KR102316283B1 - 메토트렉세이트를 이용한 면역 관용의 유도 - Google Patents

메토트렉세이트를 이용한 면역 관용의 유도 Download PDF

Info

Publication number
KR102316283B1
KR102316283B1 KR1020207027913A KR20207027913A KR102316283B1 KR 102316283 B1 KR102316283 B1 KR 102316283B1 KR 1020207027913 A KR1020207027913 A KR 1020207027913A KR 20207027913 A KR20207027913 A KR 20207027913A KR 102316283 B1 KR102316283 B1 KR 102316283B1
Authority
KR
South Korea
Prior art keywords
methotrexate
cells
matg
alemtuzumab
treatment
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
KR1020207027913A
Other languages
English (en)
Korean (ko)
Other versions
KR20200116543A (ko
Inventor
알렉산드라 조셉
수전 리처즈
멜라니 러젝
리처드 가먼
Original Assignee
젠자임 코포레이션
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
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=47177257&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=KR102316283(B1) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Application filed by 젠자임 코포레이션 filed Critical 젠자임 코포레이션
Publication of KR20200116543A publication Critical patent/KR20200116543A/ko
Application granted granted Critical
Publication of KR102316283B1 publication Critical patent/KR102316283B1/ko
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Images

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • 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
    • A61K39/0005—Vertebrate antigens
    • A61K39/0008—Antigens related to auto-immune diseases; Preparations to induce self-tolerance
    • 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
    • A61K39/39558—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against tumor tissues, cells, antigens
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61P3/00—Drugs for disorders of the metabolism
    • 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
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • 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
    • A61P7/06—Antianaemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Immunology (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Epidemiology (AREA)
  • Mycology (AREA)
  • Microbiology (AREA)
  • Biomedical Technology (AREA)
  • Rheumatology (AREA)
  • Oncology (AREA)
  • Hematology (AREA)
  • Diabetes (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Obesity (AREA)
  • Transplantation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Peptides Or Proteins (AREA)
  • Medicines Containing Material From Animals Or Micro-Organisms (AREA)
  • Materials For Medical Uses (AREA)
KR1020207027913A 2011-05-16 2012-05-03 메토트렉세이트를 이용한 면역 관용의 유도 Active KR102316283B1 (ko)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US201161486697P 2011-05-16 2011-05-16
US61/486,697 2011-05-16
PCT/US2012/036405 WO2012158362A1 (en) 2011-05-16 2012-05-03 Induction of immune tolerance by using methotrexate
KR1020197033979A KR102163285B1 (ko) 2011-05-16 2012-05-03 메토트렉세이트를 이용한 면역 관용의 유도

Related Parent Applications (1)

Application Number Title Priority Date Filing Date
KR1020197033979A Division KR102163285B1 (ko) 2011-05-16 2012-05-03 메토트렉세이트를 이용한 면역 관용의 유도

Publications (2)

Publication Number Publication Date
KR20200116543A KR20200116543A (ko) 2020-10-12
KR102316283B1 true KR102316283B1 (ko) 2021-10-21

Family

ID=47177257

Family Applications (3)

Application Number Title Priority Date Filing Date
KR1020137032882A Ceased KR20140040744A (ko) 2011-05-16 2012-05-03 메토트렉세이트를 이용한 면역 관용의 유도
KR1020197033979A Active KR102163285B1 (ko) 2011-05-16 2012-05-03 메토트렉세이트를 이용한 면역 관용의 유도
KR1020207027913A Active KR102316283B1 (ko) 2011-05-16 2012-05-03 메토트렉세이트를 이용한 면역 관용의 유도

Family Applications Before (2)

Application Number Title Priority Date Filing Date
KR1020137032882A Ceased KR20140040744A (ko) 2011-05-16 2012-05-03 메토트렉세이트를 이용한 면역 관용의 유도
KR1020197033979A Active KR102163285B1 (ko) 2011-05-16 2012-05-03 메토트렉세이트를 이용한 면역 관용의 유도

Country Status (28)

Country Link
US (3) US20140135337A1 (enExample)
EP (2) EP2709627B1 (enExample)
JP (3) JP6174572B2 (enExample)
KR (3) KR20140040744A (enExample)
CN (4) CN113209288A (enExample)
AU (1) AU2012256281B2 (enExample)
BR (1) BR112013029501A2 (enExample)
CA (1) CA2835819A1 (enExample)
CL (1) CL2013003298A1 (enExample)
CO (1) CO6841993A2 (enExample)
DO (1) DOP2013000268A (enExample)
EC (1) ECSP13013081A (enExample)
ES (1) ES2836823T3 (enExample)
GT (1) GT201300278A (enExample)
IL (2) IL229245B (enExample)
MA (1) MA35165B1 (enExample)
MX (1) MX2013013445A (enExample)
MY (1) MY173304A (enExample)
NI (1) NI201300121A (enExample)
PE (1) PE20140469A1 (enExample)
PH (1) PH12013502256A1 (enExample)
PT (1) PT2709627T (enExample)
RU (1) RU2674036C2 (enExample)
SG (1) SG194802A1 (enExample)
TN (1) TN2013000472A1 (enExample)
UA (1) UA117556C2 (enExample)
WO (1) WO2012158362A1 (enExample)
ZA (1) ZA201308315B (enExample)

Families Citing this family (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8809282B2 (en) * 2010-05-06 2014-08-19 Duke University Method of reducing titers of antibodies specific for a therapeutic agent
MX373641B (es) 2011-04-29 2020-05-04 Selecta Biosciences Inc Nanoportadores sintéticos tolerogénicos para la terapia contra alergias.
EP2709627B1 (en) 2011-05-16 2020-09-23 Genzyme Corporation Induction of immune tolerance by using methotrexate
CN105283175A (zh) * 2013-05-03 2016-01-27 西莱克塔生物科技公司 用于降低的或增强的药效学作用的致耐受性合成纳米载体和治疗性大分子
EA201592273A1 (ru) * 2013-06-04 2016-09-30 Селекта Байосайенсиз, Инк. Повторное введение неиммуносупрессивных антигенспецифических иммунотерапевтических средств
KR20170045344A (ko) 2014-09-07 2017-04-26 셀렉타 바이오사이언시즈, 인크. 항-바이러스 전달 벡터 면역 반응을 약화시키기 위한 방법 및 조성물
EP3283519A1 (en) 2015-04-15 2018-02-21 Regeneron Pharmaceuticals, Inc. Methods of increasing strength and functionality with gdf8 inhibitors
JP2016213236A (ja) * 2015-04-30 2016-12-15 日東電工株式会社 半導体装置用フィルム、及び、半導体装置の製造方法
JP7523909B2 (ja) 2017-03-11 2024-07-29 セレクタ バイオサイエンシーズ インコーポレーテッド 抗炎症剤および免疫抑制剤を含む合成ナノキャリアによる組み合わせ処置に関連する方法および組成物
WO2018209300A1 (en) * 2017-05-12 2018-11-15 Duke University Methods for the use of low-dose immune modulators transiently for treating patients undergoing protein replacement therapy
TWI821227B (zh) * 2017-12-22 2023-11-11 美商健臻公司 胺甲喋呤誘發的免疫耐受性之生物標記
IL295415A (en) 2020-02-08 2022-10-01 Genzyme Corp Compositions and methods for treating pompe disease
TW202342057A (zh) * 2022-02-07 2023-11-01 美商健生生物科技公司 用於減少用ｅｇｆｒ／ｍｅｔ雙特異性抗體治療之患者的輸注相關反應之方法

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20090155207A1 (en) * 2007-11-29 2009-06-18 Hariri Robert J Use of Immunomodulatory Compounds for the Treatment of Transverse Myelitis, Multiple Sclerosis, and Other Disorders
US20100135992A1 (en) * 2006-03-02 2010-06-03 Alexion Pharmaceuticals, Inc. Prolongation of Survival of an Allograft by Inhibiting Complement Activity

Family Cites Families (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4080325A (en) 1976-11-17 1978-03-21 The United States Of America As Represented By The Department Of Health, Education And Welfare Synthesis of methotrexate
US4558690A (en) 1982-01-26 1985-12-17 University Of Scranton Method of administration of chemotherapy to tumors
US5108987A (en) 1982-02-25 1992-04-28 Faulk Ward P Conjugates of proteins with anti-tumor agents
US5028697A (en) 1988-08-08 1991-07-02 Eli Lilly And Company Cytotoxic antibody conjugates of hydrazide derivatized methotrexate analogs via simple organic linkers
DE4000154A1 (de) 1990-01-04 1991-07-11 Symbiotec Gmbh Chemotherapeutisches mittel, insbesondere zur behandlung von krebserkrankungen
US6015557A (en) 1999-02-24 2000-01-18 Tobinick; Edward L. Tumor necrosis factor antagonists for the treatment of neurological disorders
US7485314B2 (en) * 2002-05-06 2009-02-03 Los Angeles Biomedical Research Institute At Harbor-Ucla Medical Center Induction of antigen specific immunologic tolerance
WO2005085294A1 (ja) 2004-03-05 2005-09-15 Denki Kagaku Kogyo Kabushiki Kaisha ヒアルロン酸−メトトレキサート結合体
US7884196B2 (en) 2004-10-06 2011-02-08 Oliver Lawless Vaccine composition comprising methylated DNA and immunomodulatory motifs
WO2008094937A2 (en) 2007-01-29 2008-08-07 Joslin Diabetes Center, Inc. Methods of modulating angiogenesis
US7914785B2 (en) * 2008-01-02 2011-03-29 Bergen Teknologieverforing As B-cell depleting agents, like anti-CD20 antibodies or fragments thereof for the treatment of chronic fatigue syndrome
EP2077281A1 (en) * 2008-01-02 2009-07-08 Bergen Teknologioverforing AS Anti-CD20 antibodies or fragments thereof for the treatment of chronic fatigue syndrome
CA2740077A1 (en) 2008-10-08 2010-04-15 Cambridge Enterprise Limited Methods and compositions for diagnosis and treatment
MX2011004870A (es) 2008-11-07 2011-09-06 4Sc Ag Composicion de combinacion que comprende un inhibidor de dhodh y metotrexato para tratar enfermedades autoinmunes.
EP2709627B1 (en) 2011-05-16 2020-09-23 Genzyme Corporation Induction of immune tolerance by using methotrexate

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20100135992A1 (en) * 2006-03-02 2010-06-03 Alexion Pharmaceuticals, Inc. Prolongation of Survival of an Allograft by Inhibiting Complement Activity
US20090155207A1 (en) * 2007-11-29 2009-06-18 Hariri Robert J Use of Immunomodulatory Compounds for the Treatment of Transverse Myelitis, Multiple Sclerosis, and Other Disorders

Also Published As

Publication number Publication date
JP2017141236A (ja) 2017-08-17
KR20140040744A (ko) 2014-04-03
RU2674036C2 (ru) 2018-12-04
CL2013003298A1 (es) 2014-07-25
AU2012256281B2 (en) 2017-06-15
US20140135337A1 (en) 2014-05-15
AU2012256281A1 (en) 2013-11-28
JP6694020B2 (ja) 2020-05-13
PT2709627T (pt) 2020-12-24
EP2709627B1 (en) 2020-09-23
US20200360385A1 (en) 2020-11-19
CN109620830A (zh) 2019-04-16
WO2012158362A1 (en) 2012-11-22
TN2013000472A1 (en) 2015-03-30
CO6841993A2 (es) 2014-01-20
NZ617575A (en) 2016-10-28
PE20140469A1 (es) 2014-04-23
EP2709627A4 (en) 2014-11-12
JP6174572B2 (ja) 2017-08-02
JP2014513722A (ja) 2014-06-05
UA117556C2 (uk) 2018-08-27
KR102163285B1 (ko) 2020-10-08
ZA201308315B (en) 2014-07-30
EP3824890A1 (en) 2021-05-26
RU2013155618A (ru) 2015-06-27
IL229245A0 (en) 2014-01-30
MA35165B1 (fr) 2014-06-02
ECSP13013081A (es) 2015-04-30
NI201300121A (es) 2014-02-28
NZ716716A (en) 2018-06-29
MX2013013445A (es) 2014-07-28
CN113209288A (zh) 2021-08-06
IL229245B (en) 2020-08-31
SG194802A1 (en) 2013-12-30
EP2709627A1 (en) 2014-03-26
BR112013029501A2 (pt) 2017-01-24
DOP2013000268A (es) 2014-01-31
KR20190132551A (ko) 2019-11-27
GT201300278A (es) 2015-02-12
JP2018184466A (ja) 2018-11-22
MY173304A (en) 2020-01-14
NZ742216A (en) 2018-10-26
CN103648501A (zh) 2014-03-19
CN110124039A (zh) 2019-08-16
IL276879B (en) 2022-06-01
JP6381707B2 (ja) 2018-08-29
KR20200116543A (ko) 2020-10-12
PH12013502256A1 (en) 2022-04-08
ES2836823T3 (es) 2021-06-28
US20230372347A1 (en) 2023-11-23
US11672802B2 (en) 2023-06-13
IL276879A (en) 2020-10-29
CA2835819A1 (en) 2012-11-22

Similar Documents

Publication Publication Date Title
US20230372347A1 (en) Induction of immune tolerance by using methotrexate
Miura et al. TNX-1500, a crystallizable fragment–modified anti-CD154 antibody, prolongs nonhuman primate cardiac allograft survival
US20210236512A1 (en) Clozapine for the treatment of a immunoglobulin driven b cell disease
HK40053503A (en) Induction of immune tolerance using methotrexate
HK40053628A (en) Induction of immune tolerance by using methotrexate
HK40012743A (en) Induction of immune tolerance by using methotrexate
HK40007634A (en) Induction of immune tolerance by using methotrexate
OA16781A (en) Induction of immune tolerance by using methotrexate.
NZ716716B2 (en) Induction of immune tolerance by using methotrexate
HK1194668B (en) Induction of immune tolerance by using methotrexate
HK1194668A (en) Induction of immune tolerance by using methotrexate
NZ617575B2 (en) Induction of immune tolerance by using methotrexate
NZ742216B2 (en) Induction of immune tolerance by using methotrexate

Legal Events

Date Code Title Description
A107 Divisional application of patent
PA0104 Divisional application for international application

St.27 status event code: A-0-1-A10-A18-div-PA0104

St.27 status event code: A-0-1-A10-A16-div-PA0104

PG1501 Laying open of application

St.27 status event code: A-1-1-Q10-Q12-nap-PG1501

A201 Request for examination
AMND Amendment
P11-X000 Amendment of application requested

St.27 status event code: A-2-2-P10-P11-nap-X000

P13-X000 Application amended

St.27 status event code: A-2-2-P10-P13-nap-X000

PA0201 Request for examination

St.27 status event code: A-1-2-D10-D11-exm-PA0201

E902 Notification of reason for refusal
PE0902 Notice of grounds for rejection

St.27 status event code: A-1-2-D10-D21-exm-PE0902

R17-X000 Change to representative recorded

St.27 status event code: A-3-3-R10-R17-oth-X000

T11-X000 Administrative time limit extension requested

St.27 status event code: U-3-3-T10-T11-oth-X000

T11-X000 Administrative time limit extension requested

St.27 status event code: U-3-3-T10-T11-oth-X000

AMND Amendment
P11-X000 Amendment of application requested

St.27 status event code: A-2-2-P10-P11-nap-X000

P13-X000 Application amended

St.27 status event code: A-2-2-P10-P13-nap-X000

R17-X000 Change to representative recorded

St.27 status event code: A-3-3-R10-R17-oth-X000

E601 Decision to refuse application
PE0601 Decision on rejection of patent

St.27 status event code: N-2-6-B10-B15-exm-PE0601

AMND Amendment
E13-X000 Pre-grant limitation requested

St.27 status event code: A-2-3-E10-E13-lim-X000

P11-X000 Amendment of application requested

St.27 status event code: A-2-2-P10-P11-nap-X000

P13-X000 Application amended

St.27 status event code: A-2-2-P10-P13-nap-X000

PX0901 Re-examination

St.27 status event code: A-2-3-E10-E12-rex-PX0901

PX0701 Decision of registration after re-examination

St.27 status event code: A-3-4-F10-F13-rex-PX0701

X701 Decision to grant (after re-examination)
GRNT Written decision to grant
PR0701 Registration of establishment

St.27 status event code: A-2-4-F10-F11-exm-PR0701

PR1002 Payment of registration fee

St.27 status event code: A-2-2-U10-U12-oth-PR1002

Fee payment year number: 1

PG1601 Publication of registration

St.27 status event code: A-4-4-Q10-Q13-nap-PG1601

R18-X000 Changes to party contact information recorded

St.27 status event code: A-5-5-R10-R18-oth-X000

PR1001 Payment of annual fee

St.27 status event code: A-4-4-U10-U11-oth-PR1001

Fee payment year number: 4

PR1001 Payment of annual fee

St.27 status event code: A-4-4-U10-U11-oth-PR1001

Fee payment year number: 5

U11 Full renewal or maintenance fee paid

Free format text: ST27 STATUS EVENT CODE: A-4-4-U10-U11-OTH-PR1001 (AS PROVIDED BY THE NATIONAL OFFICE)

Year of fee payment: 5