CN109844130B - 细胞vamp切割测定 - Google Patents

细胞vamp切割测定 Download PDF

Info

Publication number
CN109844130B
CN109844130B CN201780063220.0A CN201780063220A CN109844130B CN 109844130 B CN109844130 B CN 109844130B CN 201780063220 A CN201780063220 A CN 201780063220A CN 109844130 B CN109844130 B CN 109844130B
Authority
CN
China
Prior art keywords
bont
vamp
antibody
seq
cleavage
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.)
Active
Application number
CN201780063220.0A
Other languages
English (en)
Chinese (zh)
Other versions
CN109844130A (zh
Inventor
B·格雷
V·加德
M·比尔得
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Ipsen Biopharm Ltd
Original Assignee
Ipsen Biopharm Ltd
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Ipsen Biopharm Ltd filed Critical Ipsen Biopharm Ltd
Priority to CN202411324418.8A priority Critical patent/CN119529053A/zh
Publication of CN109844130A publication Critical patent/CN109844130A/zh
Application granted granted Critical
Publication of CN109844130B publication Critical patent/CN109844130B/zh
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K14/00Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/46Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • C07K14/47Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K14/00Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/195Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from bacteria
    • C07K14/33Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from bacteria from Clostridium (G)
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K16/00Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
    • C07K16/12Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from bacteria
    • C07K16/1267Gram-positive bacteria
    • C07K16/1282Clostridium (G)
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K16/00Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
    • C07K16/18Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • CCHEMISTRY; METALLURGY
    • C12BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12QMEASURING 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
    • C12Q1/00Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/34Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving hydrolase
    • C12Q1/37Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving hydrolase involving peptidase or proteinase
    • GPHYSICS
    • G01MEASURING; TESTING
    • G01NINVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/569Immunoassay; Biospecific binding assay; Materials therefor for microorganisms, e.g. protozoa, bacteria, viruses
    • G01N33/56911Bacteria
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K2317/00Immunoglobulins specific features
    • C07K2317/30Immunoglobulins specific features characterized by aspects of specificity or valency
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K2317/00Immunoglobulins specific features
    • C07K2317/90Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
    • C07K2317/92Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K2319/00Fusion polypeptide
    • GPHYSICS
    • G01MEASURING; TESTING
    • G01NINVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/195Assays involving biological materials from specific organisms or of a specific nature from bacteria
    • G01N2333/33Assays involving biological materials from specific organisms or of a specific nature from bacteria from Clostridium (G)

Landscapes

  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Organic Chemistry (AREA)
  • Molecular Biology (AREA)
  • Immunology (AREA)
  • Engineering & Computer Science (AREA)
  • General Health & Medical Sciences (AREA)
  • Biochemistry (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Medicinal Chemistry (AREA)
  • Biophysics (AREA)
  • Genetics & Genomics (AREA)
  • Zoology (AREA)
  • Hematology (AREA)
  • Urology & Nephrology (AREA)
  • Biomedical Technology (AREA)
  • Biotechnology (AREA)
  • Physics & Mathematics (AREA)
  • Analytical Chemistry (AREA)
  • Microbiology (AREA)
  • Wood Science & Technology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Food Science & Technology (AREA)
  • General Physics & Mathematics (AREA)
  • Virology (AREA)
  • Cell Biology (AREA)
  • Pathology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Engineering & Computer Science (AREA)
  • Toxicology (AREA)
  • Peptides Or Proteins (AREA)
  • Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)
  • Enzymes And Modification Thereof (AREA)
  • Apparatus Associated With Microorganisms And Enzymes (AREA)
CN201780063220.0A 2016-10-18 2017-10-18 细胞vamp切割测定 Active CN109844130B (zh)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202411324418.8A CN119529053A (zh) 2016-10-18 2017-10-18 细胞vamp切割测定

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
EP16194390.7A EP3312290A1 (en) 2016-10-18 2016-10-18 Cellular vamp cleavage assay
EP16194390.7 2016-10-18
PCT/EP2017/076569 WO2018073288A1 (en) 2016-10-18 2017-10-18 Cellular vamp cleavage assay

Related Child Applications (1)

Application Number Title Priority Date Filing Date
CN202411324418.8A Division CN119529053A (zh) 2016-10-18 2017-10-18 细胞vamp切割测定

Publications (2)

Publication Number Publication Date
CN109844130A CN109844130A (zh) 2019-06-04
CN109844130B true CN109844130B (zh) 2024-10-11

Family

ID=57208094

Family Applications (2)

Application Number Title Priority Date Filing Date
CN201780063220.0A Active CN109844130B (zh) 2016-10-18 2017-10-18 细胞vamp切割测定
CN202411324418.8A Pending CN119529053A (zh) 2016-10-18 2017-10-18 细胞vamp切割测定

Family Applications After (1)

Application Number Title Priority Date Filing Date
CN202411324418.8A Pending CN119529053A (zh) 2016-10-18 2017-10-18 细胞vamp切割测定

Country Status (5)

Country Link
US (2) US11193931B2 (https=)
EP (2) EP3312290A1 (https=)
JP (3) JP7127019B2 (https=)
CN (2) CN109844130B (https=)
WO (1) WO2018073288A1 (https=)

Families Citing this family (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2825370A1 (en) 2010-12-22 2012-06-28 President And Fellows Of Harvard College Continuous directed evolution
WO2015134121A2 (en) 2014-01-20 2015-09-11 President And Fellows Of Harvard College Negative selection and stringency modulation in continuous evolution systems
WO2016077052A2 (en) 2014-10-22 2016-05-19 President And Fellows Of Harvard College Evolution of proteases
WO2016168631A1 (en) 2015-04-17 2016-10-20 President And Fellows Of Harvard College Vector-based mutagenesis system
WO2017015545A1 (en) 2015-07-22 2017-01-26 President And Fellows Of Harvard College Evolution of site-specific recombinases
US11524983B2 (en) 2015-07-23 2022-12-13 President And Fellows Of Harvard College Evolution of Bt toxins
WO2017019895A1 (en) 2015-07-30 2017-02-02 President And Fellows Of Harvard College Evolution of talens
IL310721B2 (en) 2015-10-23 2025-11-01 Harvard College Nucleobase editors and uses thereof
EP3481852B1 (en) * 2016-07-08 2022-12-07 Children's Medical Center Corporation A novel botulinum neurotoxin and its derivatives
EP3312290A1 (en) 2016-10-18 2018-04-25 Ipsen Biopharm Limited Cellular vamp cleavage assay
US10751394B2 (en) * 2016-10-25 2020-08-25 Cellsnap Llc Neurotoxins and uses thereof
US11447809B2 (en) 2017-07-06 2022-09-20 President And Fellows Of Harvard College Evolution of tRNA synthetases
US12060553B2 (en) 2017-08-25 2024-08-13 President And Fellows Of Harvard College Evolution of BoNT peptidases
WO2019056002A1 (en) 2017-09-18 2019-03-21 President And Fellows Of Harvard College CONTINUOUS EVOLUTION FOR STABILIZED PROTEINS
US11707510B2 (en) * 2018-02-16 2023-07-25 Preclinics Discovery Gmbh Nucleic acid-based botulinum neurotoxin for therapeutic use
WO2019241649A1 (en) 2018-06-14 2019-12-19 President And Fellows Of Harvard College Evolution of cytidine deaminases
KR102017240B1 (ko) 2018-08-23 2019-09-02 주식회사 하울바이오 Snare 복합체를 억제하는 항-vamp2 항체 및 이의 용도
US20220259269A1 (en) * 2019-07-15 2022-08-18 President And Fellows Of Harvard College Evolved botulinum neurotoxins and uses thereof

Family Cites Families (69)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5223409A (en) 1988-09-02 1993-06-29 Protein Engineering Corp. Directed evolution of novel binding proteins
US6172197B1 (en) 1991-07-10 2001-01-09 Medical Research Council Methods for producing members of specific binding pairs
GB9206318D0 (en) 1992-03-24 1992-05-06 Cambridge Antibody Tech Binding substances
GB9015198D0 (en) 1990-07-10 1990-08-29 Brien Caroline J O Binding substance
US5962255A (en) 1992-03-24 1999-10-05 Cambridge Antibody Technology Limited Methods for producing recombinant vectors
PT1024191E (pt) 1991-12-02 2008-12-22 Medical Res Council Produção de auto-anticorpos a partir de reportórios de segmentos de anticorpo e exibidos em fagos
ES2156149T3 (es) 1992-12-04 2001-06-16 Medical Res Council Proteinas de union multivalente y multiespecificas, su fabricacion y su uso.
GB9313509D0 (en) 1993-06-30 1993-08-11 Medical Res Council Chemisynthetic libraries
US7227010B2 (en) * 1993-09-21 2007-06-05 United States Of America As Represented By The Secretary Of The Army Recombinant light chains of botulinum neurotoxins and light chain fusion proteins for use in research and clinical therapy
SE9304060D0 (sv) 1993-12-06 1993-12-06 Bioinvent Int Ab Sätt att selektera specifika bakteriofager
GB9411138D0 (en) * 1994-06-03 1994-07-27 Microbiological Res Authority Toxin assay
US5962637A (en) * 1994-06-03 1999-10-05 Microbiological Research Authority Toxin assay
GB9500851D0 (en) 1995-01-17 1995-03-08 Bionvent International Ab Method of selecting specific bacteriophages
GB9508204D0 (en) 1995-04-21 1995-06-07 Speywood Lab Ltd A novel agent able to modify peripheral afferent function
US6169074B1 (en) 1996-03-18 2001-01-02 The Regents Of The University Of California Peptide inhibitors of neurotransmitter secretion by neuronal cells
GB9617671D0 (en) 1996-08-23 1996-10-02 Microbiological Res Authority Recombinant toxin fragments
GB9818548D0 (en) 1998-08-25 1998-10-21 Microbiological Res Authority Treatment of mucas hypersecretion
US6641820B1 (en) 2000-01-19 2003-11-04 Allergan, Inc. Clostridial toxin derivatives and methods to treat pain
US7138127B1 (en) 2000-01-19 2006-11-21 Allergan, Inc. Clostridial toxin derivatives and methods for treating pain
FR2809733B1 (fr) * 2000-06-02 2004-04-30 Inst Nat Sante Rech Med Substrat peptidique reconnu par la toxine botulique de type bont/b et son utilisation pour doser et/ou detecter ladite toxine ou des inhibiteurs correspondants
CA2428270C (en) * 2000-11-06 2013-07-02 Leonard A. Smith Recombinant light chains of botulinum neurotoxins and light chain fusion proteins for use in research and clinical therapy
GB0115581D0 (en) * 2001-06-26 2001-08-15 Glaxo Group Ltd Method of mass spectometry
GB0321344D0 (en) 2003-09-11 2003-10-15 Health Prot Agency Re-targeted toxin conjugates
US7611856B2 (en) * 2003-11-05 2009-11-03 Los Alamos National Security, Llc Mass spectrometry-based methods for detection and differentiation of botulinum neurotoxins
US7514088B2 (en) 2005-03-15 2009-04-07 Allergan, Inc. Multivalent Clostridial toxin derivatives and methods of their use
DE602005011458D1 (de) 2004-09-01 2009-01-15 Allergan Inc Abbaubare clostridientoxine
DE102004043009A1 (de) 2004-09-06 2006-03-23 Toxogen Gmbh Transportprotein zum Einbringen chemischer Verbindungen in Nervenzellen
GB0425795D0 (en) 2004-11-24 2004-12-22 Givaudan Sa Composition
AU2005311098B2 (en) 2004-12-01 2011-08-11 Allergan, Inc. Non-cytotoxic protein conjugates
GB0426397D0 (en) 2004-12-01 2005-01-05 Health Prot Agency Fusion proteins
AU2006227816B2 (en) 2005-03-15 2012-04-05 Allergan, Inc. Modified clostridial toxins with enhanced targeting capabilities for endogenous clostridial toxin receptor systems
DE102005019302A1 (de) 2005-04-26 2006-11-16 Toxogen Gmbh Carrier zum Targeting von Nervenzellen
ATE518882T1 (de) 2005-09-19 2011-08-15 Allergan Inc Mit clostridientoxin aktivierbare clostridientoxine
EP2001902B1 (en) 2006-03-14 2013-03-27 Allergan, Inc. Modified clostridial toxins with altered targeting capabilities for clostridial toxin target cells
GB0610867D0 (en) 2006-06-01 2006-07-12 Syntaxin Ltd Treatment of pain
US8753831B2 (en) * 2007-06-05 2014-06-17 City Of Hope Methods for detection of botulinum neurotoxin
WO2009035476A1 (en) * 2007-09-14 2009-03-19 Biosentinel, Llc Resonance energy transfer assay with cleavage sequence and spacer
US8940477B2 (en) * 2007-11-08 2015-01-27 Wisconsin Alumni Research Foundation Method of detecting botulinum neurotoxin and antibodies that neutralize botulinum neurotoxin action
CN102083451A (zh) 2008-06-12 2011-06-01 赛恩泰新公司 癌症的抑制
CA2727082C (en) 2008-06-12 2019-02-26 Syntaxin Limited Fusion proteins for use in suppression of acromegaly
GB0815264D0 (en) 2008-08-21 2008-09-24 Syntaxin Ltd Non-cytotoxic proteins
GB0820970D0 (en) 2008-11-17 2008-12-24 Syntaxin Ltd Suppression of cancer
US20100303791A1 (en) 2009-05-29 2010-12-02 Allergan, Inc. Methods of Treating Chronic Neurogenic Inflammation Using Glucagon Like Hormone Retargeted Endopepidases
US20100303783A1 (en) 2009-05-29 2010-12-02 Allergan, Inc. Methods of Treating Urogenital-Neurological Disorders Using Tachykinin Retargeted Endopepidases
US20100303788A1 (en) 2009-05-29 2010-12-02 Allergan, Inc. Methods of Treating Chronic Neurogenic Inflammation Using Galanin Retargeted Endopepidases
CN102573876A (zh) 2009-08-14 2012-07-11 阿勒根公司 使用甘丙肽再靶向内肽酶治疗癌症的方法
CN102574899A (zh) 2009-08-14 2012-07-11 阿勒根公司 使用胰高血糖素样激素再靶向内肽酶治疗癌症的方法
CA2771154A1 (en) 2009-08-14 2011-02-17 Allergan, Inc. Methods of treating cancer using opioid retargeted endpeptidases
AU2010282276A1 (en) 2009-08-14 2012-03-15 Allergan, Inc. Methods of treating cancer using neurotrophin retargeted endopeptidases
WO2011020114A2 (en) 2009-08-14 2011-02-17 Allergan, Inc. Methods of treating cancer using tachykinin retargeted endopeptidases
US20120244188A1 (en) 2011-03-25 2012-09-27 Allergan, Inc. Treatment of Sensory Disturbance Disorders
US20120251575A1 (en) 2011-03-28 2012-10-04 Allergan, Inc. Endopeptidase Treatment of Involuntary Movement Disorders
US20120251574A1 (en) 2011-03-28 2012-10-04 Allergan, Inc. Endopeptidase and Neurotoxin Combination Treatment of Multiple Medical Conditions
US20120251573A1 (en) 2011-03-28 2012-10-04 Allergan, Inc. Endopeptidase Treatment of Neuroendocrine Disorders
US20120251519A1 (en) 2011-03-29 2012-10-04 Allergan, Inc. Endopeptidase Treatment of Smooth Muscle Disorders
US20120251518A1 (en) 2011-03-29 2012-10-04 Allergan, Inc. Endopeptidase Treatment of Sexual Dysfunction Disorders
WO2012135304A1 (en) 2011-03-29 2012-10-04 Allergan, Inc. Vagal nerve-based disorders
GB201108108D0 (en) 2011-05-16 2011-06-29 Syntaxin Ltd Therapeutic fusion proteins
WO2013011055A1 (en) * 2011-07-19 2013-01-24 ETH Zürich Means and methods for determining clostridial neurotoxins
US20140287433A1 (en) * 2011-07-19 2014-09-25 ETH Zürich Means and methods for determining clostridial neurotoxins
ES2653249T3 (es) * 2011-09-29 2018-02-06 Cellsnap, Llc Composiciones y métodos para ensayos de toxigenicidad
UA116985C2 (uk) 2012-05-30 2018-06-11 Президент Енд Феллоуз Оф Гарвард Колледж Рекомбінантний ботулінічний нейротоксин
US20140056870A1 (en) 2012-08-27 2014-02-27 Allergan, Inc. Fusion proteins
US9005628B2 (en) 2012-10-04 2015-04-14 Dublin City University Biotherapy for pain
KR20150087321A (ko) * 2012-11-21 2015-07-29 메르츠 파마 게엠베하 운트 코. 카가아 보툴리눔 신경독소 생물학적 활성의 결정을 위한 수단 및 방법
GB201303108D0 (en) 2013-02-21 2013-04-10 Syntaxin Ltd Therapeutics for suppressing osteoporosis
AU2014301116B2 (en) * 2013-06-28 2019-11-14 Merz Pharma Gmbh & Co. Kgaa Means and methods for the determination of the biological activity of Neurotoxin polypeptides in cells
GB201312295D0 (en) 2013-07-09 2013-08-21 Syntaxin Ltd Suppression of itch
EP3312290A1 (en) * 2016-10-18 2018-04-25 Ipsen Biopharm Limited Cellular vamp cleavage assay

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
Development of an in vitro bioassay for Clostridium botulinum type B neurotoxin in foods that is more sensitive than the mouse bioassay;M Wictome等;《Appl Environ Microbiol.》;19990930;第65卷(第9期);第3787-3792页 *

Also Published As

Publication number Publication date
JP2019537567A (ja) 2019-12-26
WO2018073288A1 (en) 2018-04-26
CN119529053A (zh) 2025-02-28
EP3312290A1 (en) 2018-04-25
JP2022130378A (ja) 2022-09-06
RU2019113794A3 (https=) 2021-09-10
US20190219575A1 (en) 2019-07-18
RU2019113794A (ru) 2020-11-20
JP7656571B2 (ja) 2025-04-03
JP2024123229A (ja) 2024-09-10
US12493035B2 (en) 2025-12-09
JP7127019B2 (ja) 2022-08-29
US11193931B2 (en) 2021-12-07
CN109844130A (zh) 2019-06-04
US20220113310A1 (en) 2022-04-14
EP3529370A1 (en) 2019-08-28

Similar Documents

Publication Publication Date Title
JP7656571B2 (ja) 細胞性vamp切断アッセイ
US11332518B2 (en) Immuno-based botulinum toxin serotype A activity assays
US8618261B2 (en) Immuno-based botulinum toxin serotype A activity assays
RU2807994C2 (ru) Анализ расщепления клеточного vamp
HK40008973A (en) Cellular vamp cleavage assay
HK40008973B (zh) 细胞vamp切割测定
AU2017210625B2 (en) Immuno-based botulinum toxin serotype A activity assays
HK1169855A1 (en) Immuno-based retargeted endopeptidase activity assays
HK1169855B (en) Immuno-based retargeted endopeptidase activity assays
HK1151298B (en) Immuno-based botulinum toxin serotype a activity assays

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
REG Reference to a national code

Ref country code: HK

Ref legal event code: DE

Ref document number: 40008973

Country of ref document: HK

GR01 Patent grant
GR01 Patent grant
TG01 Patent term adjustment
TG01 Patent term adjustment

Free format text: NEW EXPIRY DATE: 20381225