JP6501362B2 - エリスロフェロンおよびｅｒｆｅポリペプチドならびに鉄代謝を調節する方法 - Google Patents

エリスロフェロンおよびｅｒｆｅポリペプチドならびに鉄代謝を調節する方法 Download PDF

Info

Publication number
JP6501362B2
JP6501362B2 JP2015540784A JP2015540784A JP6501362B2 JP 6501362 B2 JP6501362 B2 JP 6501362B2 JP 2015540784 A JP2015540784 A JP 2015540784A JP 2015540784 A JP2015540784 A JP 2015540784A JP 6501362 B2 JP6501362 B2 JP 6501362B2
Authority
JP
Japan
Prior art keywords
erfe
iron
hepcidin
anemia
mice
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
JP2015540784A
Other languages
English (en)
Japanese (ja)
Other versions
JP2015536337A5 (enExample
JP2015536337A (ja
Inventor
ガンツ，トーマス
ネメス，エリザベータ
カウツ，レオン
Original Assignee
ザ・リージエンツ・オブ・ザ・ユニバーシテイー・オブ・カリフオルニア
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 ザ・リージエンツ・オブ・ザ・ユニバーシテイー・オブ・カリフオルニア filed Critical ザ・リージエンツ・オブ・ザ・ユニバーシテイー・オブ・カリフオルニア
Publication of JP2015536337A publication Critical patent/JP2015536337A/ja
Publication of JP2015536337A5 publication Critical patent/JP2015536337A5/ja
Application granted granted Critical
Publication of JP6501362B2 publication Critical patent/JP6501362B2/ja
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Images

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/52—Cytokines; Lymphokines; Interferons
    • C07K14/525—Tumour necrosis factor [TNF]
    • 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
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
    • A61K39/3955—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against proteinaceous materials, e.g. enzymes, hormones, lymphokines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/02—Nutrients, e.g. vitamins, minerals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/12—Drugs for disorders of the metabolism for electrolyte homeostasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/06—Antianaemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • 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
    • 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
    • C07K16/241—Tumor Necrosis Factors
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
    • G01N33/6863—Cytokines, i.e. immune system proteins modifying a biological response such as cell growth proliferation or differentiation, e.g. TNF, CNF, GM-CSF, lymphotoxin, MIF or their receptors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/10—Immunoglobulins specific features characterized by their source of isolation or production
    • C07K2317/14—Specific host cells or culture conditions, e.g. components, pH or temperature
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
    • G01N2333/52—Assays involving cytokines
    • G01N2333/525—Tumor necrosis factor [TNF]
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/22—Haematology

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Molecular Biology (AREA)
  • Immunology (AREA)
  • Biochemistry (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Biomedical Technology (AREA)
  • Genetics & Genomics (AREA)
  • Biophysics (AREA)
  • Hematology (AREA)
  • Diabetes (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Urology & Nephrology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Zoology (AREA)
  • Toxicology (AREA)
  • Obesity (AREA)
  • Cell Biology (AREA)
  • Microbiology (AREA)
  • Endocrinology (AREA)
  • Psychology (AREA)
  • Biotechnology (AREA)
  • Food Science & Technology (AREA)
  • Physics & Mathematics (AREA)
  • Epidemiology (AREA)
  • Pathology (AREA)
JP2015540784A 2012-11-01 2013-10-31 エリスロフェロンおよびｅｒｆｅポリペプチドならびに鉄代謝を調節する方法 Active JP6501362B2 (ja)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US201261721322P 2012-11-01 2012-11-01
US61/721,322 2012-11-01
PCT/US2013/067771 WO2014071015A1 (en) 2012-11-01 2013-10-31 Erythroferrone and erfe polypeptides and methods of regulating iron metabolism

Publications (3)

Publication Number Publication Date
JP2015536337A JP2015536337A (ja) 2015-12-21
JP2015536337A5 JP2015536337A5 (enExample) 2016-12-22
JP6501362B2 true JP6501362B2 (ja) 2019-04-17

Family

ID=50628048

Family Applications (1)

Application Number Title Priority Date Filing Date
JP2015540784A Active JP6501362B2 (ja) 2012-11-01 2013-10-31 エリスロフェロンおよびｅｒｆｅポリペプチドならびに鉄代謝を調節する方法

Country Status (11)

Country Link
US (2) US20160122409A1 (enExample)
EP (1) EP2914619B1 (enExample)
JP (1) JP6501362B2 (enExample)
KR (1) KR102186218B1 (enExample)
CN (1) CN104854130A (enExample)
AU (1) AU2013337808B2 (enExample)
BR (1) BR112015009954A2 (enExample)
CA (1) CA2890040A1 (enExample)
ES (1) ES2731609T3 (enExample)
RU (1) RU2684216C2 (enExample)
WO (1) WO2014071015A1 (enExample)

Families Citing this family (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3448405B1 (en) 2016-04-27 2024-07-03 Vladimir Badmaev Method maintaining iron homeostasis with shogaols
US20190284274A1 (en) * 2016-08-05 2019-09-19 Silarus Therapeutics, Inc. Erfe specific antibodies compositions and methods of use
EP3519432A1 (en) * 2016-10-03 2019-08-07 Silarus Therapeutics, Inc. Erfe fusion polypeptides compositions and methods of use
IL269318B2 (en) * 2017-03-13 2024-10-01 Intrinsic Lifesciences Llc ANTIBODIES TO HUMAN ERYTHROFERRONE AND USES THEREOF
EP3628006A4 (en) * 2017-05-16 2021-07-21 Generos Biopharma Ltd. COMPOSITIONS AND METHODS OF TREATMENT FOR RHEUMATOID ARTHRITIS
US11255865B2 (en) 2017-06-06 2022-02-22 The Regents Of The University Of California Immunoassay for human erythroferrone
WO2019148186A1 (en) * 2018-01-29 2019-08-01 Silarus Therapeutics, Inc. Antibodies binding erfe and methods of use
WO2019212364A1 (en) * 2018-05-01 2019-11-07 Christopher Joseph Pemberton Test for heart failure
US20210196823A1 (en) * 2018-06-08 2021-07-01 Pfizer Inc. Methods of Treating Metabolic Disease
US20220119516A1 (en) * 2019-01-16 2022-04-21 INSERM (Institut National de la Santé et de la Recherche Médicale) Variants of erythroferrone and their use
CA3156007A1 (en) 2019-09-27 2021-04-01 Disc Medicine, Inc. METHODS OF TREATING MYELOFIBROSE AND ASSOCIATED CONDITIONS
KR20230012539A (ko) 2020-05-13 2023-01-26 디스크 메디슨, 인크. 골수섬유증을 치료하기 위한 항-헤모주벨린 (hjv) 항체
WO2022098812A1 (en) 2020-11-04 2022-05-12 Keros Therapeutics, Inc. Methods of treating iron overload
WO2024170505A1 (en) 2023-02-13 2024-08-22 Institut National de la Santé et de la Recherche Médicale Methods of treatment of iron overload associated diseases

Family Cites Families (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7749713B2 (en) * 2002-11-19 2010-07-06 Hasan Kulaksiz Diagnostic method for diseases by screening for hepcidin in human or animal tissues, blood or body fluids and therapeutic uses therefor
GB0423973D0 (en) * 2004-10-28 2004-12-01 Ares Trading Sa C1q related points
CA2597925A1 (en) * 2005-02-16 2006-08-24 The General Hospital Corporation Use of a human hemojuvelin product to regulate hepcidin-mediated iron metabolism
TW201206954A (en) * 2007-02-02 2012-02-16 Amgen Inc Hepcidin, hepcidin antagonists and methods of use
GB0818273D0 (en) * 2008-10-06 2008-11-12 Cambridge Entpr Ltd Modulation of cellular activity and differentiation
WO2010065815A2 (en) * 2008-12-05 2010-06-10 The Regents Of The University Of California Mini-hepcidin peptides and methods of using thereof
WO2013112663A1 (en) * 2012-01-26 2013-08-01 The Johns Hopkins University Myonectin (ctrp15), compositions comprising same, and methods of use

Also Published As

Publication number Publication date
KR20150077471A (ko) 2015-07-07
US20160122409A1 (en) 2016-05-05
CN104854130A (zh) 2015-08-19
AU2013337808B2 (en) 2017-12-21
AU2013337808A1 (en) 2015-05-14
EP2914619A1 (en) 2015-09-09
CA2890040A1 (en) 2014-05-08
JP2015536337A (ja) 2015-12-21
BR112015009954A2 (pt) 2017-08-22
KR102186218B1 (ko) 2020-12-03
ES2731609T3 (es) 2019-11-18
EP2914619A4 (en) 2016-05-11
US20180355008A1 (en) 2018-12-13
RU2684216C2 (ru) 2019-04-04
WO2014071015A1 (en) 2014-05-08
RU2015120601A (ru) 2016-12-20
EP2914619B1 (en) 2019-05-29

Similar Documents

Publication Publication Date Title
JP6501362B2 (ja) エリスロフェロンおよびｅｒｆｅポリペプチドならびに鉄代謝を調節する方法
Habib et al. Myc stimulates B lymphocyte differentiation and amplifies calcium signaling
Betz et al. Batf coordinates multiple aspects of B and T cell function required for normal antibody responses
Zeng et al. Lysine-specific demethylase 1 promotes brown adipose tissue thermogenesis via repressing glucocorticoid activation
Tanno et al. Growth differentiation factor 15 in erythroid health and disease
Chuang et al. Neutropenia with impaired host defense against microbial infection in mice lacking androgen receptor
Wu et al. A novel IL-17 signaling pathway controlling keratinocyte proliferation and tumorigenesis via the TRAF4–ERK5 axis
Zou et al. p57Kip2 and p27Kip1 cooperate to maintain hematopoietic stem cell quiescence through interactions with Hsc70
Bin et al. Molecular pathogenesis of Spondylocheirodysplastic Ehlers‐Danlos syndrome caused by mutant ZIP13 proteins
Bettini et al. Thymocyte development in early growth response gene 1-deficient mice
US20200101157A1 (en) Vitro cell culture methods for beta-thalassemia using activin type ii receptor ligand traps
Babitt et al. The molecular pathogenesis of hereditary hemochromatosis
Yasuoka et al. The pro-fibrotic factor IGFBP-5 induces lung fibroblast and mononuclear cell migration
Liu et al. CREG1 promotes lysosomal biogenesis and function
Dearth et al. Expression and function of CCAAT/enhancer binding proteinβ (C/EBPβ) LAP and LIP isoforms in mouse mammary gland, tumors and cultured mammary epithelial cells
Malarkannan et al. Bcl10 plays a divergent role in NK cell-mediated cytotoxicity and cytokine generation
Zhou et al. Bone marrow immune cells respond to fluctuating nutritional stress to constrain weight regain
Li et al. Requirement for ssbp2 in hematopoietic stem cell maintenance and stress response
An et al. Soluble LILRA3 promotes neurite outgrowth and synapses formation through a high-affinity interaction with Nogo 66
Schmeissner et al. Integrin functions play a key role in the differentiation of thymocytes in vivo
Zhong et al. OVOL2 sustains postnatal thymic epithelial cell identity
Ramshaw et al. The Shc-binding site of the βc subunit of the GM-CSF/IL-3/IL-5 receptors is a negative regulator of hematopoiesis
Giroud-Gerbetant et al. Erythropoietin supplementation ameliorates the immunological and hematological deficiencies of lysinuric protein intolerance in mice
Harada et al. Stimulation of FcγRI on primary sensory neurons increases insulin-like growth factor-I production, thereby reducing reperfusion-induced renal injury in mice
Yuan In vitro and in vivo studies of VISTA: a B7 family immune checkpoint receptor

Legal Events

Date Code Title Description
A521 Request for written amendment filed

Free format text: JAPANESE INTERMEDIATE CODE: A523

Effective date: 20150701

A521 Request for written amendment filed

Free format text: JAPANESE INTERMEDIATE CODE: A523

Effective date: 20161028

A621 Written request for application examination

Free format text: JAPANESE INTERMEDIATE CODE: A621

Effective date: 20161028

A131 Notification of reasons for refusal

Free format text: JAPANESE INTERMEDIATE CODE: A131

Effective date: 20170808

A601 Written request for extension of time

Free format text: JAPANESE INTERMEDIATE CODE: A601

Effective date: 20171102

A521 Request for written amendment filed

Free format text: JAPANESE INTERMEDIATE CODE: A523

Effective date: 20180207

A131 Notification of reasons for refusal

Free format text: JAPANESE INTERMEDIATE CODE: A131

Effective date: 20180619

A521 Request for written amendment filed

Free format text: JAPANESE INTERMEDIATE CODE: A523

Effective date: 20180914

TRDD Decision of grant or rejection written
A01 Written decision to grant a patent or to grant a registration (utility model)

Free format text: JAPANESE INTERMEDIATE CODE: A01

Effective date: 20190115

A601 Written request for extension of time

Free format text: JAPANESE INTERMEDIATE CODE: A601

Effective date: 20190214

A61 First payment of annual fees (during grant procedure)

Free format text: JAPANESE INTERMEDIATE CODE: A61

Effective date: 20190315

R150 Certificate of patent or registration of utility model

Ref document number: 6501362

Country of ref document: JP

Free format text: JAPANESE INTERMEDIATE CODE: R150

R250 Receipt of annual fees

Free format text: JAPANESE INTERMEDIATE CODE: R250

R250 Receipt of annual fees

Free format text: JAPANESE INTERMEDIATE CODE: R250

R250 Receipt of annual fees

Free format text: JAPANESE INTERMEDIATE CODE: R250