alone or immune checkpoint inhibitors combined with chemotherapy, radiotherapy, anti-vascular therapy, and targeted therapy.
  • the immune checkpoint inhibitor is for PD-1, PD-L1, CTLA-4, BTLA, TIM-3, LAG-3, TIGIT, LAIR1, 2B4 and/or
  • the CD160 immune checkpoint inhibitor is preferably an anti-PD-1 antibody or an anti-PD-L1 antibody.
  • the antibodies are nivolumab, pambrolizumab, sintilizumab, teriprizumab, and domestic immune checkpoint inhibitors, especially anti-PD-1 antibodies Or anti-PD-L1 antibody.
  • the biomarker that is, the combination of autoantibodies
  • a sample such as plasma or serum
  • the autoantibody biomarkers can be used to predict or judge whether a subject, such as a tumor patient, can benefit from immunotherapy (whether the immunotherapy effect is good or poor; whether the immunotherapy is effective; or whether the subject is effective
  • the patient’s tumor is sensitive or insensitive to immunotherapy), at least for the corresponding auxiliary judgment.
  • the level of autoantibodies in a sample can be quantified by referring to a standard curve, and then the cutoff value is used to determine the presence ( ⁇ cutoff value, positive) or absence of autoantibody biomarkers ( ⁇ cutoff value) , Is negative) judgment.
  • the cutoff value of the autoantibody level can be a reference level from a healthy person or a healthy person; for example, it can be defined as the average value of a person who is confirmed to have no cancer through a physical examination plus 2 standard deviations.
  • the autoantibody biomarker provided by the present invention can be detected by a variety of methods, for example, it can be detected by the antigen-antibody specific reaction between the tumor-associated antigen that causes the autoantibody to appear and the antigen-antibody specific reaction. Therefore, correspondingly, the present invention also provides a reagent for detecting the autoantibody biomarker.
  • the reagents may be reagents used in detection methods such as enzyme-linked immunosorbent assay (ELISA), protein/peptide chip detection, immunoblotting, bead immunoassay, microfluidic immunoassay, etc.
  • ELISA enzyme-linked immunosorbent assay
  • the reagent is used to detect the autoantibody biomarker of the present invention through an antigen-antibody reaction, for example, by ELISA.
  • the reagent may be an antigen protein combination for detecting the autoantibody combination, and the antigen protein combination includes at least one selected from the following antigen proteins: Trim21, BRCA2, Annexin 1, HUD, NY- ESO-1, P53, IMP2, HSP105, MAGE-A3, AKAP4, PRAME.
  • the reagent can be used to detect whether the corresponding autoantibody biomarker in a sample (such as plasma or serum) of a subject, such as a tumor patient, is positive, so as to realize the prediction or clinical effect of the administration of tumor immunotherapy as described above. judge.
  • the amino acid sequence contained in the tumor-associated antigen or antigen protein is as follows:
  • Trim21 includes the amino acid sequence shown in SEQ ID NO:1;
  • BRCA2 includes the amino acid sequence shown in SEQ ID NO: 2;
  • Annexin 1 includes the amino acid sequence shown in SEQ ID NO: 3;
  • HUD includes the amino acid sequence shown in SEQ ID NO: 4;
  • NY-ESO-1 includes the amino acid sequence shown in SEQ ID NO: 5;
  • P53 includes the amino acid sequence shown in SEQ ID NO: 6;
  • IMP2 includes the amino acid sequence shown in SEQ ID NO: 7;
  • HSP105 includes the amino acid sequence shown in SEQ ID NO: 8;
  • MAGE-A3 includes the amino acid sequence shown in SEQ ID NO: 9;
  • AKAP4 includes the amino acid sequence shown in SEQ ID NO: 10;
  • PRAME includes the amino acid sequence shown in SEQ ID NO: 11.
  • the present invention provides the use of the biomarker or reagent in the preparation of a product for predicting or judging the effect of tumor immunotherapy in a subject.
  • the tumor immunotherapy effects include good tumor immunotherapy effects and poor tumor immunotherapy effects, respectively, depending on the corresponding biomarkers or reagents.
  • the subject is a mammal, preferably a primate mammal, more preferably a human.
  • the tumor is kidney cancer, liver cancer, ovarian cancer, cervical cancer, head and neck squamous cell carcinoma, nasopharyngeal cancer, urothelial cancer, laryngeal cancer, gastric cancer, melanoma, prostate cancer, Hodge King’s lymphoma, bladder cancer, colorectal cancer, lung cancer, especially lung cancer, such as small cell lung cancer, non-small cell lung cancer, lung squamous cell carcinoma, lung adenocarcinoma and other subtypes of lung cancer.
  • the immunotherapy includes treatment with immune checkpoint inhibitors; preferably, the immunotherapy is the treatment of immune checkpoint inhibitors alone or immune checkpoint inhibitors combined with chemotherapy, radiotherapy, anti-vascular therapy, and targeted therapy.
  • the immune checkpoint inhibitor is for PD-1, PD-L1, CTLA-4, BTLA, TIM-3, LAG-3, TIGIT, LAIR1, 2B4 and/or
  • the CD160 immune checkpoint inhibitor is preferably an anti-PD-1 antibody or an anti-PD-L1 antibody.
  • the antibodies are nivolumab, pambrolizumab, sintilizumab, teriprizumab, and domestic immune checkpoint inhibitors, especially anti-PD-1 Antibody or anti-PD-L1 antibody.
  • the present invention provides a kit comprising the reagent of the present invention.
  • the kit can be used for enzyme-linked immunosorbent assay (ELISA), protein/peptide chip detection, western blotting, microbead immunoassay, microfluidic immunoassay, etc. to the autoantibody biomarker Kits for detection of substances.
  • ELISA enzyme-linked immunosorbent assay
  • the kit is used to detect the autoantibody biomarker of the present invention through an antigen-antibody reaction, for example, by ELISA.
  • the kit is an enzyme-linked immunosorbent assay (ELISA) detection kit. That is, using this kit, the enzyme-linked immunosorbent assay is used to detect whether the autoantibody biomarker in the subject's sample is positive.
  • the kit can also include other components required for ELISA detection of autoantibody biomarkers, all of which are well known in the art.
  • the antigen protein in the kit can be linked with a tag peptide, such as His tag, streptavidin tag, Myc tag; for another example, the kit can include a solid phase carrier, such as with immobilized antigen Microporous protein carrier, such as an enzyme-labeled plate; it may also include adsorbed protein for immobilizing antigen protein on a solid carrier, dilution of blood such as serum, washing solution, enzyme-labeled secondary antibody, color development Liquid, stop liquid, etc.
  • a tag peptide such as His tag, streptavidin tag, Myc tag
  • the kit can include a solid phase carrier, such as with immobilized antigen Microporous protein carrier, such as an enzyme-labeled plate; it may also include adsorbed protein for immobilizing antigen protein on a solid carrier, dilution of blood such as serum, washing solution, enzyme-labeled secondary antibody, color development Liquid, stop liquid, etc.
  • the present invention provides a method for predicting or judging the effect of tumor immunotherapy in a subject.
  • the present invention provides a method for predicting or judging the sensitivity of a subject's tumor to immunotherapy.
  • the above methods include testing whether the following biomarkers in a sample from a subject are positive:
  • the biomarker is a combination of autoantibodies, and the combination of autoantibodies includes at least one selected from the group consisting of autoantibodies against the following tumor-associated antigens: Trim21, BRCA2, Annexin 1, HUD, NY-ESO-1, P53, IMP2, HSP105, MAGE-A3, AKAP4, PRAME.
  • the method may include detecting whether the following biomarkers in a sample from a subject are positive:
  • the biomarker is an autoantibody combination, and the autoantibody combination includes at least one selected from the group consisting of autoantibodies against the following tumor-associated antigens: Trim21, BRCA2, Annexin 1, HUD, NY-ESO-1, P53, IMP2.
  • the biomarker is positive, it is predicted or judged that the subject has a good tumor immunotherapy effect; the subject benefits from the tumor immunotherapy; the treatment is effective; or the subject's tumor is sensitive to the immunotherapy.
  • the autoantibody combination includes two, three or four autoantibodies selected from the following tumor-associated antigens: Trim21, BRCA2, Annexin 1, HUD; more preferably, the autoantibody combination includes anti- Tumor-associated antigen autoantibodies: Trim21 and BRCA2; further preferably, the autoantibody combination also includes one or two of the following autoantibodies against the following tumor-associated antigens: Annexin 1, HUD.
  • the autoantibody combination includes autoantibodies against the following tumor-associated antigens:
  • the present invention provides a method for predicting or judging the effect of a subject’s tumor immunotherapy, or a method for predicting or judging the sensitivity of a subject’s tumor to immunotherapy, the method comprising detecting from Whether the following biomarkers in the subject’s sample are positive:
  • the biomarker is a combination of autoantibodies, and the combination of autoantibodies includes autoantibodies against tumor-associated antigens Trim21, BRCA2, Annexin 1, and HUD, namely anti-Trim21 autoantibody, anti-BRACA2 autoantibody, anti-Annexin 1 autoantibody, and anti-tumor related antigens.
  • HUD autoantibodies namely anti-Trim21 autoantibody, anti-BRACA2 autoantibody, anti-Annexin 1 autoantibody, and anti-tumor related antigens.
  • the method may include detecting whether the following biomarkers in a sample from the subject are positive:
  • the biomarker is a combination of autoantibodies, and the combination of autoantibodies includes at least one selected from the group consisting of autoantibodies against the following tumor-associated antigens: HSP105, MAGE-A3, AKAP4, and PRAME.
  • HSP105 tumor-associated antigens
  • MAGE-A3, AKAP4, and PRAME tumor-associated antigens
  • the autoantibody combination includes autoantibodies selected from the following tumor-associated antigens: HSP105, or HSP105 and AKAP4.
  • the autoantibody combination includes autoantibodies against the following tumor-associated antigens:
  • the present invention provides a method for predicting or judging the effect of a subject’s tumor immunotherapy, or a method for predicting or judging the sensitivity of a subject’s tumor to immunotherapy, the method comprising detecting from Whether the following biomarkers in the subject’s sample are positive:
  • the biomarker is a combination of autoantibodies, and the combination of autoantibodies includes autoantibodies against tumor-associated antigens HSP105 and AKAP4, that is, anti-HSP105 autoantibodies and anti-AKAP4 autoantibodies.
  • the detection can be carried out using the reagent of the present invention, for example, an antigen-protein combination or a kit containing the reagent.
  • the subject is a mammal, preferably a primate mammal, more preferably a human.
  • the tumor is kidney cancer, liver cancer, ovarian cancer, cervical cancer, head and neck squamous cell carcinoma, nasopharyngeal cancer, urothelial cancer, laryngeal cancer, gastric cancer, melanoma, prostate cancer, Hodge King's lymphoma, bladder cancer, colorectal cancer, lung cancer, especially lung cancer, such as small cell lung cancer, non-small cell lung cancer, lung squamous cell carcinoma, lung adenocarcinoma and other subtypes of lung cancer.
  • the immunotherapy includes treatment with immune checkpoint inhibitors; preferably, the immunotherapy is the treatment of immune checkpoint inhibitors alone or immune checkpoint inhibitors combined with chemotherapy, radiotherapy, anti-vascular therapy, and targeted therapy.
  • the immune checkpoint inhibitor is for PD-1, PD-L1, CTLA-4, BTLA, TIM-3, LAG-3, TIGIT, LAIR1, 2B4 and/or
  • the CD160 immune checkpoint inhibitor is preferably an anti-PD-1 antibody or an anti-PD-L1 antibody.
  • the antibodies are nivolumab, pambrolizumab, sintilizumab, teriprizumab, and domestic immune checkpoint inhibitors, especially anti-PD-1 Antibody or anti-PD-L1 antibody.
  • the sample is serum, plasma, interstitial fluid, cerebrospinal fluid, or urine before the subject receives tumor immunotherapy; preferably, the autoantibody is IgA (for example, IgA1, IgA2), IgM or IgG ( For example, IgG1, IgG2, IgG3, IgG4).
  • IgA for example, IgA1, IgA2
  • IgM for example, IgG1, IgG2, IgG3, IgG4
  • the method includes the following steps:
  • the autoantibody biomarker in the sample is positive, predict or judge: the subject has a good or poor tumor immunotherapy effect; the subject benefits or does not benefit from tumor immunotherapy; the treatment is effective Or ineffective; or, the subject's tumor is sensitive or insensitive to immunotherapy.
  • the present invention provides a method for treating tumors in a subject, the method comprising detecting whether the following biomarkers in a sample from the subject are positive:
  • the biomarker is a combination of autoantibodies, and the combination of autoantibodies includes at least one selected from the group consisting of autoantibodies against the following tumor-associated antigens: Trim21, BRCA2, Annexin 1, HUD, NY-ESO-1, P53, IMP2, HSP105, MAGE-A3, AKAP4, PRAME.
  • the method may include detecting whether the following biomarkers in a sample from a subject are positive:
  • the biomarker is an autoantibody combination, and the autoantibody combination includes at least one selected from the group consisting of autoantibodies against the following tumor-associated antigens: Trim21, BRCA2, Annexin 1, HUD, NY-ESO-1, P53, IMP2.
  • the biomarker is positive, the subject is subjected to tumor immunotherapy.
  • the autoantibody combination includes two, three or four autoantibodies selected from the following tumor-associated antigens: Trim21, BRCA2, Annexin 1, HUD; more preferably, the autoantibody combination includes anti- Autoantibodies against tumor-associated antigens: Trim21 and BRCA2; further preferably, the autoantibody combination also includes one or two of the following autoantibodies against the following tumor-associated antigens: Annexin 1, HUD.
  • the autoantibody combination includes autoantibodies against the following tumor-associated antigens:
  • the present invention provides a method for treating tumors in a subject, the method comprising detecting whether the following biomarkers in a sample from the subject are positive:
  • the biomarker is a combination of autoantibodies, and the combination of autoantibodies includes autoantibodies against tumor-associated antigens Trim21, BRCA2, Annexin 1, and HUD, namely anti-Trim21 autoantibody, anti-BRACA2 autoantibody, anti-Annexin 1 autoantibody, and anti-tumor related antigens.
  • HUD autoantibodies namely anti-Trim21 autoantibody, anti-BRACA2 autoantibody, anti-Annexin 1 autoantibody, and anti-tumor related antigens.
  • the method may include detecting whether the following biomarkers in a sample from the subject are positive:
  • the biomarker is a combination of autoantibodies, and the combination of autoantibodies includes at least one selected from the group consisting of autoantibodies against the following tumor-associated antigens: HSP105, MAGE-A3, AKAP4, and PRAME.
  • HSP105 tumor-associated antigens
  • MAGE-A3, AKAP4, and PRAME tumor-associated antigens
  • the autoantibody combination includes autoantibodies selected from the following tumor-associated antigens: HSP105, or HSP105 and AKAP4.
  • the autoantibody combination includes autoantibodies against the following tumor-associated antigens:
  • the present invention provides a method for treating tumors in a subject, the method comprising detecting whether the following biomarkers in a sample from the subject are positive:
  • the biomarker is a combination of autoantibodies, and the combination of autoantibodies includes autoantibodies against tumor-associated antigens HSP105 and AKAP4, that is, anti-HSP105 autoantibodies and anti-AKAP4 autoantibodies.
  • the detection can be carried out using the reagent of the present invention, for example, an antigen-protein combination or a kit containing the reagent.
  • the subject is a mammal, preferably a primate mammal, more preferably a human.
  • the tumor is kidney cancer, liver cancer, ovarian cancer, cervical cancer, head and neck squamous cell carcinoma, nasopharyngeal cancer, urothelial cancer, laryngeal cancer, gastric cancer, melanoma, prostate cancer, Hodge King’s lymphoma, bladder cancer, colorectal cancer, lung cancer, especially lung cancer, such as small cell lung cancer, non-small cell lung cancer, lung squamous cell carcinoma, lung adenocarcinoma and other subtypes of lung cancer.
  • the immunotherapy includes treatment with immune checkpoint inhibitors; preferably, the immunotherapy is the treatment of immune checkpoint inhibitors alone or immune checkpoint inhibitors combined with chemotherapy, radiotherapy, anti-vascular therapy, and targeted therapy.
  • the immune checkpoint inhibitor is for PD-1, PD-L1, CTLA-4, BTLA, TIM-3, LAG-3, TIGIT, LAIR1, 2B4 and/or
  • the CD160 immune checkpoint inhibitor is preferably an anti-PD-1 antibody or an anti-PD-L1 antibody.
  • the antibodies are nivolumab, pambrolizumab, sintilizumab, teriprizumab, and domestic immune checkpoint inhibitors, especially anti-PD-1 Antibody or anti-PD-L1 antibody.
  • the sample is serum, plasma, interstitial fluid, cerebrospinal fluid, or urine before the subject receives tumor immunotherapy; preferably, the autoantibody is IgA (for example, IgA1, IgA2), IgM or IgG ( For example, IgG1, IgG2, IgG3, IgG4).
  • IgA for example, IgA1, IgA2
  • IgM for example, IgG1, IgG2, IgG3, IgG4
  • the method includes the following steps:
  • the subject When the autoantibody biomarker in the sample is positive, the subject is allowed to undergo tumor immunotherapy, or the subject is not allowed to undergo tumor immunotherapy.
  • the present invention provides a biomarker for predicting or judging the effect of tumor immunotherapy, and the biomarker is a combination of autoantibodies.
  • the autoantibody combination of the present invention includes two combinations that predict good tumor immunotherapy effect and poor tumor immunotherapy effect.
  • the former can be called a positive prediction of tumor immunotherapy effect, and the latter can be called tumor immunity. Negative prediction of treatment effect.
  • the effective rate of immune checkpoint blocking therapy for tumor patients who test positive is more significant. Lower than the autoantibody combination test negative tumor patients (P ⁇ 0.05).
  • the autoantibody biomarkers provided by the present invention can provide accurate prediction or judgment results. Based on the prediction or judgment result, the patient or clinician can better decide whether the patient needs immunotherapy, so as to avoid excessive medical treatment, reduce treatment costs, and reduce or avoid adverse reactions.
  • the two autoantibody combinations provided by the present invention can also be used alone or in combination as required.
  • the positive conditions of the autoantibody biomarkers predicted in the positive direction and the negative conditions of the autoantibody biomarkers predicted in the negative direction can be combined.
  • Figure 1 shows the tumor response to immunotherapy after the treatment of patients who showed positive or negative autoantibody combination before treatment, where Figure 1-A: P_Ab. combination, Figure 1-B: N_Ab. combination.
  • Figure 2 shows the survival curve of patients who showed positive or negative autoantibody combination before treatment after treatment, where Figure 2-A: training set and Figure 2-B: validation set.
  • Figure 3 shows the survival curve of patients who showed positive or negative autoantibody combination before treatment after treatment, wherein Figure 3-A to Figure 3-RNP respectively show the results of corresponding autoantibody combination A to autoantibody combination RNP.
  • Figure 4 shows the survival curve of patients who showed positive or negative autoantibody combination before treatment after treatment, wherein Figure 4-K to Figure 4-P show the results of corresponding autoantibody combination K to autoantibody combination P, respectively.
  • Figure 5 shows the survival curve of patients who showed positive or negative autoantibody or autoantibody combination before treatment after treatment, where Figure 5-A: IMP2, Figure 5-B: anti-XAGE-1 and anti-NY-ESO-1.
  • Figure 6 shows the survival curve of patients who showed positive or negative autoantibody combination before treatment after treatment, where Figure 6-A: first-line immunotherapy, Figure 6-B: posterior-line immunotherapy, and Figure 6-C: immune single agent Treatment), Figure 6-D: Immunotherapy combined with chemotherapy.
  • the term "antigen” or the term “antigenic protein” can be used interchangeably.
  • the following experimental operations or definitions are involved in the present invention. It should be noted that the present invention can also be implemented using other conventional techniques in the field, and is not limited to the following experimental operations.
  • the cDNA of the tumor-associated antigen (TAA) was cloned into the 6XHis-labeled PET28(a) expression vector.
  • a streptavidin protein or the like biotin-binding tag protein
  • the obtained recombinant expression vector was transformed into Escherichia coli for expression.
  • the protein was denatured with 6M guanidine hydrochloride, and renatured in vitro according to standard methods, and then Ni-NTA affinity was carried out by 6XHis tag Column purification to obtain antigen protein.
  • Venous blood was collected in EDTA-treated or citric acid-treated blood collection tubes one week to one day before immunotherapy. Then centrifuge at 1000-2000RCF at room temperature for 15 minutes; after centrifugation, gently transfer the supernatant to another clean centrifuge tube at room temperature, and place it in a refrigerator at -80°C for long-term storage.
  • the prepared antigen protein is coated on the surface of the microwell of a 96-well solid phase plate.
  • a 96-well solid phase plate was coated overnight with 5-10ug/ml biotin-labeled bovine serum albumin; on the second day, the uncoated bovine serum albumin in the microwells of the solid phase plate was washed away.
  • Add 300uL of blocking solution containing BSA to block at room temperature for 1h; add antigen protein and incubate for 1.5h, then wash off unadsorbed antigen protein. After coating the antigen protein, add 300ul of the stabilized solution containing BSA to the microwells, incubate for 1h, and then use it or dry it under vacuum for later use.
  • the purified antigen protein is indirectly coated on the surface of the solid phase plate through the specific reaction between biotin and streptavidin.
  • the diluted plasma sample is added to the microwells coated with the antigen protein, and the autoantibodies in the plasma sample are specifically combined with the antigen protein on the surface of the solid phase plate after incubation.
  • PBS buffer prepare your own, with a pH of 7.6.
  • Stop and read Add 50ul/well of stop solution according to the order of adding color reagent, and read at 450nm in the microplate reader.
  • the cutoff value of the autoantibody level is defined as equal to the average value of the healthy control cohort in the control group (people confirmed to have no cancer through physical examination) plus 2 standard deviations (SD).
  • the results of multiple autoantibodies are combined to judge the predictive effect when analyzing the results.
  • the rule is: multiple autoantibodies are detected in a patient sample. As long as one or more of the autoantibodies are positive, the antibody combination is judged to be positive; and if all autoantibodies are negative, the antibody combination is judged to be negative .
  • the target lesion at baseline (before treatment) is evaluated, and the baseline sum of the longest diameter of the target lesion is recorded to determine the objective reaction.
  • the best curative effect refers to the record of the best curative effect from the beginning of the treatment study to the end of the treatment, which is confirmed after considering various factors.
  • PD Compared with the minimum sum of the diameters of all target lesions before treatment, the sum of the diameters of all target lesions is increased by at least 20% and the absolute value of the total increase in diameter must be greater than 5mm; or new lesions appear.
  • PR Compared with the sum of the diameters of all target lesions before treatment, the sum of the diameters of all target lesions is reduced by at least 30%.
  • SD Compared with the minimum sum of the diameters of all target lesions before treatment, the shrinkage of the target lesion does not meet the partial remission (PR), and the increase does not meet the disease progression (PD). It refers to a type between PR and PD. The state of the time.
  • PR partial remission
  • PD disease progression
  • CR All target lesions disappear, and the short axis value of any pathological lymph node (whether it is a target lesion or not) must be less than 10mm.
  • PFS Progression-free survival time, that is, the time from the beginning of randomization to the recurrence of the disease or the death of the patient due to various reasons.
  • mPFS Median progression-free survival time, that is, the median time from randomization to disease recurrence or death due to various reasons.
  • PD-L1 expression level Use immunohistochemistry to evaluate the percentage of tumor cells stained with PD-L1 membrane of any intensity in all tumor cells. The test results are divided into four groups, namely negative (less than 1%) , Low expression group (1%-49%), high expression group ( ⁇ 50%), unknown.
  • the healthy control group are those who have not been or are not diagnosed with cancer among the medical examiners.
  • the lung cancer group includes 10 patients with small cell lung cancer, 12 patients with lung squamous cell carcinoma, 19 patients with lung adenocarcinoma, and 6 patients with other subtypes of lung cancer. Plasma was collected before treatment. The information of the experimental population is shown in Table 1.
  • the detection specificity of each antigen is set to ⁇ 93.6% (in the healthy control group of 47 cases, there are ⁇ 6.4 % Positive rate); and the sensitivity in the lung cancer group (positive rate, that is, the proportion of autoantibody positive in the total number of lung cancer patients in 47 cases) is similar to that found in other literature, the positive detection rate of a single autoantibody Low, usually between 5-20%. Therefore, in the preliminary screening of lung cancer-related antigens, antigen proteins are divided into four groups based on sensitivity. The screened antigen protein and the sensitivity and specificity determined by the test are shown in Table 2.
  • this study tries to include various scenarios of immunotherapy for patients with lung cancer.
  • Thirty-eight lung cancer patients used immunotherapy as the first-line treatment, while 40 lung cancer patients received one or more treatments such as chemotherapy and targeted therapy, and then chose immunotherapy (post-line treatment).
  • the immunotherapy used by the enrolled patients included immune checkpoint inhibitors, including imported nivolumab and pembrolizumab, as well as domestic immune checkpoint inhibitors (Table 3).
  • the treatment plan for lung cancer patients includes two situations: immunotherapy is monotherapy (25 patients), or immunotherapy combined with chemotherapy (53 patients).
  • P_Ab autoantibodies against this antigen. Patients showing positive signals of such autoantibodies have basically achieved the "PR” and “SD” in BOR. “, that is, a good curative effect, and the patient population as a whole meets the percentage of "PR"/"PD” ⁇ 2.
  • This type of autoantibody is preliminarily determined as a positive predictive antibody, which has a positive predictive effect of good immunotherapy curative effect.
  • N_Ab Some tumor-associated antigens are "negatively related" antigens.
  • autoantibodies against this antigen are named "N_Ab.”
  • Patients showing positive signals of such autoantibodies all have "PD” and "SD” in BOR.
  • the patient population as a whole meets the "PD" percentage/"PR” percentage ⁇ 2.
  • Determining such autoantibodies as negative predictive antibodies has the negative predictive effect of poor immunotherapy efficacy. It is preliminarily determined that both the positive predictive antibody and the negative predictive antibody can be used to predict the effect of immunotherapy, and have good and poor predictive effects of immunotherapy respectively.
  • the treatment methods include immune monotherapy patients and immune-combined chemotherapy patients (Table 3)) as a "validation set" to verify whether the discovered autoantibodies still have the characteristics of efficacy prediction.
  • the results of multiple autoantibodies are combined to judge the predictive effect when analyzing the results.
  • the rule is: if multiple autoantibodies are detected in a patient, as long as one or more of the autoantibodies are positive, the antibody combination is judged to be positive; and if all autoantibodies are negative, the antibody combination is judged to be negative.
  • anti-Trim21 autoantibodies, anti-BRACA2 autoantibodies, anti-Annexin 1 autoantibodies and anti-HUD antibodies were selected as a combination of autoantibodies.
  • Negative refers to patients whose anti-Trim21 autoantibody, anti-BRACA2 autoantibody, anti-Annexin 1 autoantibody and anti-HUD antibody are all negative (ie, the antibody combination is negative);
  • Figure 1-B N_Ab. combination
  • N_Ab. positive refers to patients whose anti-HSP105 autoantibody and anti-AKAP4 antibody are positive (that is, the combination of antibodies is positive)
  • N_Ab. negative refers to both anti-HSP105 autoantibody and anti-AKAP4 antibody negative The patient (ie, the antibody combination is negative).
  • Figure 1-A in Figure 1 shows that in the training set (first-line), 47.6% of patients with positive correlation autoantibodies have a treatment effect of "PR” after treatment, and 42% of patients have a treatment effect of "SD". , 9.5% of the patients had a treatment effect of "PD"; while the positively correlated autoantibody combination was negative, 28.6% of the patients had a treatment effect of "PR", 50% of the patients had a treatment effect of "SD", and 21.4% of the patients The therapeutic effect is "PD”.
  • 50% of the patients with positive correlation autoantibody combination had a treatment effect of "PR"
  • 37.5% of patients had a treatment effect of "SD”
  • 12.5% of patients had a treatment effect of "PR”.
  • PD for patients with a negative combination of positively correlated autoantibodies, after treatment, 50% of patients have a treatment effect of "PD” and 50% of patients have a treatment effect of "SD”.
  • Figure 1-B in Figure 1 shows that in the training set (first-line), 50% of patients with positive negative autoantibody combinations have a treatment effect of "PD” after treatment, and 50% of patients have a treatment effect of "SD” , 0% of patients have a treatment effect of "PR”.
  • the validation set after treatment, 42.9% of patients with positive negative autoantibodies have a treatment effect of "PD", 42.9% of patients have a treatment effect of "SD", and 14.3% of patients have a treatment effect of " PR”.
  • the Kaplan-Meier method was used to analyze the progression-free survival of patients in the training set and the validation set, and to draw a survival curve. The results found that the positive and negative groups of autoantibody combinations showed great differences in the progression-free survival curve.
  • the training set first-line
  • the median progression-free survival time of patients with positive antibody combinations was greater than 10 Month
  • the antibody combination negative patient is 5.52 months
  • the p-value is 0.0512, see Figure 2-A in Figure 2.
  • the validation set back line
  • the median progression-free time was 7.56 months, while the antibody combination negative patient was 2.43 months, and the p-value was less than 0.005, as shown in Figure 2-B in Figure 2.
  • the PD-L1 expression level and IMP2, XAGE-1 and NY-ESO-1 autoantibodies were used as prediction methods, and the patient's response to immunotherapy was observed. The results are shown in Table 7.
  • PD-L1 is used as a common marker for predicting the effect of immunotherapy. Because fluorescence detection of PD-L1 tissue expression requires the use of qualified tumor tissue samples from lung cancer patients, the source of the samples is not easy to obtain, and for other reasons, in the immunotherapy patients studied in the present invention, about 50% of patients There is no information on PD-L1 markers.
  • the antibody combination R-positive patients had 68.2% PR, 22.9% SD and 10% PD after treatment; the antibody combination RPN-positive patients had 72.7% PR, 28.6% SD and 15% after treatment. PD.
  • These autoantibody combinations can predict the efficacy of immunotherapy as well as PD-L1.
  • the median progression-free survival time of the IMP2 antibody positive and negative groups was 10.02 months and 5.52 months, respectively, but the P value was 0.7867, which was not statistically significant.
  • the survival curves of the positive and negative groups of anti-XAGE-1 and anti-NY-ESO-1 autoantibody combinations basically overlap, and the results are the median of the positive and negative groups of patients. There is no difference in progression-free survival time. Therefore, regardless of the combination of anti-XAGE-1 antibody and anti-NY-ESO-1 antibody or anti-IMP2 antibody, the predictive effect of the therapeutic effect of patients with immunotherapy is not particularly ideal.
  • the risk ratio of positive antibody combination (HR: Hazard Ratio) (Mantel- Haenszel) predictive value is 0.2541 (0.0684-0.8786).
  • the median progression-free survival time of the two groups of patients with antibody combination positive and negative is (>10 months) and 5.52 months (P value is 0.0309).
  • the predictive value of HR for positive antibody combination was 0.2948 (0.1409-0.6167), and the median progression-free survival time of the two groups of positive and negative antibody combination were (8.18 months) and 2.43 months (P value 0.0012) .

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Abstract

L'invention concerne un biomarqueur permettant de prédire l'effet d'une immunothérapie antitumorale. Le biomarqueur constitue un groupe d'auto-anticorps contre des antigènes associés à une tumeur. Le biomarqueur comprend au moins l'un des auto-anticorps suivants contre l'antigène associé à une tumeur : Trim21, BRCA2, Annexine1, HUD, NY-ESO-1, P53, IMP2, HSP105, MAGE-A3, AKAP4 et PRAME. Le biomarqueur peut être détecté dans des échantillons de patients atteints de tumeurs afin de prédire l'effet clinique d'une immunothérapie, ce qui permet d'aider à déterminer si l'immunothérapie est bénéfique pour des patients atteints de tumeurs. L'invention concerne en outre une combinaison d'antigène et de protéine permettant de détecter le biomarqueur, un kit contenant la combinaison d'antigène et de protéine, et une méthode de détection ou de diagnostic correspondant.
PCT/CN2021/076771 2020-02-21 2021-02-19 Biomarqueur se rapportant à l'effet d'une immunothérapie antitumorale et son application WO2021164713A1 (fr)

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