CA3059350A1 - Treatment and inhibition of inflammatory lung diseases in patients having risk alleles in the genes encoding il33 and il1rl1 - Google Patents
Treatment and inhibition of inflammatory lung diseases in patients having risk alleles in the genes encoding il33 and il1rl1 Download PDFInfo
- Publication number
- CA3059350A1 CA3059350A1 CA3059350A CA3059350A CA3059350A1 CA 3059350 A1 CA3059350 A1 CA 3059350A1 CA 3059350 A CA3059350 A CA 3059350A CA 3059350 A CA3059350 A CA 3059350A CA 3059350 A1 CA3059350 A1 CA 3059350A1
- Authority
- CA
- Canada
- Prior art keywords
- variant
- antagonist
- seq
- eosinophilic
- subject
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 108700028369 Alleles Proteins 0.000 title claims abstract description 109
- 238000011282 treatment Methods 0.000 title claims description 43
- 230000005764 inhibitory process Effects 0.000 title claims description 18
- 108090000623 proteins and genes Proteins 0.000 title description 41
- 230000002757 inflammatory effect Effects 0.000 title description 16
- 208000019693 Lung disease Diseases 0.000 title description 11
- 102100033500 Interleukin-33 Human genes 0.000 claims abstract description 436
- 108010067003 Interleukin-33 Proteins 0.000 claims abstract description 436
- 239000005557 antagonist Substances 0.000 claims abstract description 205
- 208000006673 asthma Diseases 0.000 claims abstract description 161
- 230000002327 eosinophilic effect Effects 0.000 claims abstract description 114
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 claims abstract description 108
- 208000030853 Asthma-Chronic Obstructive Pulmonary Disease Overlap Syndrome Diseases 0.000 claims abstract description 104
- 108700003107 Interleukin-1 Receptor-Like 1 Proteins 0.000 claims abstract description 103
- 108040006852 interleukin-4 receptor activity proteins Proteins 0.000 claims abstract description 97
- 208000000592 Nasal Polyps Diseases 0.000 claims abstract description 24
- 238000000034 method Methods 0.000 claims description 99
- 210000003979 eosinophil Anatomy 0.000 claims description 57
- 239000000427 antigen Substances 0.000 claims description 54
- 239000012634 fragment Substances 0.000 claims description 54
- 102000036639 antigens Human genes 0.000 claims description 53
- 108091007433 antigens Proteins 0.000 claims description 53
- 102100036706 Interleukin-1 receptor-like 1 Human genes 0.000 claims description 45
- 210000000349 chromosome Anatomy 0.000 claims description 38
- 206010039085 Rhinitis allergic Diseases 0.000 claims description 30
- 201000010105 allergic rhinitis Diseases 0.000 claims description 30
- 101710180389 Interleukin-1 receptor accessory protein Proteins 0.000 claims description 22
- 230000002401 inhibitory effect Effects 0.000 claims description 18
- 238000011161 development Methods 0.000 claims description 8
- 206010068786 Overlap syndrome Diseases 0.000 claims description 7
- 102100039880 Interleukin-1 receptor accessory protein Human genes 0.000 claims description 6
- 206010036790 Productive cough Diseases 0.000 claims description 4
- 210000003802 sputum Anatomy 0.000 claims description 4
- 208000024794 sputum Diseases 0.000 claims description 4
- 210000004369 blood Anatomy 0.000 claims description 3
- 239000008280 blood Substances 0.000 claims description 3
- 102000045959 Interleukin-1 Receptor-Like 1 Human genes 0.000 abstract description 76
- 210000004072 lung Anatomy 0.000 description 73
- 241000699670 Mus sp. Species 0.000 description 61
- 125000003275 alpha amino acid group Chemical group 0.000 description 56
- 241000699666 Mus <mouse, genus> Species 0.000 description 46
- 241000282414 Homo sapiens Species 0.000 description 33
- 210000004027 cell Anatomy 0.000 description 32
- 102000004169 proteins and genes Human genes 0.000 description 32
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 28
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 28
- 239000002953 phosphate buffered saline Substances 0.000 description 28
- 201000010099 disease Diseases 0.000 description 26
- 230000002068 genetic effect Effects 0.000 description 25
- 230000014509 gene expression Effects 0.000 description 23
- 238000004458 analytical method Methods 0.000 description 21
- 101000852968 Homo sapiens Interleukin-1 receptor-like 1 Proteins 0.000 description 20
- 210000001744 T-lymphocyte Anatomy 0.000 description 19
- 239000000284 extract Substances 0.000 description 18
- 101000585365 Homo sapiens Sulfotransferase 2A1 Proteins 0.000 description 17
- 230000000694 effects Effects 0.000 description 17
- 102000004127 Cytokines Human genes 0.000 description 16
- 108090000695 Cytokines Proteins 0.000 description 16
- 102000044594 Interleukin-1 Receptor Accessory Human genes 0.000 description 16
- 239000000523 sample Substances 0.000 description 16
- 102000005962 receptors Human genes 0.000 description 15
- 108020003175 receptors Proteins 0.000 description 15
- 230000001684 chronic effect Effects 0.000 description 14
- 230000011664 signaling Effects 0.000 description 12
- 208000011623 Obstructive Lung disease Diseases 0.000 description 11
- 210000002966 serum Anatomy 0.000 description 11
- 108010035532 Collagen Proteins 0.000 description 10
- 102000003816 Interleukin-13 Human genes 0.000 description 10
- 108090000176 Interleukin-13 Proteins 0.000 description 10
- 208000023504 respiratory system disease Diseases 0.000 description 10
- 102000008186 Collagen Human genes 0.000 description 9
- 101000738771 Homo sapiens Receptor-type tyrosine-protein phosphatase C Proteins 0.000 description 9
- 102000004388 Interleukin-4 Human genes 0.000 description 9
- 108090000978 Interleukin-4 Proteins 0.000 description 9
- 102100037422 Receptor-type tyrosine-protein phosphatase C Human genes 0.000 description 9
- 229920001436 collagen Polymers 0.000 description 9
- 210000002175 goblet cell Anatomy 0.000 description 9
- 230000037361 pathway Effects 0.000 description 9
- 210000001519 tissue Anatomy 0.000 description 9
- 239000000872 buffer Substances 0.000 description 8
- 206010016654 Fibrosis Diseases 0.000 description 7
- 239000003153 chemical reaction reagent Substances 0.000 description 7
- 210000000981 epithelium Anatomy 0.000 description 7
- 230000004761 fibrosis Effects 0.000 description 7
- 230000002829 reductive effect Effects 0.000 description 7
- 238000012360 testing method Methods 0.000 description 7
- 101000960952 Homo sapiens Interleukin-1 receptor accessory protein Proteins 0.000 description 6
- 102000000743 Interleukin-5 Human genes 0.000 description 6
- 108010002616 Interleukin-5 Proteins 0.000 description 6
- 206010025080 Lung consolidation Diseases 0.000 description 6
- 230000008901 benefit Effects 0.000 description 6
- 238000003745 diagnosis Methods 0.000 description 6
- 238000005516 engineering process Methods 0.000 description 6
- 102000046828 human IL1RAP Human genes 0.000 description 6
- 238000007477 logistic regression Methods 0.000 description 6
- 230000007170 pathology Effects 0.000 description 6
- 238000012163 sequencing technique Methods 0.000 description 6
- 230000000391 smoking effect Effects 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 102000010787 Interleukin-4 Receptors Human genes 0.000 description 5
- 108010038486 Interleukin-4 Receptors Proteins 0.000 description 5
- 238000001282 Kruskal–Wallis one-way analysis of variance Methods 0.000 description 5
- 206010035664 Pneumonia Diseases 0.000 description 5
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 5
- 210000001132 alveolar macrophage Anatomy 0.000 description 5
- 230000001413 cellular effect Effects 0.000 description 5
- 230000003247 decreasing effect Effects 0.000 description 5
- 239000003814 drug Substances 0.000 description 5
- 230000006870 function Effects 0.000 description 5
- 238000011534 incubation Methods 0.000 description 5
- 238000002826 magnetic-activated cell sorting Methods 0.000 description 5
- 150000007523 nucleic acids Chemical group 0.000 description 5
- 239000008188 pellet Substances 0.000 description 5
- 238000010149 post-hoc-test Methods 0.000 description 5
- 238000011002 quantification Methods 0.000 description 5
- 239000011780 sodium chloride Substances 0.000 description 5
- 238000011285 therapeutic regimen Methods 0.000 description 5
- 108020004414 DNA Proteins 0.000 description 4
- 102100025137 Early activation antigen CD69 Human genes 0.000 description 4
- 206010015719 Exsanguination Diseases 0.000 description 4
- 241000282412 Homo Species 0.000 description 4
- 101000934374 Homo sapiens Early activation antigen CD69 Proteins 0.000 description 4
- 206010061218 Inflammation Diseases 0.000 description 4
- 102000000589 Interleukin-1 Human genes 0.000 description 4
- 108010002352 Interleukin-1 Proteins 0.000 description 4
- 101000960950 Mus musculus Interleukin-1 receptor accessory protein Proteins 0.000 description 4
- 230000000996 additive effect Effects 0.000 description 4
- 239000000969 carrier Substances 0.000 description 4
- 239000002299 complementary DNA Substances 0.000 description 4
- 238000001514 detection method Methods 0.000 description 4
- 230000004927 fusion Effects 0.000 description 4
- 238000003306 harvesting Methods 0.000 description 4
- 230000036541 health Effects 0.000 description 4
- 230000004054 inflammatory process Effects 0.000 description 4
- 230000004199 lung function Effects 0.000 description 4
- 238000005259 measurement Methods 0.000 description 4
- 230000001404 mediated effect Effects 0.000 description 4
- 230000003340 mental effect Effects 0.000 description 4
- 239000002773 nucleotide Substances 0.000 description 4
- 125000003729 nucleotide group Chemical group 0.000 description 4
- 230000002685 pulmonary effect Effects 0.000 description 4
- 230000009467 reduction Effects 0.000 description 4
- 238000002560 therapeutic procedure Methods 0.000 description 4
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 3
- FWMNVWWHGCHHJJ-SKKKGAJSSA-N 4-amino-1-[(2r)-6-amino-2-[[(2r)-2-[[(2r)-2-[[(2r)-2-amino-3-phenylpropanoyl]amino]-3-phenylpropanoyl]amino]-4-methylpentanoyl]amino]hexanoyl]piperidine-4-carboxylic acid Chemical compound C([C@H](C(=O)N[C@H](CC(C)C)C(=O)N[C@H](CCCCN)C(=O)N1CCC(N)(CC1)C(O)=O)NC(=O)[C@H](N)CC=1C=CC=CC=1)C1=CC=CC=C1 FWMNVWWHGCHHJJ-SKKKGAJSSA-N 0.000 description 3
- 102100021943 C-C motif chemokine 2 Human genes 0.000 description 3
- 101710155857 C-C motif chemokine 2 Proteins 0.000 description 3
- 108010001336 Horseradish Peroxidase Proteins 0.000 description 3
- 101100490443 Mus musculus Acvr1 gene Proteins 0.000 description 3
- 241000700159 Rattus Species 0.000 description 3
- 108020004459 Small interfering RNA Proteins 0.000 description 3
- 101150000629 TGFB1 gene Proteins 0.000 description 3
- 108700012920 TNF Proteins 0.000 description 3
- 101150033527 TNF gene Proteins 0.000 description 3
- 230000002378 acidificating effect Effects 0.000 description 3
- 239000000654 additive Substances 0.000 description 3
- 210000003719 b-lymphocyte Anatomy 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 238000007405 data analysis Methods 0.000 description 3
- 230000007423 decrease Effects 0.000 description 3
- 230000008021 deposition Effects 0.000 description 3
- 239000000428 dust Substances 0.000 description 3
- 210000003743 erythrocyte Anatomy 0.000 description 3
- 230000007614 genetic variation Effects 0.000 description 3
- 238000003205 genotyping method Methods 0.000 description 3
- 239000002663 humin Substances 0.000 description 3
- 210000002865 immune cell Anatomy 0.000 description 3
- 230000028993 immune response Effects 0.000 description 3
- 230000003993 interaction Effects 0.000 description 3
- 239000003446 ligand Substances 0.000 description 3
- 238000012417 linear regression Methods 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 230000003843 mucus production Effects 0.000 description 3
- 230000007935 neutral effect Effects 0.000 description 3
- 108020004707 nucleic acids Proteins 0.000 description 3
- 102000039446 nucleic acids Human genes 0.000 description 3
- 108090000765 processed proteins & peptides Proteins 0.000 description 3
- 208000000884 Airway Obstruction Diseases 0.000 description 2
- 239000001741 Ammonium adipate Substances 0.000 description 2
- 101150076800 B2M gene Proteins 0.000 description 2
- 238000009010 Bradford assay Methods 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 102000016911 Deoxyribonucleases Human genes 0.000 description 2
- 108010053770 Deoxyribonucleases Proteins 0.000 description 2
- 108700022150 Designed Ankyrin Repeat Proteins Proteins 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 108010067306 Fibronectins Proteins 0.000 description 2
- 102000016359 Fibronectins Human genes 0.000 description 2
- 239000012981 Hank's balanced salt solution Substances 0.000 description 2
- 101001076418 Homo sapiens Interleukin-1 receptor type 1 Proteins 0.000 description 2
- 101000998137 Homo sapiens Interleukin-33 Proteins 0.000 description 2
- 102100026016 Interleukin-1 receptor type 1 Human genes 0.000 description 2
- 102000004889 Interleukin-6 Human genes 0.000 description 2
- 108090001005 Interleukin-6 Proteins 0.000 description 2
- 206010025102 Lung infiltration Diseases 0.000 description 2
- 241000124008 Mammalia Species 0.000 description 2
- 206010054949 Metaplasia Diseases 0.000 description 2
- 101100477560 Mus musculus Siglec5 gene Proteins 0.000 description 2
- 102100032870 Natural cytotoxicity triggering receptor 1 Human genes 0.000 description 2
- 229940124158 Protease/peptidase inhibitor Drugs 0.000 description 2
- 241000283984 Rodentia Species 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 238000002835 absorbance Methods 0.000 description 2
- 150000001413 amino acids Chemical class 0.000 description 2
- 230000004888 barrier function Effects 0.000 description 2
- 102000023732 binding proteins Human genes 0.000 description 2
- 108091008324 binding proteins Proteins 0.000 description 2
- 229960000074 biopharmaceutical Drugs 0.000 description 2
- 230000000903 blocking effect Effects 0.000 description 2
- 210000000621 bronchi Anatomy 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- 208000035475 disorder Diseases 0.000 description 2
- 210000002919 epithelial cell Anatomy 0.000 description 2
- 238000010195 expression analysis Methods 0.000 description 2
- MHMNJMPURVTYEJ-UHFFFAOYSA-N fluorescein-5-isothiocyanate Chemical compound O1C(=O)C2=CC(N=C=S)=CC=C2C21C1=CC=C(O)C=C1OC1=CC(O)=CC=C21 MHMNJMPURVTYEJ-UHFFFAOYSA-N 0.000 description 2
- 102000055002 human IL1RL1 Human genes 0.000 description 2
- 102000045906 human IL33 Human genes 0.000 description 2
- 238000003018 immunoassay Methods 0.000 description 2
- 230000008595 infiltration Effects 0.000 description 2
- 238000001764 infiltration Methods 0.000 description 2
- 230000004968 inflammatory condition Effects 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- 230000002934 lysing effect Effects 0.000 description 2
- 229920002521 macromolecule Polymers 0.000 description 2
- 238000010197 meta-analysis Methods 0.000 description 2
- 230000015689 metaplastic ossification Effects 0.000 description 2
- 229940062713 mite extract Drugs 0.000 description 2
- 244000052769 pathogen Species 0.000 description 2
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 2
- 229920001184 polypeptide Polymers 0.000 description 2
- 102000004196 processed proteins & peptides Human genes 0.000 description 2
- 230000001681 protective effect Effects 0.000 description 2
- 238000007634 remodeling Methods 0.000 description 2
- 150000003384 small molecules Chemical class 0.000 description 2
- 238000007619 statistical method Methods 0.000 description 2
- 150000003431 steroids Chemical class 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 102000040650 (ribonucleotides)n+m Human genes 0.000 description 1
- NFGXHKASABOEEW-UHFFFAOYSA-N 1-methylethyl 11-methoxy-3,7,11-trimethyl-2,4-dodecadienoate Chemical compound COC(C)(C)CCCC(C)CC=CC(C)=CC(=O)OC(C)C NFGXHKASABOEEW-UHFFFAOYSA-N 0.000 description 1
- 208000036065 Airway Remodeling Diseases 0.000 description 1
- 208000012657 Atopic disease Diseases 0.000 description 1
- 102100024222 B-lymphocyte antigen CD19 Human genes 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- 108091079001 CRISPR RNA Proteins 0.000 description 1
- 241000700198 Cavia Species 0.000 description 1
- 201000003883 Cystic fibrosis Diseases 0.000 description 1
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 238000002965 ELISA Methods 0.000 description 1
- 208000027004 Eosinophilic disease Diseases 0.000 description 1
- 206010051841 Exposure to allergen Diseases 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 1
- 108020005004 Guide RNA Proteins 0.000 description 1
- 101000980825 Homo sapiens B-lymphocyte antigen CD19 Proteins 0.000 description 1
- 101001046686 Homo sapiens Integrin alpha-M Proteins 0.000 description 1
- 101001057504 Homo sapiens Interferon-stimulated gene 20 kDa protein Proteins 0.000 description 1
- 101001055144 Homo sapiens Interleukin-2 receptor subunit alpha Proteins 0.000 description 1
- 101000917826 Homo sapiens Low affinity immunoglobulin gamma Fc region receptor II-a Proteins 0.000 description 1
- 101000917824 Homo sapiens Low affinity immunoglobulin gamma Fc region receptor II-b Proteins 0.000 description 1
- 101000917858 Homo sapiens Low affinity immunoglobulin gamma Fc region receptor III-A Proteins 0.000 description 1
- 101000917839 Homo sapiens Low affinity immunoglobulin gamma Fc region receptor III-B Proteins 0.000 description 1
- 102000039996 IL-1 family Human genes 0.000 description 1
- 108091069196 IL-1 family Proteins 0.000 description 1
- 102100022338 Integrin alpha-M Human genes 0.000 description 1
- 102100022297 Integrin alpha-X Human genes 0.000 description 1
- 102100026878 Interleukin-2 receptor subunit alpha Human genes 0.000 description 1
- 108010052014 Liberase Proteins 0.000 description 1
- 102100029204 Low affinity immunoglobulin gamma Fc region receptor II-a Human genes 0.000 description 1
- 102100029185 Low affinity immunoglobulin gamma Fc region receptor III-B Human genes 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 101100437231 Mus musculus B2m gene Proteins 0.000 description 1
- 101000863881 Mus musculus Sialic acid-binding Ig-like lectin 5 Proteins 0.000 description 1
- 101100206400 Mus musculus Tgfb1 gene Proteins 0.000 description 1
- 101100046526 Mus musculus Tnf gene Proteins 0.000 description 1
- 102000005717 Myeloma Proteins Human genes 0.000 description 1
- 108010045503 Myeloma Proteins Proteins 0.000 description 1
- 108010004217 Natural Cytotoxicity Triggering Receptor 1 Proteins 0.000 description 1
- 108020004711 Nucleic Acid Probes Proteins 0.000 description 1
- 108091028043 Nucleic acid sequence Proteins 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 229920001213 Polysorbate 20 Polymers 0.000 description 1
- 241000288906 Primates Species 0.000 description 1
- 238000010802 RNA extraction kit Methods 0.000 description 1
- 238000011529 RT qPCR Methods 0.000 description 1
- 108091028113 Trans-activating crRNA Proteins 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000036428 airway hyperreactivity Effects 0.000 description 1
- 208000037883 airway inflammation Diseases 0.000 description 1
- 239000013566 allergen Substances 0.000 description 1
- 230000000692 anti-sense effect Effects 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 238000001815 biotherapy Methods 0.000 description 1
- 238000004820 blood count Methods 0.000 description 1
- 229940098773 bovine serum albumin Drugs 0.000 description 1
- 239000006285 cell suspension Substances 0.000 description 1
- 230000003833 cell viability Effects 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 208000037976 chronic inflammation Diseases 0.000 description 1
- 208000037893 chronic inflammatory disorder Diseases 0.000 description 1
- 235000019504 cigarettes Nutrition 0.000 description 1
- 230000000295 complement effect Effects 0.000 description 1
- 239000002131 composite material Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000012790 confirmation Methods 0.000 description 1
- 238000007596 consolidation process Methods 0.000 description 1
- 239000003246 corticosteroid Substances 0.000 description 1
- 229960001334 corticosteroids Drugs 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 230000016396 cytokine production Effects 0.000 description 1
- 230000007123 defense Effects 0.000 description 1
- 238000012217 deletion Methods 0.000 description 1
- 230000037430 deletion Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- BFMYDTVEBKDAKJ-UHFFFAOYSA-L disodium;(2',7'-dibromo-3',6'-dioxido-3-oxospiro[2-benzofuran-1,9'-xanthene]-4'-yl)mercury;hydrate Chemical compound O.[Na+].[Na+].O1C(=O)C2=CC=CC=C2C21C1=CC(Br)=C([O-])C([Hg])=C1OC1=C2C=C(Br)C([O-])=C1 BFMYDTVEBKDAKJ-UHFFFAOYSA-L 0.000 description 1
- 230000002888 effect on disease Effects 0.000 description 1
- 238000001943 fluorescence-activated cell sorting Methods 0.000 description 1
- 238000007490 hematoxylin and eosin (H&E) staining Methods 0.000 description 1
- 206010020718 hyperplasia Diseases 0.000 description 1
- 230000004047 hyperresponsiveness Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000002779 inactivation Effects 0.000 description 1
- 208000027866 inflammatory disease Diseases 0.000 description 1
- 238000003780 insertion Methods 0.000 description 1
- 230000037431 insertion Effects 0.000 description 1
- 229940028885 interleukin-4 Drugs 0.000 description 1
- 229940100602 interleukin-5 Drugs 0.000 description 1
- 108020001756 ligand binding domains Proteins 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 239000011344 liquid material Substances 0.000 description 1
- 239000006166 lysate Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 238000002493 microarray Methods 0.000 description 1
- 230000000116 mitigating effect Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 210000003097 mucus Anatomy 0.000 description 1
- 230000001338 necrotic effect Effects 0.000 description 1
- 230000003448 neutrophilic effect Effects 0.000 description 1
- 238000010606 normalization Methods 0.000 description 1
- 239000002853 nucleic acid probe Substances 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 230000008506 pathogenesis Effects 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- KHIWWQKSHDUIBK-UHFFFAOYSA-N periodic acid Chemical compound OI(=O)(=O)=O KHIWWQKSHDUIBK-UHFFFAOYSA-N 0.000 description 1
- 210000005259 peripheral blood Anatomy 0.000 description 1
- 239000011886 peripheral blood Substances 0.000 description 1
- 230000000505 pernicious effect Effects 0.000 description 1
- 238000005191 phase separation Methods 0.000 description 1
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 1
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 230000000770 proinflammatory effect Effects 0.000 description 1
- 238000000751 protein extraction Methods 0.000 description 1
- 208000010707 pulmonary consolidation Diseases 0.000 description 1
- 239000002464 receptor antagonist Substances 0.000 description 1
- 229940044551 receptor antagonist Drugs 0.000 description 1
- 230000000306 recurrent effect Effects 0.000 description 1
- 230000008439 repair process Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 230000004043 responsiveness Effects 0.000 description 1
- 239000012146 running buffer Substances 0.000 description 1
- 238000003118 sandwich ELISA Methods 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 238000013207 serial dilution Methods 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 230000009131 signaling function Effects 0.000 description 1
- 239000000779 smoke Substances 0.000 description 1
- 239000011343 solid material Substances 0.000 description 1
- 239000012089 stop solution Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 230000003319 supportive effect Effects 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 230000007838 tissue remodeling Effects 0.000 description 1
- 238000011144 upstream manufacturing Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/24—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against cytokines, lymphokines or interferons
- C07K16/244—Interleukins [IL]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
- C07K16/2866—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against receptors for cytokines, lymphokines, interferons
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
- C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
- C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
- C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
- A61K2039/507—Comprising a combination of two or more separate antibodies
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
- C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- C12Q2600/00—Oligonucleotides characterized by their use
- C12Q2600/106—Pharmacogenomics, i.e. genetic variability in individual responses to drugs and drug metabolism
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- C12Q2600/00—Oligonucleotides characterized by their use
- C12Q2600/112—Disease subtyping, staging or classification
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- C12Q2600/00—Oligonucleotides characterized by their use
- C12Q2600/156—Polymorphic or mutational markers
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- General Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Genetics & Genomics (AREA)
- Medicinal Chemistry (AREA)
- Immunology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pulmonology (AREA)
- Molecular Biology (AREA)
- Biophysics (AREA)
- Biochemistry (AREA)
- Analytical Chemistry (AREA)
- Wood Science & Technology (AREA)
- Zoology (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Biotechnology (AREA)
- Pathology (AREA)
- General Engineering & Computer Science (AREA)
- Microbiology (AREA)
- Physics & Mathematics (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Peptides Or Proteins (AREA)
- Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)
- Investigating Or Analysing Biological Materials (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US201762485077P | 2017-04-13 | 2017-04-13 | |
| US62/485,077 | 2017-04-13 | ||
| PCT/US2018/023266 WO2018190990A1 (en) | 2017-04-13 | 2018-03-20 | Treatment and inhibition of inflammatory lung diseases in patients having risk alleles in the genes encoding il33 and il1rl1 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA3059350A1 true CA3059350A1 (en) | 2018-10-18 |
Family
ID=61911717
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA3059350A Pending CA3059350A1 (en) | 2017-04-13 | 2018-03-20 | Treatment and inhibition of inflammatory lung diseases in patients having risk alleles in the genes encoding il33 and il1rl1 |
Country Status (11)
| Country | Link |
|---|---|
| US (2) | US11708415B2 (enExample) |
| EP (3) | EP3957752B1 (enExample) |
| JP (3) | JP7321939B2 (enExample) |
| KR (2) | KR102751957B1 (enExample) |
| CN (1) | CN110431240A (enExample) |
| AU (3) | AU2018252974B2 (enExample) |
| CA (1) | CA3059350A1 (enExample) |
| IL (2) | IL269873B2 (enExample) |
| MX (2) | MX2019012171A (enExample) |
| SG (1) | SG11201909457XA (enExample) |
| WO (1) | WO2018190990A1 (enExample) |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU2018252974B2 (en) * | 2017-04-13 | 2024-10-17 | Regeneron Pharmaceuticals, Inc. | Treatment and inhibition of inflammatory lung diseases in patients having risk alleles in the genes encoding IL33 and IL1RL1 |
| CN118994394A (zh) | 2017-06-12 | 2024-11-22 | 蓝鳍生物医药公司 | 抗-il1rap抗体和抗体药物缀合物 |
| JP7165618B2 (ja) * | 2019-04-23 | 2022-11-04 | ジェネシスヘルスケア株式会社 | アレルギー性鼻炎のリスクを判定する方法 |
| MA55807A (fr) * | 2019-05-01 | 2022-03-09 | Regeneron Pharma | Méthodes de traitement ou de prévention de l'asthme par administration d'un antagoniste d'il-33 |
| MX2022000649A (es) | 2019-07-16 | 2022-06-08 | Sanofi Biotechnology | Metodos para tratar o prevenir el asma mediante la administracion de un antagonista de il-4r. |
| MX2024005769A (es) * | 2021-11-11 | 2024-05-24 | Regeneron Pharma | Tratamiento de la enfermedad pulmonar basado en la estratificacion de puntuacion de riesgo poligenico para la interleucina 33 (il-33). |
Family Cites Families (33)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6323334B1 (en) | 1999-09-24 | 2001-11-27 | Millennium Pharmaceuticals, Inc. | Nucleic acid molecules encoding a 103 gene product and uses therefor |
| EP2990420B1 (en) | 2000-05-26 | 2016-12-21 | Immunex Corporation | Use of interleukin-4 receptor antibodies and compositions thereof |
| WO2005047331A2 (en) | 2003-11-07 | 2005-05-26 | Immunex Corporation | Antibodies that bind interleukin-4 receptor |
| NZ549040A (en) | 2004-02-17 | 2009-07-31 | Schering Corp | Use for interleukin-33 (IL33) and the IL-33 receptor complex |
| CN101426518A (zh) * | 2006-01-11 | 2009-05-06 | 艾罗文斯公司 | 用于治疗人类和非-人类灵长类中哮喘的方法和组合物 |
| FR2900817B1 (fr) * | 2006-05-12 | 2008-12-19 | Gambro Lundia Ab | Bandage a usage medical pour un tube implante dans un patient, ainsi que le procede d'application de ce bandage sur la peau d'un patient |
| CN1896275B (zh) * | 2006-06-29 | 2010-04-07 | 四川大学华西医院 | 一种检测与慢性阻塞性肺部疾病相关的snp的pcr试剂盒 |
| US7560530B1 (en) | 2006-07-20 | 2009-07-14 | Schering Corporation | IL-33 receptor |
| US7608693B2 (en) | 2006-10-02 | 2009-10-27 | Regeneron Pharmaceuticals, Inc. | High affinity human antibodies to human IL-4 receptor |
| WO2008054606A2 (en) | 2006-10-02 | 2008-05-08 | Regeneron Pharmaceuticals, Inc. | High affinity human antibodies to human il-4 receptor |
| US8092804B2 (en) | 2007-12-21 | 2012-01-10 | Medimmune Limited | Binding members for interleukin-4 receptor alpha (IL-4Rα)-173 |
| US8367333B2 (en) * | 2008-12-12 | 2013-02-05 | Decode Genetics Ehf. | Genetic variants as markers for use in diagnosis, prognosis and treatment of eosinophilia, asthma, and myocardial infarction |
| WO2011031600A1 (en) | 2009-09-10 | 2011-03-17 | Schering Corporation | Use of il-33 antagonists to treat fibrotic disease |
| BR112013021473A2 (pt) | 2011-02-23 | 2020-08-04 | F. Hoffmann-La Roche Ag | anticorpos contra il33r humano e seus usos |
| US9090694B2 (en) | 2012-04-30 | 2015-07-28 | Janssen Biotech, Inc. | ST2L antibody antagonists |
| JO3623B1 (ar) | 2012-05-18 | 2020-08-27 | Amgen Inc | البروتينات المرتبطة بمولد المستضاد st2 |
| HUE064945T2 (hu) | 2012-08-21 | 2024-04-28 | Sanofi Biotechnology | Eljárások asztma kezelésére vagy megelõzésére IL-4R antagonista beadásával |
| CA2894219C (en) * | 2012-12-10 | 2020-08-11 | Vib Vzw | Novel interleukin-33 inhibitors |
| JO3532B1 (ar) * | 2013-03-13 | 2020-07-05 | Regeneron Pharma | الأجسام المضادة لمضاد انترلوكين-33 واستعمالاتها |
| MX364591B (es) * | 2013-03-15 | 2019-05-02 | Regeneron Pharma | Antagonistas de il-33 y usos de estos. |
| TWI682781B (zh) | 2013-07-11 | 2020-01-21 | 美商再生元醫藥公司 | 藉由投與ｉｌ－４ｒ抑制劑治療嗜酸性食道炎的方法 |
| CA3190793A1 (en) | 2013-12-26 | 2015-07-02 | Mitsubishi Tanabe Pharma Corporation | Human anti-il-33 neutralizing monoclonal antibody |
| AU2015204674B2 (en) | 2014-01-10 | 2020-09-03 | Anaptysbio, Inc. | Antibodies directed against interleukin-33 (IL-33) |
| IL315136A (en) * | 2014-02-21 | 2024-10-01 | Sanofi Biotechnology | Methods for treating or preventing asthma by administering an il-4rantagonist |
| NO2785538T3 (enExample) | 2014-05-07 | 2018-08-04 | ||
| CN107109494B (zh) | 2014-11-10 | 2023-10-27 | 豪夫迈·罗氏有限公司 | Il-33介导型疾病的治疗方法和诊断方法 |
| CA2960297A1 (en) | 2014-11-10 | 2016-05-19 | Genentech, Inc. | Anti-interleukin-33 antibodies and uses thereof |
| EP3218412A1 (en) * | 2014-11-14 | 2017-09-20 | Sanofi Biotechnology | Methods for treating chronic sinusitis with nasal polyps by administering an il-4r antagonist |
| CN104531689A (zh) * | 2014-12-12 | 2015-04-22 | 上海交通大学医学院附属新华医院 | 与哮喘相关的基因单核苷酸多态性位点、预测哮喘的试剂盒及其应用 |
| NZ736026A (en) | 2015-03-31 | 2023-02-24 | Medimmune Ltd | A novel il33 form, mutated forms of il33, antibodies, assays and methods of using the same |
| MX2018004170A (es) * | 2015-10-06 | 2018-06-06 | Regeneron Pharma | Biomarcadores relacionados con enfermedades mediadas por interleucina-33 (il-33) y usos de los mismos. |
| TWI857389B (zh) | 2016-12-01 | 2024-10-01 | 美商再生元醫藥公司 | 治療發炎症狀的方法 |
| AU2018252974B2 (en) * | 2017-04-13 | 2024-10-17 | Regeneron Pharmaceuticals, Inc. | Treatment and inhibition of inflammatory lung diseases in patients having risk alleles in the genes encoding IL33 and IL1RL1 |
-
2018
- 2018-03-20 AU AU2018252974A patent/AU2018252974B2/en active Active
- 2018-03-20 KR KR1020237039438A patent/KR102751957B1/ko active Active
- 2018-03-20 WO PCT/US2018/023266 patent/WO2018190990A1/en not_active Ceased
- 2018-03-20 EP EP21162316.0A patent/EP3957752B1/en active Active
- 2018-03-20 EP EP18716446.2A patent/EP3610041A1/en not_active Withdrawn
- 2018-03-20 IL IL269873A patent/IL269873B2/en unknown
- 2018-03-20 IL IL314591A patent/IL314591A/en unknown
- 2018-03-20 JP JP2019555834A patent/JP7321939B2/ja active Active
- 2018-03-20 MX MX2019012171A patent/MX2019012171A/es unknown
- 2018-03-20 CA CA3059350A patent/CA3059350A1/en active Pending
- 2018-03-20 SG SG11201909457X patent/SG11201909457XA/en unknown
- 2018-03-20 EP EP25162154.6A patent/EP4549586A3/en active Pending
- 2018-03-20 KR KR1020197030870A patent/KR102605045B1/ko active Active
- 2018-03-20 CN CN201880018649.2A patent/CN110431240A/zh active Pending
-
2019
- 2019-10-10 MX MX2024002689A patent/MX2024002689A/es unknown
- 2019-10-11 US US16/599,709 patent/US11708415B2/en active Active
-
2023
- 2023-06-07 US US18/330,736 patent/US20230374145A1/en active Pending
- 2023-07-26 JP JP2023121229A patent/JP7557581B2/ja active Active
-
2024
- 2024-09-13 JP JP2024158740A patent/JP2024163308A/ja active Pending
- 2024-09-30 AU AU2024220212A patent/AU2024220212A1/en active Pending
- 2024-09-30 AU AU2024220214A patent/AU2024220214A1/en active Pending
Also Published As
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US20230374145A1 (en) | Treatment And Inhibition Of Inflammatory Lung Diseases In Patients Having Risk Alleles In The Genes Encoding IL33 And IL1RL1 | |
| US20240209102A1 (en) | Methods of treating inflammatory conditions | |
| US20130177575A1 (en) | Novel therapeutic target and diagnostic marker for asthma and related conditions | |
| KR20160122756A (ko) | 인간 페리오스틴을 검출하기 위한 신규 검정법 | |
| HK40069286A (en) | Treatment and inhibition of inflammatory lung diseases in patients having risk alleles in the genes encoding il33 and il1rl1 | |
| Emancipator | Prospects and perspectives on IgA nephropathy from animal models | |
| RU2776241C2 (ru) | Лечение и ингибирование воспалительных заболеваний легких у пациентов с аллелями риска в генах, кодирующих il33 и il1rl1 | |
| US12466876B2 (en) | Testis development related protein antibodies | |
| NZ794842A (en) | Methods of treating inflammatory conditions | |
| EA043630B1 (ru) | Способы лечения воспалительных состояний |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request |
Effective date: 20210412 |
|
| EEER | Examination request |
Effective date: 20210412 |
|
| EEER | Examination request |
Effective date: 20210412 |
|
| EEER | Examination request |
Effective date: 20210412 |
|
| EEER | Examination request |
Effective date: 20210412 |
|
| EEER | Examination request |
Effective date: 20210412 |
|
| EEER | Examination request |
Effective date: 20210412 |
|
| EEER | Examination request |
Effective date: 20210412 |