CN114166924A - Use of urine protein markers for diagnosing hereditary angioedema - Google Patents
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Abstract
The present disclosure relates to the use of urine protein markers for the diagnosis of hereditary angioedema. In particular, the present disclosure relates to the use of an identification agent that specifically identifies one or more proteins selected from those described in table 1 in the manufacture of a device for diagnosing hereditary angioedema in a subject. In another aspect, the present disclosure relates to a kit or chip for diagnosing hereditary angioedema, which comprises the identification reagent.
Description
Technical Field
The present disclosure relates to clinical medicine; in particular to a urine protein marker related to human hereditary angioedema. In particular, the disclosure relates to urine protein markers for human hereditary angioedema diagnosis obtained by using a urine sample of a hereditary angioedema patient and a mass spectrometry proteomics technology, and uses thereof.
Background
Disease markers are measurable changes associated with pathophysiological processes and can be used for disease diagnosis, disease course monitoring, efficacy assessment, and the like. Urine is an ideal clinical sample source of disease markers and can be obtained in large quantities without wound. Furthermore, the lack of regulation of homeostatic mechanisms in urine can enrich the body's discharge for a variety of changes that are potential marker sources (see Wu J & Gao Y. physiological conditions can be reflected in human urine protein and metabolism. Ext Review of the sciences, 2015; 12(6): 623-.
Urine proteomics (urinary proteomics) aims at establishing a non-invasive 'liquid biopsy' diagnosis method, and partially replaces tissue aspiration biopsy by detecting specific disease markers in urine, so that the urine proteomics becomes an important research direction and has a very huge clinical transformation application prospect. Dia (data independent acquisition) is a latest data-independent proteome quantification technology, and divides the whole full scan range of a mass spectrum into a plurality of windows, so that all fragment information of all ions in a sample can be acquired without difference and omission. Since DIA technology can unambiguously obtain information on all peptide fragments in a clinical sample without loss of low abundance proteins, it is particularly suitable for robust and accurate quantification of proteins under different laboratory conditions (see Navarro P et al A multicenter student benchmarks software protocols for laboratory-free protein quantification. Nature Biotechnology, 2016; 34 (11): 1130-. PRM (parallel interaction monitoring) is a targeted proteomics technology, and an ion monitoring technology based on Orbitrap high-resolution mass spectrometry can selectively detect a target peptide segment of a target protein so as to realize targeted quantification.
Hereditary Angioedema (HAE) is a rare, potentially life-threatening disease characterized by recurrent episodes of subcutaneous and submucosal swelling. HAE is a rare disease with an incidence of 1 in every 5 million people and is not usually easily discovered. Skin and abdominal attacks are the most common features of HAE and are easily misdiagnosed as edema or an acute abdomen leading to ineffective treatment or unnecessary surgery for the patient. In addition, more than 50% of HAE patients develop laryngeal edema and die asphyxiation without rescue. Therefore, the discovery of early diagnostic markers is crucial for the clinical management of HAE.
Disclosure of Invention
In view of the above-mentioned need in the art, according to some embodiments of the present disclosure, there is provided a use of an identifying agent selected from any one of the following proteins in the manufacture of a diagnostic device for hereditary angioedema:
inhibitors of plasma protease C1, ketohexokinase, phenazine biosynthesis domain proteins, contractile protein alpha chain, profibrinin 1, cathepsin H precursor, IST1 homolog, malate dehydrogenase, Cochlin, disintegrin and metalloproteinase domain-containing protein 10, basement membrane-specific heparan sulfate proteoglycan core protein, kininogen 1 protein, v-assembly domain-containing t-cell activation inhibitor 1, epidermal growth factor precursor, adhesion molecule A, N-acetylated alpha-catenin dipeptidase 2, transmembrane glycoprotein NMB, procollagen endopeptidase enhancer 2, urokinase plasminogen activator surface receptor, thrombospondin disintegrin metallopeptidase 1, cathepsin Z, cathepsin L1, endothelial cell selective adhesion molecule, kallikrein 1, complement component C9, complement component C1, Calbindin, complement component C7, aquaporin 2, follicle stimulating hormone beta subunit, protocadherin alpha-C2, vascular endothelial growth factor receptor 2, cadherin-related family member 5, immunoglobulin heavy chain constant region gamma 4, and aspartic protease a.
In particular embodiments, an increased level of expression of a protein selected from the group consisting of: contractile protein alpha chain, profibrinin 1, cathepsin H precursor, IST1 homolog, Cochlin, disintegrin and metalloprotease domain containing protein 10, basement membrane specific heparan sulfate proteoglycan core protein, connexoring adhesion molecule A, N-acetylated alpha-catenated dipeptidase 2, transmembrane glycoprotein NMB, procollagen C-endopeptidase enhancer 2, urokinase plasminogen activator surface receptor, thrombospondin disintegrin metallopeptidase 1, cathepsin Z, cathepsin L1, endothelial cell selective adhesion molecule, complement component C9, complement component C1, complement component C7, aquaporin 2, follicle stimulating hormone beta subunit, protocadherin alpha-C2, vascular endothelial growth factor receptor 2, calcium adhesion related family member 5, or a combination thereof.
In particular embodiments, a decreased level of expression of a protein selected from the group consisting of: a plasma protease C1 inhibitor, ketohexokinase, phenazine biosynthesis domain protein, malate dehydrogenase, kininogen 1, immunoglobulin heavy chain constant region γ 4, v-domain containing t cell activation inhibitor 1, epidermal growth factor precursor, kallikrein 1, aspartic protease a, calcium binding protein, or combinations thereof. Otherwise, the risk is reduced.
In embodiments relating to the diagnosis of hereditary angioedema, a control refers to an individual who does not have hereditary angioedema. The control need not be a clinically healthy individual, preferably a healthy individual.
The term "identification reagent" as used in the present application refers to a reagent capable of quantitatively and/or qualitatively detecting a protein of interest. In particular, but not by way of limitation, the identification reagents of the invention are capable of specifically recognizing the presence or absence of a protein of interest in a test sample; or capable of detecting the level of the protein of interest in the test sample.
In one embodiment of the present application, the identification reagent is used to identify proteins in a urine sample, including, but not limited to, for quantitative and/or qualitative detection of proteins in a urine sample.
In one embodiment of the present application, the identification agent is capable of identifying an increase or decrease in the amount of protein in the urine sample of the subject, preferably greater than or equal to 1.5 fold, as compared to a healthy control group or a non-hereditary angioedema control group. The identification agents of the present application are capable of identifying, or binding to, or searching for, or monitoring, or targeting such tagged peptides (e.g., peptides contained by the proteins listed in table 1). In some embodiments, an identification reagent suitable for use in the present disclosure is a mass spectrometry identification reagent, an antibody, or an antigen binding fragment thereof.
In a specific embodiment, the antibody is a monoclonal antibody. The species source of the monoclonal antibody is not limited by the present disclosure, and any antibody capable of binding to the above-described protein can be used.
In particular embodiments, antigen-binding fragments include, but are not limited to: fab, Fab ', (Fab')2Fv, ScFv, bispecific antibody, trispecific antibody, tetraspecific antibody, bis-scFv, mimi antibody. Any antibody fragment that retains antigen binding activity is suitable for use in the present disclosure.
In one embodiment, when mass spectrometric identification reagents are used, the identification reagents are widely understood and cannot be interpreted as merely chemical or biological reagents for the presence of the entity. The term also encompasses mass spectrometric identification parameters. As an example, the whole full scan range of the mass spectrum is divided into several windows, and all ions in each window are selected, fragmented and detected at high speed and cyclically, so that all fragment information of all ions in the sample is obtained without omission or difference. The acquisition method is like blanket bombing, and all targets are hit without omission; and comparing the mass-to-charge ratio information of the fragments in a database to identify the identity and the quantification of the protein. It should be understood that although a specific identification method is used in the specific example, the technical effect of the present application is not achieved depending on the specific identification method (e.g., mass spectrometry procedure, mass spectrometer model, parameters set in the mass spectrometry method, specific peptide sequence identified in the mass spectrometry, chromatography column model; antibody supplier, specific epitope targeted by antibody, antibody typing, immunological procedure and parameters), because the core of the technical solution of the present application is to find the relationship between the amount of the aforementioned protein present in urine and the disease, and thus any means capable of determining the protein content is available.
The tag peptide (also referred to as specific peptide herein) refers to a peptide fragment capable of representing a protein, and is characterized by the presence and specificity only in the amino acid sequence of the protein.
It is to be understood that although the proteins are identified and quantified based on a particular sequence in the specific examples, this does not mean that peptide fragments at other positions in the proteins listed in table 1 cannot be used, as long as such fragments are capable of distinguishing different proteins from each other, and are applicable to the present application. The position or length of the fragments can be determined by the skilled person in accordance with conventional techniques in combination with the operational requirements of the identification method used, given the teaching of the present application.
In a specific embodiment, the expression level is a protein level.
In a specific embodiment, the expression level is the level of protein expression in a urine sample from the subject.
In specific embodiments, the subject is a human.
In the presently disclosed embodiments, the patient is a hereditary angioedema patient.
In particular embodiments, the protein markers according to the present disclosure can be used for diagnosing hereditary angioedema.
According to other embodiments, there is also provided a kit or chip for diagnosing hereditary blood edema, which comprises or consists of an identifying agent for a protein selected from the group consisting of: inhibitors of plasma protease C1, ketohexokinase, phenazine biosynthesis domain proteins, contractile protein alpha chain, profibrinin 1, cathepsin H precursor, IST1 homolog, malate dehydrogenase, Cochlin, disintegrin and metalloproteinase domain-containing protein 10, basement membrane-specific heparan sulfate proteoglycan core protein, kininogen 1, v-assembly domain-containing t-cell activation inhibitor 1, epidermal growth factor precursor, adhesion molecule A, N-acetylated alpha-catenase 2, transmembrane glycoprotein NMB, procollagen endopeptidase enhancer 2, urokinase plasminogen activator surface receptor, thrombospondin disintegrin metallopeptidase 1, cathepsin Z, cathepsin L1, endothelial cell selective adhesion molecule, kallikrein 1, complement component C9, complement component C1, platelet-reactive protein kinase 1, platelet-selective adhesion protein, and the like, Calbindin, complement component C7, aquaporin 2, follicle stimulating hormone beta subunit, protocadherin alpha-C2, vascular endothelial growth factor receptor 2, cadherin-related family member 5, immunoglobulin heavy chain constant region gamma 4, aspartic protease a, or a combination thereof.
In some embodiments, the kit comprises an agent for identifying the above-described protein.
In other embodiments, the chip has immobilized thereon an identifying agent for the protein.
In some embodiments, the identification agent is an antibody or antigen-binding fragment thereof.
According to some embodiments, there is provided a method for diagnosing whether a subject has hereditary angioedema, comprising the steps of:
1) obtaining a urine sample from the subject or a control,
2) optionally, separating the protein from the urine sample,
3) determining the expression level of a protein selected from the group consisting of:
inhibitors of plasma protease C1, ketohexokinase, phenazine biosynthesis domain proteins, contractile protein alpha chain, profibrinin 1, cathepsin H precursor, IST1 homolog, malate dehydrogenase, Cochlin, disintegrin and metalloproteinase domain-containing protein 10, basement membrane-specific heparan sulfate proteoglycan core protein, kininogen 1, v-assembly domain-containing t-cell activation inhibitor 1, epidermal growth factor precursor, adhesion molecule A, N-acetylated alpha-catenin dipeptidase 2, transmembrane glycoprotein NMB, procollagen endopeptidase enhancer 2, urokinase plasminogen activator surface receptor, thrombospondin disintegrin metallopeptidase 1, cathepsin Z, cathepsin L1, endothelial cell selective adhesion molecule, kallikrein-1, complement component C9, complement component C1, Calbindin, complement component C7, aquaporin 2, follicle stimulating hormone β subunit, protocadherin α -C2, vascular endothelial growth factor receptor 2, cadherin-related family member 5, immunoglobulin heavy chain constant region γ 4, aspartic protease a, or a combination thereof;
4) and the protein expression level in the sample obtained from the control.
In specific embodiments, the expression level is determined using mass spectrometry, ELISA, or Western methods.
When the protein and its expression level are determined by mass spectrometry, a protease digestion step may also be included after the step of obtaining a urine sample. In a specific embodiment, the protein in the urine sample is fragmented with a protease.
According to some embodiments, there is provided a method for diagnosing hereditary angioedema in a subject, comprising the steps of:
1) urine samples were obtained from the subject and from the control,
2) determining the expression level of a protein selected from the group consisting of: inhibitors of plasma protease C1, ketohexokinase, phenazine biosynthesis domain proteins, contractile protein alpha chain, profibrinin 1, cathepsin H precursor, IST1 homolog, malate dehydrogenase, Cochlin, disintegrin and metalloproteinase domain-containing protein 10, basement membrane-specific heparan sulfate proteoglycan core protein, kininogen 1, v-assembly domain-containing t-cell activation inhibitor 1, epidermal growth factor precursor, adhesion molecule A, N-acetylated alpha-catenase 2, transmembrane glycoprotein NMB, procollagen endopeptidase enhancer 2, urokinase plasminogen activator surface receptor, thrombospondin disintegrin metallopeptidase 1, cathepsin Z, cathepsin L1, endothelial cell selective adhesion molecule, kallikrein 1, complement component C9, complement component C1, platelet-reactive protein kinase 1, platelet-selective adhesion protein, and the like, Calbindin, complement component C7, aquaporin 2, follicle stimulating hormone β subunit, protocadherin α -C2, vascular endothelial growth factor receptor 2, cadherin-related family member 5, immunoglobulin heavy chain constant region γ 4, aspartic protease a, or a combination thereof;
3) comparing the expression level of the protein in the subject to the expression level of the protein in a control;
4) determining whether the subject has, or is assessed at risk for, hereditary angioedema.
In particular embodiments, an increased level of expression of a protein selected from the group consisting of: contractile protein alpha chain, profibrinin 1, cathepsin H precursor, IST1 homolog, Cochlin, disintegrin and metalloprotease domain containing protein 10, basement membrane specific heparan sulfate proteoglycan core protein, connexoring adhesion molecule A, N-acetylated alpha-catenated dipeptidase 2, transmembrane glycoprotein NMB, procollagen C-endopeptidase enhancer 2, urokinase plasminogen activator surface receptor, thrombospondin disintegrin metallopeptidase 1, cathepsin Z, cathepsin L1, endothelial cell selective adhesion molecule, complement component C9, complement component C1, complement component C7, aquaporin 2, follicle stimulating hormone beta subunit, protocadherin alpha-C2, vascular endothelial growth factor receptor 2, calcium adhesion related family member 5, or a combination thereof.
In particular embodiments, a decreased level of expression of a protein selected from the group consisting of: a plasma protease C1 inhibitor, ketohexokinase, phenazine biosynthesis domain protein, malate dehydrogenase, kininogen 1, immunoglobulin heavy chain constant region γ 4, v-domain containing t cell activation inhibitor 1, epidermal growth factor precursor, kallikrein 1, aspartic protease a, calcium binding protein, or combinations thereof.
Drawings
FIG. 1 shows the ROC curve for HAE diagnosis when plasma protease C1 inhibitor, kallikrein 1 and thrombospondin metallopeptidase 1 are used in combination.
Detailed Description
The disclosure will be further illustrated by the following non-limiting examples. It will be apparent to those skilled in the art that many modifications can be made to the disclosure without departing from the spirit thereof, and such modifications are intended to be within the scope of the disclosure. The experimental materials used are all available from commercial companies, unless otherwise specified.
Example 1 Collection and preparation of urine samples for Mass Spectrometry
Queue 1: morning urine samples were obtained from 28 patients with hereditary angioedema from Beijing coordination Hospital, the Chinese medical academy of sciences (19 women, 9 men; average age 42.6 years); comparison was made with urine protein expression of 29 healthy controls (of which 20 women, 9 men; mean age 43.0 years). Queue 2: morning urine samples were obtained from 24 patients with hereditary angioedema from Beijing coordination Hospital, the Chinese medical academy of sciences (15 women, 9 men; average age 42.8 years); comparison was made with urine protein expression of 18 healthy controls (of which 15 women, 3 men; mean age 41.8 years). The study was approved by the ethical committee and patients signed informed consent.
Controls were healthy individuals without hereditary angioedema.
The preparation steps of the urine sample for mass spectrometry detection are as follows:
1) collecting urine from patients with hereditary angioedema and controls;
2) extracting urine protein of a patient: centrifuging 5000g of patient urine for 30min, collecting supernatant, mixing the urine with acetone at a volume ratio of 1:4, and precipitating urine protein at-20 ℃ overnight. Centrifuging at 12000g for 30min at 4 deg.C, removing supernatant, naturally air drying precipitate, and dissolving with lysis solution;
3) preparation of proteome sample: urine proteins are cleaved on the membrane using the FASP method, see Wisniwski JR et al, Universal sample preparation method for protein analysis, Nature methods 2009; 6:359-62.
Example 2 urine protein profiling
1. Materials and reagents
1) The instrument comprises the following steps:
the Orbitrap Q active HF high resolution mass spectrometer was purchased from Thermo Fisher; HPLC, EASY-nLC 1200 was purchased from Thermo Fisher.
2) Reagent:
chromatographic grade acetonitrile, formic acid and methanol are produced by Waters corporation; acetylammonium Iodide (IAA), ammonium bicarbonate, Dithiothreitol (DTT) were purchased from Sigma; mass Spectroscopy grade pancreatin was purchased from Promega.
2. Identification by mass spectrometry
And (3) carrying out tandem mass spectrometry on the enzyme-cut peptide fragment in the queue 1 by using an Orbitrap Q active HF high-resolution mass spectrometer, acquiring mass spectrum data by using a DIA quantitative proteomics technology, and then verifying the screened target protein in the queue 2 by using a PRM targeted proteomic quantitative technology. DIA parameter setting: modify the mass spectrum variable window, scan time 60min, collision energy: 28%; the primary scanning resolution is set to 60000, and the secondary resolution is 30000; the maximum injection time of the parent ions is 80 ms; parent ion scan range: 300-1300 m/z; sub-ion scan range: starting at 350 m/z; setting 40 scanning windows; the window size is determined according to the number of primary parent ions and is evenly distributed. Setting PRM parameters: each full scan is followed by 25 targeted scans, scan time 60 min. The primary full scanning resolution is 60000, the scanning range is 300-1250m/z, AGC 3e6 and the maximum injection time is 80 ms; the collision energy was 28% and the secondary scan resolution was 30000.
3. Proteomic quantitative analysis
The obtained DIA mass spectrum data is retrieved by Proteome scanner software (version 2.1), and a result file is imported into Spectronaut software to establish a spectrogram library. The DIA official sample mass spectra raw data were imported into the Spectronaut software and matched to the data in the spectra library with q < 1.0%, with retention time corrected by iRT reagents. And screening the proteins with more than 2 specific polypeptides for subsequent proteome quantification. And screening out the protein with the protein expression quantity change fold of more than 1.5 times and the p value of less than 0.05 as the differential protein. In PRM targeting quantification, firstly, a mixed sample is used for collecting DDA data of 6 needles, and a protome discover software is used for searching a library, and a library searching result is led into Skyline software to establish a spectrogram library. And (3) leading the protein sequence Fasta file with targeted quantification into a Skyline spectrogram library, and deriving the m/z and retention time table of the corresponding peptide segment of the targeted protein. And leading the acquired PRM original data back to Skyline, screening quantitative fragment ions, and leading out the peak area of the secondary fragment ions of each peptide fragment for PRM quantification.
4. Results of mass spectrometry
Urine samples from 28 diagnosed hereditary angioedema patients and 29 healthy persons were collected in cohort 1, and a total of 1897 proteins were identified at a level of at least 2 specific polypeptides and protein identification FDRs < 1%.
Comparing with a control sample, screening out the differential proteins with the change multiple of more than 1.5 times and the t test p of an independent sample of less than 0.05, wherein 35 differential proteins can be used as diagnostic markers.
Table 1 shows that 35 candidate markers, 24 proteins are elevated and 11 proteins are reduced compared to the control group.
TABLE 1 hereditary angioedema patients and control differential urine protein markers
Example 3 application of urine protein markers in HAE diagnosis
To further confirm the sensitivity and specificity of the screened protein markers in HAE diagnosis, we validated candidate markers in a new clinical cohort for the proteins in table 1 using PRM-targeted proteomic techniques and plotted ROC curves for the above markers in differentiating HAE patients from subjects. The method comprises the following specific steps: urine samples of 24 HAE patients (of which 15 women, 9 men, and mean age 42.8 years) and 18 healthy control subjects (of which 15 women, 3 men, and mean age 41.8 years) were newly collected in cohort 2, and the expression levels of 7 different proteins including plasma protease C1 inhibitor, pre-fibrin 1, epidermal growth factor precursor, malate dehydrogenase, kininogen 1, kallikrein 1, thrombospondin disintegrin metallopeptidase 1 in the samples were tested using PRM targeted proteome quantification technique using a blind method. The results show that the expression levels of plasma protease C1 inhibitor, 0.32 fold change, 1.48 fold change for pre-fibrin 1, 0.50 fold change for epidermal growth factor precursor, 0.49 fold change for malate dehydrogenase, 0.50 fold change for kallikrein 1, 2.10 fold change for thrombospondin metallopeptidase 1, and 0.46 fold change for aspartic protease a in the urine of patients, alone or in combination, are able to distinguish HAE patients from subjects, compared to healthy controls.
Illustratively, as shown in fig. 1, the combination of the plasma protease C1 inhibitor, kallikrein 1 and thrombospondin metallopeptidase 1 has a good diagnostic effect on HAE diagnosis, and the area under ROC curve AUC value is 0.925 (fig. 1).
Claims (9)
1. Use of an identification agent for the manufacture of a device for diagnosing hereditary angioedema in a subject, the identification agent specifically identifying one or more proteins selected from the group consisting of:
inhibitors of plasma protease C1, ketohexokinase, phenazine biosynthesis domain proteins, contractile protein alpha chain, profibrinin 1, cathepsin H precursor, IST1 homolog, malate dehydrogenase, Cochlin, disintegrin and metalloproteinase domain-containing protein 10, basement membrane-specific heparan sulfate proteoglycan core protein, kininogen 1, v-assembly domain-containing t-cell activation inhibitor 1, epidermal growth factor precursor, adhesion molecule A, N-acetylated alpha-catenase 2, transmembrane glycoprotein NMB, procollagen endopeptidase enhancer 2, urokinase plasminogen activator surface receptor, thrombospondin disintegrin metallopeptidase 1, cathepsin Z, cathepsin L1, endothelial cell selective adhesion molecule, kallikrein 1, complement component C9, complement component C1, platelet-reactive protein kinase 1, platelet-selective adhesion protein, and the like, Calbindin, complement component C7, aquaporin 2, follicle stimulating hormone beta subunit, protocadherin alpha-C2, vascular endothelial growth factor receptor 2, cadherin-associated family member 5, immunoglobulin heavy chain constant region gamma 4, and aspartic protease a;
preferably, the identification reagent specifically identifies a combination of:
a combination of a plasma protease C1 inhibitor, kallikrein 1 and thrombospondin metallopeptidase 1.
2. Use according to claim 1, wherein the subject is a mammalian subject, preferably a human.
3. The use of claim 1 or 2, wherein the protein is a protein in urine.
4. The use according to claim 1 or 2, wherein the device is a kit or chip.
5. The use according to claim 1 or 2, the identification agent being selected from: mass spectrometric identification of reagents, antibodies or antigen binding fragments thereof.
6. The use of claim 5, wherein the antibody is a monoclonal antibody.
7. The use of claim 5, wherein the mass spectrometry identification reagent comprises a mass spectrometry identification parameter.
8. Use according to claim 1, wherein:
an increased risk of developing or having hereditary vascular edema in a subject is indicated when the expression level of a protein selected from any one or more of: plasma protease C1 inhibitor, ketohexokinase, phenazine biosynthesis domain protein, malate dehydrogenase, kininogen 1, immunoglobulin heavy chain constant region γ 4, v-domain containing t cell activation inhibitor 1, epidermal growth factor precursor, kallikrein 1, aspartic protease a and calcium binding protein; and/or
An increased expression level of a protein selected from any one or more of the following: contractile protein alpha chain, profibrinin 1, cathepsin H precursor, IST1 homolog, Cochlin, disintegrin and metalloprotease domain containing protein 10, basement membrane specific heparan sulfate proteoglycan core protein, junctional adhesion molecule A, N-acetylated alpha-catenated dipeptidase 2, transmembrane glycoprotein NMB, procollagen C-endopeptidase enhancer 2, urokinase plasminogen activator surface receptor, thrombospondin disintegrin metallopeptidase 1, cathepsin Z, cathepsin L1, endothelial cell selective adhesion molecule, complement component C9, complement component C1, complement component C7, aquaporin 2, follicle stimulating hormone beta subunit, protocadherin alpha-C2, vascular endothelial growth factor receptor 2, and calc adhesion-related family member 5.
9. A kit or chip for diagnosing hereditary angioedema comprising an identification reagent that specifically identifies any one or more proteins selected from the group consisting of:
inhibitors of plasma protease C1, ketohexokinase, phenazine biosynthesis domain proteins, contractile protein alpha chain, profibrinin 1, cathepsin H precursor, IST1 homolog, malate dehydrogenase, Cochlin, disintegrin and metalloproteinase domain-containing protein 10, basement membrane-specific heparan sulfate proteoglycan core protein, kininogen 1, v-assembly domain-containing t-cell activation inhibitor 1, epidermal growth factor precursor, adhesion molecule A, N-acetylated alpha-catenase 2, transmembrane glycoprotein NMB, procollagen endopeptidase enhancer 2, urokinase plasminogen activator surface receptor, thrombospondin disintegrin metallopeptidase 1, cathepsin Z, cathepsin L1, endothelial cell selective adhesion molecule, kallikrein 1, complement component C9, complement component C1, platelet-reactive protein kinase 1, platelet-selective adhesion protein, and the like, Calbindin, complement component C7, aquaporin 2, follicle stimulating hormone beta subunit, protocadherin alpha-C2, vascular endothelial growth factor receptor 2, cadherin-related family member 5, immunoglobulin heavy chain constant region gamma 4, aspartic protease a;
preferably, the identifying agent is selected from: mass spectrometric identification of reagents, antibodies or antigen binding fragments thereof;
more preferably, the mass spectrometric identification reagent comprises mass spectrometric identification parameters;
more preferably, the antibody is a monoclonal antibody.
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| WO2024003617A3 (en) * | 2022-06-30 | 2024-02-08 | Takeda Pharmaceutical Company Limited | Protein biomarkers for lanadelumab treatment |
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