WO2022105894A1 - Marqueur pour déterminer la réponse du psoriasis à l'anticorps ciblant l'il-17a et sa récurrence - Google Patents

Marqueur pour déterminer la réponse du psoriasis à l'anticorps ciblant l'il-17a et sa récurrence Download PDF

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WO2022105894A1
WO2022105894A1 PCT/CN2021/131921 CN2021131921W WO2022105894A1 WO 2022105894 A1 WO2022105894 A1 WO 2022105894A1 CN 2021131921 W CN2021131921 W CN 2021131921W WO 2022105894 A1 WO2022105894 A1 WO 2022105894A1
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response
acid
antibody
psoriasis
sample
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PCT/CN2021/131921
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English (en)
Chinese (zh)
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郑捷
李霞
陈利红
乐云辰
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上海交通大学医学院附属瑞金医院
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Priority claimed from CN202011315009.3A external-priority patent/CN114518416B/zh
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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
    • G01N30/02—Column chromatography
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/194—Carboxylic acids, e.g. valproic acid having two or more carboxyl groups, e.g. succinic, maleic or phthalic acid

Definitions

  • the invention relates to the technical field of medical biological detection, in particular to a marker for judging the response of psoriasis patients to IL-17A antibody and its recurrence.
  • Psoriasis commonly known as psoriasis, is a chronic inflammatory skin disease with a long course of disease and a tendency to recur easily.
  • the disease mainly occurs in young adults and has a great impact on the physical health and mental status of patients.
  • the clinical manifestations are mainly erythema and scales, which can occur all over the body, and are more common on the scalp and extensor sides of the limbs, which are mostly aggravated in winter.
  • Interleukin 17A (IL-17A) monoclonal antibody is an effective drug for the treatment of psoriasis.
  • IL-17A interleukin 17A
  • clinical treatment found that different psoriasis patients responded differently to anti-interleukin 17A (IL-17A) monoclonal antibodies, including rapid response, moderate response and slow response.
  • Patients with rapid response to anti-IL-17A monoclonal antibody can be treated quickly and effectively with better efficacy; while patients with slow response show poor efficacy and long treatment time of anti-IL-17A monoclonal antibody, even anti-IL-17A monoclonal antibody -17A monoclonal antibody cannot effectively treat these psoriasis patients, and other effective therapeutic drugs need to be replaced.
  • patients with psoriasis are also at risk of recurrence after treatment.
  • Targeted treatment regimens for psoriasis patients with a higher risk of recurrence after treatment can reduce the risk of recurrence.
  • the frequency of medication or the dosage of medication can be increased, and topical preparations can be performed at the same time, so as to effectively prevent the recurrence of psoriasis patients.
  • there is a lack of drugs or markers for prognosis of psoriasis recurrence which is not conducive to the prognosis judgment of patients' recurrence.
  • the object of the present invention is to provide a method for predicting the response of psoriasis patients to anti-interleukin 17 (IL-17) monoclonal antibody and judging the prognosis of recurrence.
  • IL-17 anti-interleukin 17
  • a first aspect of the present invention provides a use of medium-chain fatty acids or a detection reagent thereof for preparing a detection reagent or a detection kit, and the detection reagent or detection kit is used for:
  • the medium chain fatty acid is selected from the group consisting of azelaic acid, 6-hydroxyhexanoic acid, or a combination thereof.
  • the IL-17A antibody includes ixekizumab.
  • the judgment includes auxiliary judgment, early judgment or pre-judgment.
  • the judgment is in vitro judgment.
  • the judging the response of the psoriasis patient to the IL-17A antibody comprises judging the speed of the psoriasis patient's response to the IL-17A antibody.
  • the prognosis includes predicting recurrence after drug withdrawal.
  • the prognosis is in vitro prognosis.
  • the psoriasis patients for prognosis include patients after IL-17A antibody treatment is discontinued.
  • the recurrence includes early recurrence and late recurrence.
  • the earlier relapse includes relapse within 5 months after drug withdrawal.
  • the late recurrence includes recurrence after 5 months after drug withdrawal.
  • the antibody includes a monoclonal antibody or a polyclonal antibody.
  • the detection reagent or the detection sample of the detection kit includes a blood sample.
  • the sample used for the judgment is a blood sample.
  • the sample for prognosis is a blood sample.
  • the sample is derived from the psoriasis patient.
  • the blood sample includes serum, plasma or blood.
  • the response response includes an early response.
  • the early response refers to that the PASI score of the psoriasis patient is reduced by more than 50% compared with the baseline at 2 weeks after using the IL-17A antibody.
  • the judgment is made by detecting the content of chain fatty acids in the sample.
  • the prognosis is performed by detecting the content of medium-chain fatty acids in the sample.
  • the prognostic psoriasis patients include patients after IL-17A antibody treatment is discontinued.
  • the sample includes serum, plasma or blood.
  • the psoriasis includes plaque psoriasis.
  • the plaque psoriasis includes moderate to severe plaque psoriasis.
  • the azelaic acid includes azelaic acid standard.
  • the 6-hydroxyhexanoic acid includes 6-hydroxyhexanoic acid standard.
  • the detection kit also includes a label or an instruction manual, and the label or instruction manual records the following content:
  • the response response includes a rapid response response, a moderate response response or a slow response response.
  • the detection kit also includes a label or an instruction manual, and the label or instruction manual records the following content:
  • the detection kit also includes a label or an instruction manual, and the label or instruction manual records the following content:
  • the response of the psoriasis patient to the IL-17A antibody is determined to be a rapid response
  • the response of the psoriasis patient to the IL-17A antibody is determined to be a moderate response response;
  • the response of the psoriasis patient to the IL-17A antibody is judged to be a slow response
  • the GC-MS response value of 6-hydroxyhexanoic acid in the serum sample is greater than 90000, it is judged that the response of the psoriasis patient to IL-17A antibody is a rapid response, wherein the GC-MS of 6-hydroxyhexanoic acid is The MS response value is the response value of the characteristic ion m/z 261 of 6-hydroxyhexanoic acid in 100 ⁇ L of serum;
  • the GC-MS response value of 6-hydroxyhexanoic acid in the serum sample is greater than 34500 and less than or equal to 90000, it is determined that the response of the psoriasis patient to the IL-17A antibody is a moderate response, wherein 6-hydroxy
  • the GC-MS response of caproic acid is the response using the characteristic ion m/z 261 of 6-hydroxycaproic acid in 100 ⁇ L of serum; and/or
  • the GC-MS response value of 6-hydroxyhexanoic acid in the serum sample is less than or equal to 34500, it is judged that the response of the psoriasis patient to the IL-17A antibody is a slow response, wherein the 6-hydroxyhexanoic acid is a slow response.
  • the GC-MS response value was the response value of the characteristic ion m/z 261 of 6-hydroxyhexanoic acid in 100 ⁇ L of serum.
  • the serum samples include serum samples from patients with psoriasis before, during or after administration.
  • the detection kit also includes a label or an instruction manual, and the label or instruction manual records the following content:
  • the detection kit also includes a label or an instruction manual, and the label or instruction manual records the following content:
  • the prognosis of the psoriasis patient is judged to be good (late recurrence);
  • the prognosis of the psoriasis patient is judged to be poor (early recurrence);
  • the prognosis of the psoriasis patient is judged to be good (late recurrence), wherein the GC-MS response value of 6-hydroxycaproic acid is Use the response value of the characteristic ion m/z 261 of 6-hydroxyhexanoic acid in 100 ⁇ L of serum; and/or
  • the prognosis of the psoriasis patient is judged to be poor (early recurrence), wherein the GC-MS response value of 6-hydroxycaproic acid is is the response value of the characteristic ion m/z 261 of 6-hydroxyhexanoic acid in 100 ⁇ L of serum.
  • the serum samples include serum samples from patients with psoriasis before, during or after administration.
  • the second aspect of the present invention provides the use of a companion diagnostic kit for preparing a diagnostic kit for evaluating whether a patient with psoriasis is suitable for treatment with IL-17A antibody and/or for IL-17A 17A antibody response;
  • the companion diagnostic kit includes:
  • the medium chain fatty acid is selected from the group consisting of azelaic acid, 6-hydroxyhexanoic acid, or a combination thereof.
  • the companion diagnostic kit also includes a label or an instruction for use, and the label or instruction for use records the following content:
  • the accompanying diagnostic kit also includes a label or an instruction manual, and the label or instruction manual records the following content:
  • the response of the psoriasis patient to the IL-17A antibody is determined to be a rapid response
  • the response of the psoriasis patient to the IL-17A antibody is determined to be a moderate response response;
  • the response of the psoriasis patient to the IL-17A antibody is judged to be a slow response
  • the GC-MS response value of 6-hydroxyhexanoic acid in the serum sample is greater than 90000, it is judged that the response of the psoriasis patient to IL-17A antibody is a rapid response, wherein the GC-MS of 6-hydroxyhexanoic acid is The MS response value is the response value of the characteristic ion m/z 261 of 6-hydroxyhexanoic acid in 100 ⁇ L of serum;
  • the GC-MS response value of 6-hydroxyhexanoic acid in the serum sample is greater than 34500 and less than or equal to 90000, it is determined that the response of the psoriasis patient to the IL-17A antibody is a moderate response, wherein 6-hydroxy
  • the GC-MS response of caproic acid is the response using the characteristic ion m/z 261 of 6-hydroxycaproic acid in 100 ⁇ L of serum; and/or
  • the GC-MS response value of 6-hydroxyhexanoic acid in the serum sample is less than or equal to 34500, it is judged that the response of the psoriasis patient to the IL-17A antibody is a slow response, wherein the 6-hydroxyhexanoic acid is a slow response.
  • the GC-MS response value was the response value of the characteristic ion m/z 261 of 6-hydroxyhexanoic acid in 100 ⁇ L of serum.
  • a third aspect of the present invention provides a medicine box, the medicine box comprises:
  • medium-chain fatty acid and/or its detection reagent said medium-chain fatty acid is selected from the group consisting of azelaic acid, 6-hydroxyhexanoic acid, or a combination thereof;
  • the kit also includes a label or an instruction manual, and the label or instruction manual records the following content:
  • medium chain fatty acid and/or its detection reagent measure sample such as psoriasis patient serum
  • Described medium chain fatty acid and/or its detection reagent measure sample such as psoriasis patient serum
  • IL-17A antibody a medium chain fatty acid and/or its detection reagent measure sample
  • the kit also includes a label or an instruction manual, and the label or instruction manual records the following content:
  • the kit also includes a label or an instruction manual, and the label or instruction manual records the following content:
  • the response of the psoriasis patient to the IL-17A antibody is determined to be a rapid response
  • the response of the psoriasis patient to the IL-17A antibody is determined to be a moderate response response;
  • the response of the psoriasis patient to the IL-17A antibody is judged to be a slow response
  • the GC-MS response value of 6-hydroxyhexanoic acid in the serum sample is greater than 90000, it is judged that the response of the psoriasis patient to IL-17A antibody is a rapid response, wherein the GC-MS of 6-hydroxyhexanoic acid is The MS response value is the response value of the characteristic ion m/z 261 of 6-hydroxyhexanoic acid in 100 ⁇ L of serum;
  • the GC-MS response value of 6-hydroxyhexanoic acid in the serum sample is greater than 34500 and less than or equal to 90000, it is determined that the response of the psoriasis patient to the IL-17A antibody is a moderate response, wherein 6-hydroxy
  • the GC-MS response of caproic acid is the response using the characteristic ion m/z 261 of 6-hydroxycaproic acid in 100 ⁇ L of serum; and/or
  • the GC-MS response value of 6-hydroxyhexanoic acid in the serum sample is less than or equal to 34500, it is judged that the response of the psoriasis patient to the IL-17A antibody is a slow response, wherein the 6-hydroxyhexanoic acid is a slow response.
  • the GC-MS response value was the response value of the characteristic ion m/z 261 of 6-hydroxyhexanoic acid in 100 ⁇ L of serum.
  • a fourth aspect of the present invention provides a device or system, the device or system comprising:
  • detection module described detection module is used to measure the content of medium-chain fatty acid in the sample, and described medium-chain fatty acid is selected from the following group: azelaic acid, 6-hydroxyhexanoic acid, or a combination thereof; and / or
  • the output module outputs the response of the psoriasis patient to the IL-17A antibody and/or the prognosis of the psoriasis patient according to the content of the medium chain fatty acid in the sample detected by the detection module Information.
  • the information output by the output module includes:
  • the information output by the output module includes:
  • the response of the psoriasis patient to the IL-17A antibody is determined to be a rapid response
  • the response of the psoriasis patient to the IL-17A antibody is determined to be a moderate response response;
  • the response of the psoriasis patient to the IL-17A antibody is judged to be a slow response
  • the GC-MS response value of 6-hydroxyhexanoic acid in the serum sample is greater than 90000, it is judged that the response of the psoriasis patient to IL-17A antibody is a rapid response, wherein the GC-MS of 6-hydroxyhexanoic acid is The MS response value is the response value of the characteristic ion m/z 261 of 6-hydroxyhexanoic acid in 100 ⁇ L of serum;
  • the GC-MS response value of 6-hydroxyhexanoic acid in the serum sample is greater than 34500 and less than or equal to 90000, it is determined that the response of the psoriasis patient to the IL-17A antibody is a moderate response, wherein 6-hydroxy
  • the GC-MS response of caproic acid is the response using the characteristic ion m/z 261 of 6-hydroxycaproic acid in 100 ⁇ L of serum; and/or
  • the GC-MS response value of 6-hydroxyhexanoic acid in the serum sample is less than or equal to 34500, it is judged that the response of the psoriasis patient to the IL-17A antibody is a slow response, wherein the 6-hydroxyhexanoic acid is a slow response.
  • the GC-MS response value was the response value of the characteristic ion m/z 261 of 6-hydroxyhexanoic acid in 100 ⁇ L of serum.
  • the device or system is high performance liquid chromatography (HPLC), gas chromatography (GC), high performance liquid chromatography-mass spectrometry (HPLC-MS) combined or gas chromatography-mass spectrometry (GC-MS) combined.
  • HPLC high performance liquid chromatography
  • GC gas chromatography
  • HPLC-MS high performance liquid chromatography-mass spectrometry
  • GC-MS gas chromatography-mass spectrometry
  • the device or system further includes a solvent delivery module, a sample injection module, a separation module, a detector, a data processing and recording module.
  • the solvent delivery module includes a liquid reservoir, a degasser, an infusion pump and/or an elution device.
  • the sample injection module includes a sample injector.
  • the separation module includes a chromatographic column.
  • FIG. 1 Partial least squares-discriminant analysis (PLS-DA) model analysis shows that serum azelaic acid and 6-hydroxyhexanoic acid levels at baseline are better predictors of anti-interleukin-17 (IL-17) resistance in psoriasis patients ) early response of monoclonal antibody. Patients with high baseline azelaic acid and 6-hydroxycaproic acid levels responded more quickly to anti-IL-17A mAbs.
  • PLS-DA Partial least squares-discriminant analysis
  • FIG. 2 ROC curve analysis shows that the cutoff value of baseline (pre-treatment) serum azelaic acid concentration in patients with rapid and moderate response is 2.41 ⁇ g/mL.
  • FIG. 3 ROC curve analysis shows that the cut-off value of serum azelaic acid concentration at baseline (before treatment) in patients with moderate and slow responses was 2.17 ⁇ g/mL.
  • FIG. 4 ROC curve analysis shows that the critical value of GC-MS response of baseline (before treatment) serum 6-hydroxyhexanoic acid in patients with rapid and moderate response is 90,000 (using 100 ⁇ L of serum 6-hydroxyhexanoic acid characteristic ion m/ The GC-MS response value of z 261 was used as the critical value for judgment).
  • FIG. 5 ROC curve analysis shows that the critical value of GC-MS response of baseline (pre-treatment) serum 6-hydroxyhexanoic acid in patients with moderate and slow responses is 34500 (using 100 ⁇ L of serum 6-hydroxyhexanoic acid characteristic ion m The GC-MS response value of /z 261 was used as the critical value for judgment).
  • Figure 6 Random forest model shows that baseline serum azelaic acid and 6-hydroxycaproic acid concentrations better predict relapse after discontinuation of anti-IL-17A mAb treatment. Patients with higher baseline azelaic acid and 6-hydroxycaproic acid levels relapsed later, ie, were less likely to relapse, after discontinuation of anti-IL-17A mAb therapy.
  • Figure 7 ROC curve analysis shows that the cut-off value of baseline serum azelaic acid concentration in patients with early relapse versus late relapse is 2.38 ⁇ g/mL.
  • Figure 8 ROC curve analysis showing the cutoff value of 27700 for the GC-MS response of baseline serum 6-hydroxyhexanoic acid in patients with early relapse and late relapse (using 100 ⁇ L of serum 6-hydroxyhexanoic acid characteristic ion m/z 261 The GC-MS response value was used as the critical value for judgment).
  • Figure 9 Analysis of serum from an additional 9 patients who relapsed after discontinuation also found that patients with late relapses had higher baseline azelaic acid levels compared to those with earlier relapses. ROC curve analysis showed that the cutoff value of baseline serum azelaic acid concentration was 2.24 ⁇ g/mL in patients with early relapse and late relapse. Combined with the results shown in Figure 7, it can be judged that patients with azelaic acid levels higher than 2.38 ⁇ g/mL at baseline relapsed later after drug discontinuation, and patients with azelaic acid level below 2.24 ⁇ g/mL relapsed earlier, at the critical value of these two concentrations. Patients in between cannot be judged.
  • Figure 10 Analysis of sera from an additional 9 patients who relapsed after discontinuation also found that patients with later relapses had higher 6-hydroxycaproic acid levels at baseline compared to those with earlier relapses. ROC curve analysis showed a cutoff value of 35200 for the GC-MS response of baseline serum azelaic acid concentrations in patients with early relapse versus late relapse. Combined with the results shown in Figure 8, it can be judged that patients with GC-MS response levels of 6-hydroxycaproic acid at baseline higher than 35200 relapsed later after drug withdrawal, and patients with lower than 27700 relapsed earlier, located at these two response thresholds. Patients between the two groups could not be judged (the GC-MS response value of the characteristic ion m/z 261 of 6-hydroxyhexanoic acid in 100 ⁇ L of serum was used as the critical value for judgment).
  • medium-chain fatty acids such as azelaic acid and/or 6-hydroxycaproic acid
  • azelaic acid and/or 6-hydroxycaproic acid can effectively judge the response of psoriasis patients to IL-17A antibody and the response to silver Prognostic markers in patients with psoriasis.
  • the experimental study of the present invention shows that when the content of azelaic acid and/or 6-hydroxycaproic acid in the serum of a patient with psoriasis is higher, the response of the patient with psoriasis to IL-17A antibody is faster;
  • the present invention unexpectedly found for the first time that the detection of medium-chain fatty acids (such as azelaic acid and/or 6-hydroxycaproic acid) can determine the response of IL-17A antibody to psoriasis patients and the response of IL-17A antibody after treatment with IL-17A antibody. Patients were judged for prognosis and recurrence. On this basis, the inventors have completed the present invention.
  • medium-chain fatty acids such as azelaic acid and/or 6-hydroxycaproic acid
  • the terms “comprising,” “including,” and “containing” are used interchangeably to include not only closed definitions, but also semi-closed, and open definitions. In other words, the terms include “consisting of”, “consisting essentially of”.
  • ROC curve is a receiver operating characteristic curve, a graph consisting of false positive probability (1-specificity) on the horizontal axis, true positive probability (sensitivity) on the vertical axis, and The curve drawn by the test subject due to the different results obtained by using different judgment standards under specific stimulation conditions. Choose the best diagnostic cutoff. The closer the ROC curve is to the upper left corner, the higher the accuracy of the test. The point of the ROC curve closest to the upper left corner is the best threshold with the fewest errors, with the lowest total number of false positives and false negatives. A comparison of the ability of two or more different diagnostic tests to identify a disease.
  • the ROC curve of each test can be drawn into the same coordinate to visually identify the pros and cons.
  • the subjects represented by the ROC curve near the upper left corner Works most accurately. It can be compared by calculating the area under the ROC curve (AUC) of each metabolite in serum and its corresponding GCMS value. Which metabolite and its GCMS corresponding value have the largest AUC, and which serum metabolite has the highest diagnostic value. optimal.
  • PASI Psoriasis area and severity index
  • the term "Random Forest (Random Forrest) analysis model” is a classifier that contains multiple decision trees. The main job of decision trees is to select features to divide the data set.
  • the characteristic value in the present invention refers to serum metabolites, and the serum metabolites are used to classify patients to find the serum metabolites that can best divide the response to IL-17A antibody and recurrence.
  • PLS-DA Partial Least Squares-Discriminant Analysis
  • the PLS-DA model needs to find the serum metabolite that can best distinguish the patient's response to IL-17A antibody and relapse.
  • VIP refers to Variable Important for the Projection, and the VIP score is used to judge the importance of feature values for dividing the dataset.
  • GC-MS refers to gas chromatography-mass spectrometry.
  • 6-HC 6-hydroxyhexanoic acid, CAS: 1191-25-9.
  • the CAS number for azelaic acid is 123-99-9.
  • the term "less than or equal to” includes less than and/or equal to.
  • the term "greater than or equal to” includes greater than and/or equal to.
  • IL-17A refers to interleukin-17A.
  • the medium-chain fatty acids, medium-chain fatty acid detection reagents, detection kits, companion diagnostic kits, diagnostic kits, kits, and devices or test samples of the present invention can be blood samples.
  • the blood sample comprises serum, plasma or blood
  • the sample of the present invention is derived from the psoriasis patient.
  • the present invention provides the use of a medium-chain fatty acid or a detection reagent thereof for preparing a detection reagent or a detection kit, and the detection reagent or detection kit is used for:
  • the medium-chain fatty acid includes (but is not limited to): azelaic acid, 6-hydroxyhexanoic acid, or a combination thereof.
  • the medium-chain fatty acids including detection reagents such as azelaic acid and/or 6-hydroxyhexanoic acid are not particularly limited, as long as accurate detection is satisfied.
  • the medium-chain fatty acid detection reagent is an antibody or a detection reagent suitable for methods such as high performance liquid phase.
  • the IL-17A antibody includes a monoclonal antibody or a polyclonal antibody, and the IL-17A antibody has high affinity and specificity with interleukin-17A (IL-17A), and can inhibit Binding of IL-17A to the IL-17 receptor.
  • the IL-17A antibody includes ixekizumab.
  • the psoriasis patients for prognosis include patients after IL-17A antibody treatment is discontinued.
  • the prognosis includes predicting recurrence after drug withdrawal.
  • the recurrence according to the present invention includes early recurrence and late recurrence.
  • the earlier relapse includes relapse within 5 months of drug discontinuation.
  • the later relapse includes relapse after 5 months after drug withdrawal.
  • the detection reagent or the detection sample of the detection kit includes (but is not limited to) a blood sample.
  • the sample is derived from the psoriasis patient.
  • the sample includes serum, plasma or blood.
  • the sample used for the judgment is a blood sample.
  • the sample for prognosis is a blood sample.
  • the blood sample includes serum, plasma or blood.
  • the judgment is made by detecting the content of chain fatty acids in the sample.
  • the prognosis is performed by detecting the content of medium-chain fatty acids in the sample.
  • the sample includes serum, plasma or blood.
  • the response response includes an early response.
  • the early response refers to that the PASI score of the psoriasis patient is reduced by more than 50% compared with the baseline at 2 weeks after using the IL-17A antibody.
  • the psoriasis includes plaque psoriasis.
  • the plaque psoriasis includes moderate to severe plaque psoriasis.
  • the detection kit further includes a label or an instruction manual, and the label or instruction manual records the following content:
  • the psoriasis patient's PASI score decreased by less than or equal to 50% from baseline after receiving IL-17A antibody treatment for 2 weeks, the psoriasis patient's response to IL-17A antibody was a slow response response.
  • the response response includes a rapid response response, a moderate response response or a slow response response.
  • the detection kit further includes a label or an instruction manual, and the label or instruction manual records the following content:
  • the detection kit further includes a label or an instruction manual, and the label or instruction manual records the following content:
  • the response of the psoriasis patient to the IL-17A antibody is determined to be a rapid response
  • the response of the psoriasis patient to the IL-17A antibody is determined to be a moderate response response;
  • the response of the psoriasis patient to the IL-17A antibody is judged to be a slow response
  • the GC-MS response value of 6-hydroxyhexanoic acid in the serum sample is greater than 90000, it is judged that the response of the psoriasis patient to IL-17A antibody is a rapid response, wherein the GC-MS of 6-hydroxyhexanoic acid is The MS response value is the response value of the characteristic ion m/z 261 of 6-hydroxyhexanoic acid in 100 ⁇ L of serum;
  • the GC-MS response value of 6-hydroxyhexanoic acid in the serum sample is greater than 34500 and less than or equal to 90000, it is determined that the response of the psoriasis patient to the IL-17A antibody is a moderate response, wherein 6-hydroxy
  • the GC-MS response of caproic acid is the response using the characteristic ion m/z 261 of 6-hydroxycaproic acid in 100 ⁇ L of serum; and/or
  • the GC-MS response value of 6-hydroxyhexanoic acid in the serum sample is less than or equal to 34500, it is judged that the response of the psoriasis patient to the IL-17A antibody is a slow response, wherein the 6-hydroxyhexanoic acid is a slow response.
  • the GC-MS response value was the response value of the characteristic ion m/z 261 of 6-hydroxyhexanoic acid in 100 ⁇ L of serum.
  • the detection kit further includes a label or an instruction manual, and the label or instruction manual records the following content:
  • the detection kit further includes a label or an instruction manual, and the label or instruction manual records the following content:
  • the prognosis of the psoriasis patient is judged to be good (late recurrence).
  • the prognosis of the psoriasis patient is judged to be poor (early recurrence).
  • the prognosis of the psoriasis patient is judged to be good (late recurrence), wherein the GC-MS response value of 6-hydroxycaproic acid is The response value of the characteristic ion m/z 261 of 6-hydroxyhexanoic acid in 100 ⁇ L of serum was used.
  • the prognosis of the psoriasis patient is judged to be poor (early recurrence), wherein the GC-MS response value of 6-hydroxycaproic acid is is the response value of the characteristic ion m/z 261 of 6-hydroxyhexanoic acid in 100 ⁇ L of serum.
  • medium-chain fatty acid such as azelaic acid and/or 6-hydroxyhexanoic acid
  • medium-chain fatty acid can be used as a standard to draw a standard curve, and use
  • the content of medium chain fatty acids such as azelaic acid and/or 6-hydroxyhexanoic acid
  • the present invention also provides the use of a companion diagnostic kit for preparing a diagnostic kit for evaluating whether a patient with psoriasis is suitable for treatment with IL-17A antibody and/or for IL-17A antibody treatment response response.
  • the companion diagnostic kit includes:
  • the medium chain fatty acid is selected from the group consisting of azelaic acid, 6-hydroxyhexanoic acid, or a combination thereof.
  • the present invention provides a kind of medicine box, described medicine box comprises:
  • medium-chain fatty acids and/or detection reagents thereof wherein the medium-chain fatty acids are selected from the group consisting of azelaic acid, 6-hydroxyhexanoic acid, or a combination thereof.
  • the response of psoriasis patients to the IL-17A antibody and/or to silver Prognosis of psoriasis patients, so as to determine the response speed of psoriasis patients to IL-17A antibody and/or the prognosis of psoriasis patients after IL-17A antibody treatment of psoriasis patients is discontinued.
  • the present invention also provides a device or system, the device or system comprising:
  • detection module described detection module is used to measure the content of medium-chain fatty acid in the sample, and described medium-chain fatty acid is selected from the following group: azelaic acid, 6-hydroxyhexanoic acid, or a combination thereof; and / or
  • the output module outputs the response of the psoriasis patient to the IL-17A antibody and/or the prognosis of the psoriasis patient according to the content of the medium chain fatty acid in the sample detected by the detection module Information.
  • the device or system is a high performance liquid chromatograph (HPLC), a gas chromatograph (GC), a high performance liquid chromatograph-mass spectrometer (HPLC-MS) combination or a gas chromatograph- Mass spectrometry (GC-MS).
  • HPLC high performance liquid chromatograph
  • GC gas chromatograph
  • HPLC-MS high performance liquid chromatograph-mass spectrometer
  • GC-MS gas chromatograph- Mass spectrometry
  • the device or system further includes a solvent delivery module, a sample injection module, a separation module, a detector, a data processing and recording module.
  • the solvent delivery module includes a liquid reservoir, a degasser, an infusion pump and/or an elution device.
  • Reservoir used to store enough mobile phase to meet the requirements. Equipped with a solvent filter to prevent particles in the mobile phase from entering the pump.
  • Degasser The purpose of degassing is to prevent the release of air bubbles into the detector when the mobile phase flows out of the chromatographic column, which will cause noise and cannot be detected normally.
  • Infusion pump The mobile phase in the liquid reservoir continuously enters the liquid circuit system in the form of high pressure, so that the sample can complete the separation process in the chromatographic column.
  • Elution device It is a device that increases the elution capacity by gradually changing the composition of the mobile phase during the separation process.
  • the sample injection module includes a sample injector.
  • the injector is a device that feeds the sample into the chromatographic column.
  • injection methods There are two types of injection methods: valve injection or automatic injection. More commonly used is the use of automatic sampler loading.
  • the separation module includes a chromatographic column.
  • the chromatographic column separates the sample and is the heart of the entire chromatographic system. Its quality directly affects the separation effect.
  • the detector converts the sample components continuously flowing out of the chromatographic column into easily measurable electrical signals, which are received by the data system to obtain a chromatogram of sample separation.
  • the data processing and recording module processes the chromatographic data and participates in the automatic control of the HPLC instrument.
  • the present invention unexpectedly finds for the first time that medium-chain fatty acids (such as azelaic acid and 6-hydroxycaproic acid) can effectively judge the response of psoriasis patients to IL-17A antibody and predict the recurrence of psoriasis patients. Therefore, medium-chain fatty acids such as azelaic acid and 6-hydroxycaproic acid can be used as markers to predict the response to IL-17A antibody in psoriasis patients before drug treatment, and can also predict psoriasis patients after drug discontinuation. recurrence, thus providing important guidance for the treatment and prognosis of psoriasis.
  • medium-chain fatty acids such as azelaic acid and 6-hydroxycaproic acid
  • Serum sample processing 100 ⁇ L of serum samples were frozen and thawed at room temperature, 400 ⁇ L of pre-cooled methanol was added, vortexed for 5 minutes, and after standing for 10 minutes, centrifuged at 12 000 rpm for 15 minutes at 4°C. Aspirate appropriate amount of supernatant for metabolomic analysis
  • Serum gas chromatography-mass spectrometry (GC-MS) metabolomic analysis The sample-treated serum supernatant was completely dried with nitrogen at 40 °C, and then 50 ⁇ L of methoxyamine pyridine solution (15 mg/mL) was added and vortexed.
  • the GC-MS analysis system consisted of a 7890B gas phase instrument and a 5977A single quadrupole mass spectrometer detector (Agilent Technologies, Santa Clara, CA, USA). Chromatographic separation adopts DB-5MS capillary column (30m ⁇ 250 ⁇ m ⁇ 0.25 ⁇ m). The injection volume was 1 ⁇ L, the split ratio was 20:1, and the helium flow rate was 1.2 mL/min. The temperatures of the injection port, mass spectrometer interface and mass spectrometer detector were set to 300°C, 280°C and 230°C, respectively. The initial temperature of the column oven was kept at 70 °C for 3 min, and the gradient was heated to 300 °C (5 °C/min) for 5 min. The gain factor was set to 2.0, and the ion source was electron impact (70 eV). The scanning range of mass spectrometry was 33-600 m/z, and the solvent delay time was set to 6 min.
  • the Random Forest (Random Forrest) analysis model showed that baseline levels of azelaic acid and 6-hydroxycaproic acid had higher scores in predicting the speed of recurrence, and the prediction accuracy decreased when azelaic acid and 6-hydroxycaproic acid were removed from the model. maximum ( Figure 6).
  • the areas under the ROC curves of azelaic acid and 6-hydroxycaproic acid reached 0.778 and 0.667, respectively, and patients with lower baseline levels relapsed more quickly (ie, earlier) after drug discontinuation ( Figures 7-8).

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Abstract

Un marqueur pour déterminer la réponse du psoriasis à l'anticorps ciblant l'IL-17A et sa récurrence sont divulgués. Est en outre divulguée l'utilisation d'un acide gras à chaîne moyenne ou d'un réactif de détection associé, qui est utilisé pour préparer un réactif de détection ou un kit de détection, et le réactif de détection ou le kit de détection est utilisé pour : (a) déterminer la réponse d'un patient atteint du psoriasis à l'anticorps ciblant l'IL-17A ; et/ou (b) réaliser un pronostic pour le patient atteint du psoriasis, l'acide gras à chaîne moyenne étant choisi dans le groupe suivant constitué par l'acide azélaïque, l'acide 6-hydroxyhexanoïque ou une combinaison de ceux-ci.
PCT/CN2021/131921 2020-11-20 2021-11-19 Marqueur pour déterminer la réponse du psoriasis à l'anticorps ciblant l'il-17a et sa récurrence WO2022105894A1 (fr)

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