MX2023002544A - Anticuerpo biespecifico contra cumulo de diferenciacion 3 (cd3) y cumulo de diferenciacion 20 (cd20) en terapia de combinacion para tratar linfoma folicular. - Google Patents

Anticuerpo biespecifico contra cumulo de diferenciacion 3 (cd3) y cumulo de diferenciacion 20 (cd20) en terapia de combinacion para tratar linfoma folicular.

Info

Publication number
MX2023002544A
MX2023002544A MX2023002544A MX2023002544A MX2023002544A MX 2023002544 A MX2023002544 A MX 2023002544A MX 2023002544 A MX2023002544 A MX 2023002544A MX 2023002544 A MX2023002544 A MX 2023002544A MX 2023002544 A MX2023002544 A MX 2023002544A
Authority
MX
Mexico
Prior art keywords
follicular lymphoma
bispecific antibody
combination therapy
antibody against
treating follicular
Prior art date
Application number
MX2023002544A
Other languages
English (en)
Inventor
Tahamtan Ahmadi
W Breij Esther C
Christopher Chiu
Brian Elliott
Original Assignee
Genmab As
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 Genmab As filed Critical Genmab As
Publication of MX2023002544A publication Critical patent/MX2023002544A/es

Links

Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00Medicinal preparations containing antigens or antibodies
    • A61K39/395Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K16/00Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2887Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against CD20
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/41641,3-Diazoles
    • A61K31/41841,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00Antineoplastic agents
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00Antineoplastic agents
    • A61P35/02Antineoplastic agents specific for leukemia
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K16/00Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • C07K16/2809Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against the T-cell receptor (TcR)-CD3 complex
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K16/00Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/46Hybrid immunoglobulins
    • C07K16/468Immunoglobulins having two or more different antigen binding sites, e.g. multifunctional antibodies
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00Medicinal preparations containing antigens or antibodies
    • A61K2039/505Medicinal preparations containing antigens or antibodies comprising antibodies
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00Medicinal preparations containing antigens or antibodies
    • A61K2039/505Medicinal preparations containing antigens or antibodies comprising antibodies
    • A61K2039/507Comprising a combination of two or more separate antibodies
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00Medicinal preparations containing antigens or antibodies
    • A61K2039/545Medicinal preparations containing antigens or antibodies characterised by the dose, timing or administration schedule
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K2317/00Immunoglobulins specific features
    • C07K2317/20Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/24Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K2317/00Immunoglobulins specific features
    • C07K2317/30Immunoglobulins specific features characterized by aspects of specificity or valency
    • C07K2317/31Immunoglobulins specific features characterized by aspects of specificity or valency multispecific
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K2317/00Immunoglobulins specific features
    • C07K2317/50Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/52Constant or Fc region; Isotype
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K2317/00Immunoglobulins specific features
    • C07K2317/50Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/56Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
    • C07K2317/565Complementarity determining region [CDR]

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Immunology (AREA)
  • Medicinal Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Molecular Biology (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • Genetics & Genomics (AREA)
  • Epidemiology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Oncology (AREA)
  • Hematology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Microbiology (AREA)
  • Mycology (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Peptides Or Proteins (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Se proporcionan métodos de tratamiento clínico del linfoma folicular (por ejemplo, linfoma folicular recidivante y/o resistente) en sujetos humanos usando un anticuerpo biespecífico el cual se une a CD3 y CD20 en combinación con regímenes de cuidado estándar de rituximab y bendamustina.
MX2023002544A 2020-09-10 2021-09-10 Anticuerpo biespecifico contra cumulo de diferenciacion 3 (cd3) y cumulo de diferenciacion 20 (cd20) en terapia de combinacion para tratar linfoma folicular. MX2023002544A (es)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US202063076792P 2020-09-10 2020-09-10
PCT/EP2021/075020 WO2022053656A1 (en) 2020-09-10 2021-09-10 Bispecific antibody against cd3 and cd20 in combination therapy for treating follicular lymphoma

Publications (1)

Publication Number Publication Date
MX2023002544A true MX2023002544A (es) 2023-03-14

Family

ID=77914293

Family Applications (1)

Application Number Title Priority Date Filing Date
MX2023002544A MX2023002544A (es) 2020-09-10 2021-09-10 Anticuerpo biespecifico contra cumulo de diferenciacion 3 (cd3) y cumulo de diferenciacion 20 (cd20) en terapia de combinacion para tratar linfoma folicular.

Country Status (11)

Country Link
US (2) US20230357440A1 (es)
EP (1) EP4210743A1 (es)
JP (1) JP2023542290A (es)
KR (1) KR20230066391A (es)
CN (1) CN116406293A (es)
AU (1) AU2021341509A1 (es)
BR (1) BR112023004216A2 (es)
CA (1) CA3189883A1 (es)
IL (1) IL301098A (es)
MX (1) MX2023002544A (es)
WO (1) WO2022053656A1 (es)

Families Citing this family (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EA201791554A1 (ru) * 2015-01-08 2017-12-29 Генмаб А/С Биспецифичные антитела против cd3 и cd20
JP2023524149A (ja) * 2020-05-08 2023-06-08 ジェンマブ エー/エス Cd3およびcd20に対する二重特異性抗体
IL301085A (en) 2020-09-10 2023-05-01 Genmab As A bispecific antibody against CD3 and CD20 in combination therapy for the treatment of diffuse large B-cell lymphoma
CN116782933A (zh) 2020-09-10 2023-09-19 健玛保 用于治疗弥漫性大b细胞淋巴瘤的联合疗法中的针对cd3和cd20的双特异性抗体
US20230312757A1 (en) 2020-09-10 2023-10-05 Genmab A/S Bispecific antibodies against cd3 and cd20 for treating chronic lymphocytic leukemia
JP2023542289A (ja) 2020-09-10 2023-10-06 ジェンマブ エー/エス 濾胞性リンパ腫を治療するための併用療法におけるcd3及びcd20に対する二重特異性抗体

Family Cites Families (49)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
LU91067I2 (fr) 1991-06-14 2004-04-02 Genentech Inc Trastuzumab et ses variantes et dérivés immuno chimiques y compris les immotoxines
GB9203459D0 (en) 1992-02-19 1992-04-08 Scotgen Ltd Antibodies with germ-line variable regions
US5736137A (en) 1992-11-13 1998-04-07 Idec Pharmaceuticals Corporation Therapeutic application of chimeric and radiolabeled antibodies to human B lymphocyte restricted differentiation antigen for treatment of B cell lymphoma
DE69830901T2 (de) 1997-05-02 2006-05-24 Genentech Inc., San Francisco ein verfahren zur herstellung multispezifischer antikörper die heteromultimere und gemeinsame komponenten besitzen
AU2003270426A1 (en) 2002-09-12 2004-04-30 Avanir Pharmaceuticals PHENYL-INDOLE COMPOUNDS FOR MODULATING IgE AND INHIBITING CELLULAR PROLIFERATION
DK3284753T3 (da) 2002-10-17 2021-07-05 Genmab As Humane monoklonale antistoffer mod cd20 til anvendelse i behandlingen af multipel sclerose
EP1740946B1 (en) 2004-04-20 2013-11-06 Genmab A/S Human monoclonal antibodies against cd20
ES2592271T3 (es) 2005-03-31 2016-11-29 Chugai Seiyaku Kabushiki Kaisha Métodos de producción de polipéptidos mediante la regulación de la asociación de los polipéptidos
WO2007042261A2 (en) 2005-10-11 2007-04-19 Micromet Ag Compositions comprising cross-species-specific antibodies and uses thereof
US10155816B2 (en) 2005-11-28 2018-12-18 Genmab A/S Recombinant monovalent antibodies and methods for production thereof
EP2139924B1 (en) 2007-03-29 2016-07-06 Genmab A/S Bispecific antibodies and methods for production thereof
RS58217B1 (sr) 2007-04-03 2019-03-29 Amgen Res Munich Gmbh Interspecijski specifičan vezujući domen
WO2008145141A1 (en) 2007-05-31 2008-12-04 Genmab A/S Method for extending the half-life of exogenous or endogenous soluble molecules
JP6157046B2 (ja) 2008-01-07 2017-07-05 アムジェン インコーポレイテッド 静電的ステアリング(electrostaticsteering)効果を用いた抗体Fcヘテロ二量体分子を作製するための方法
CA2738568C (en) 2008-10-01 2024-02-20 Micromet Ag Cross-species-specific single domain bispecific single chain antibody
EP3505636A1 (en) 2009-04-27 2019-07-03 OncoMed Pharmaceuticals, Inc. Method for making heteromultimeric molecules
TW201109438A (en) 2009-07-29 2011-03-16 Abbott Lab Dual variable domain immunoglobulins and uses thereof
WO2011028952A1 (en) 2009-09-02 2011-03-10 Xencor, Inc. Compositions and methods for simultaneous bivalent and monovalent co-engagement of antigens
ES2592385T3 (es) 2009-12-29 2016-11-29 Aptevo Research And Development Llc Proteínas de unión a heterodímeros y usos de los mismos
TWI426920B (zh) 2010-03-26 2014-02-21 Hoffmann La Roche 雙專一性、雙價抗-vegf/抗-ang-2抗體
US9150663B2 (en) 2010-04-20 2015-10-06 Genmab A/S Heterodimeric antibody Fc-containing proteins and methods for production thereof
JP6141831B2 (ja) 2011-05-21 2017-06-07 マクロジェニクス,インコーポレーテッド ヒト及び非ヒトcd3に結合可能なcd3結合分子
CA2837975C (en) 2011-08-23 2022-04-05 Roche Glycart Ag Bispecific t cell activating antigen binding molecules
CN118290588A (zh) 2011-10-27 2024-07-05 健玛保 异二聚体蛋白的生成
ES2732243T3 (es) 2012-02-16 2019-11-21 Santarus Inc Composiciones farmacéuticas de anticuerpos ANTI-VLA1 (CD49A)
SG10201605703TA (en) 2012-07-06 2016-09-29 Genmab Bv Dimeric protein with triple mutations
JOP20200236A1 (ar) 2012-09-21 2017-06-16 Regeneron Pharma الأجسام المضادة لمضاد cd3 وجزيئات ربط الأنتيجين ثنائية التحديد التي تربط cd3 وcd20 واستخداماتها
RU2015140915A (ru) 2013-02-26 2017-04-03 Роше Гликарт Аг Биспецифические антигенсвязывающие молекулы, активирующие т-клетки
EP2961770A1 (en) 2013-02-26 2016-01-06 Roche Glycart AG Bispecific t cell activating antigen binding molecules
JP6546162B2 (ja) 2013-07-05 2019-07-17 ゲンマブ エー/エス ヒト化またはキメラcd3抗体
EP3019622A4 (en) 2013-07-12 2017-06-14 Zymeworks Inc. Bispecific cd3 and cd19 antigen binding contructs
WO2015095392A1 (en) 2013-12-17 2015-06-25 Genentech, Inc. Anti-cd3 antibodies and methods of use
TWI701042B (zh) 2014-03-19 2020-08-11 美商再生元醫藥公司 用於腫瘤治療之方法及抗體組成物
DK3221359T3 (da) 2014-11-17 2020-06-22 Regeneron Pharma Fremgangsmåder til tumorbehandling ved anvendelse af CD3XCD20-bispecifikt antistof
EA201791554A1 (ru) 2015-01-08 2017-12-29 Генмаб А/С Биспецифичные антитела против cd3 и cd20
US20160199399A1 (en) 2015-01-09 2016-07-14 Medical Prognosis Institute A/S Methods for predicting drug responsiveness in cancer patients
CN104922688A (zh) 2015-02-10 2015-09-23 昆明贵研药业有限公司 奥沙利铂的环糊精复合物及制备方法
EP3464370A1 (en) 2016-06-01 2019-04-10 Xencor, Inc. Bispecific antibodies that bind cd20 and cd3 for use in the treatment of lymphoma
CN109923128A (zh) 2016-11-15 2019-06-21 基因泰克公司 用于用抗cd20/抗cd3双特异性抗体进行治疗的给药
AU2018259078B2 (en) 2017-04-27 2021-10-07 Astrazeneca Ab C5-anilinoquinazoline compounds and their use in treating cancer
BR112020015052A2 (pt) 2018-02-09 2020-12-08 Genmab A/S Composição farmacêutica, uso da composição farmacêutica, métodos para tratar câncer em um sujeito, para preparar uma composição farmacêutica e para preparar uma forma de dosagem unitária, forma de dosagem unitária, recipiente, e, kit-de-partes
MX2021006238A (es) 2018-11-30 2021-10-01 Juno Therapeutics Inc Metodos para tratamiento que usan terapia celular adoptiva.
EP4013509A1 (en) * 2019-08-15 2022-06-22 Genmab A/S Pharmaceutical compositions comprising bispecific antibodies directed against cd3 and cd20 and their uses
JP2023524149A (ja) * 2020-05-08 2023-06-08 ジェンマブ エー/エス Cd3およびcd20に対する二重特異性抗体
JP2023542289A (ja) 2020-09-10 2023-10-06 ジェンマブ エー/エス 濾胞性リンパ腫を治療するための併用療法におけるcd3及びcd20に対する二重特異性抗体
US20230312757A1 (en) 2020-09-10 2023-10-05 Genmab A/S Bispecific antibodies against cd3 and cd20 for treating chronic lymphocytic leukemia
CA3192256A1 (en) 2020-09-10 2022-03-17 Brian Elliott Bispecific antibody against cd3 and cd20 in combination therapy for treating diffuse large b-cell lymphoma
CN116782933A (zh) 2020-09-10 2023-09-19 健玛保 用于治疗弥漫性大b细胞淋巴瘤的联合疗法中的针对cd3和cd20的双特异性抗体
IL301085A (en) 2020-09-10 2023-05-01 Genmab As A bispecific antibody against CD3 and CD20 in combination therapy for the treatment of diffuse large B-cell lymphoma

Also Published As

Publication number Publication date
CA3189883A1 (en) 2022-03-17
CN116406293A (zh) 2023-07-07
BR112023004216A2 (pt) 2023-04-11
US11535679B2 (en) 2022-12-27
AU2021341509A1 (en) 2023-04-13
EP4210743A1 (en) 2023-07-19
JP2023542290A (ja) 2023-10-06
US20230357440A1 (en) 2023-11-09
US20220112300A1 (en) 2022-04-14
WO2022053656A1 (en) 2022-03-17
KR20230066391A (ko) 2023-05-15
IL301098A (en) 2023-05-01

Similar Documents

Publication Publication Date Title
MX2023002540A (es) Anticuerpo biespecifico contra el cumulo de diferenciacion 3 (cd3) y el cumulo de diferenciacion 20 (cd20) en terapia combinada para el tratamiento del linfoma folicular.
MX2023002544A (es) Anticuerpo biespecifico contra cumulo de diferenciacion 3 (cd3) y cumulo de diferenciacion 20 (cd20) en terapia de combinacion para tratar linfoma folicular.
MX2023002542A (es) Anticuerpo biespecifico contra cumulo de difirenciacion 3 (cd3) y cumulo de difirenciacion 20 (cd20) en terapia combinada para el tratamiento del linfoma difuso de celulas b grandes.
MX2023002545A (es) Anticuerpo biespecifico contra cumulo de diferenciacion 3 (cd3) y cumulo de diferenciacion 20 (cd20) en terapia de combinacion para el tratamiento de linfoma difuso de celulas b grandes.
MX2023002541A (es) Anticuerpo biespecifico contra el cumulo de diferenciacion 3 (cd3) y el cumulo de diferenciacion 20 (cd20) en terapia combinada para el tratamiento del linfoma difuso de celulas b grandes.
MX2020008882A (es) Dosificación para tratamiento con anticuerpos antagonistas anti-tigit y anti-pd-l1.
PH12019502661A1 (en) Articles of manufacture and methods for treatment using adoptive cell therapy
MX2022013797A (es) Anticuerpos biespecificos contra cd3 y cd20.
BRPI0511187A (pt) método para tratar cáncer em um indivìduo
MX2023002546A (es) Anticuerpos biespecificos contra cumulo de diferenciacion 3 (cd3) y contra cumulo de diferenciacion 20 (cd20) para tratar leucemia linfocitica cronica.
MX2022013163A (es) Anticuerpo contra nectin-4 y aplicacion del mismo.
UA94899C2 (ru) Фиксированное дозирование антител к her
MX2019014274A (es) Metodo de tratamiento.
CR20220521A (es) Anticuerpos
CR20230128A (es) Anticuerpo anti-nectina-4, conjugado que lo incluye y aplicación de los mismos
MX2021010116A (es) Anticuerpo anti-pd-l1 y uso de este.
BR112022018987A2 (pt) Métodos de tratamento de mieloma múltiplo
JOP20210245A1 (ar) طرق لعلاج الداء النشواني من النوع خفيف السلسلة
MX2023001776A (es) Anticuerpos contra ilt2 y uso de los mismos.
MX2023001702A (es) Dosificacion y administracion de anticuerpos anti-c5 para el tratamiento de la microangiopatia trombotica asociada al trasplante de celulas madre hematopoyeticas (hsct-tma).
MX2021013943A (es) Pautas posologicas para la administracion de un anticuerpo biespecifico frente a lag-3/pd-l1.
MX2022003610A (es) Administracion de dosis para tratamiento con anticuerpos antagonistas anti-tigit y anti-pd-l1.
MX2021010313A (es) Dosificacion para el tratamiento con anticuerpos anti-tigit y anti-cd20 o anti-cd38.
MX2021005266A (es) Regimen de dosificacion del anticuerpo anti-gen de activacion de linfocitos 3 (anti-lag3) y terapia combinada con anticuerpo anti-muerte progamada-1 (anti-pd-1) para el tratamiento del cancer.
MX2023006983A (es) Tratamiento de canceres con un anticuerpo que se une al receptor 5 acoplado a proteina g (lgr5) y al receptor del factor de crecimiento epidermico (egfr).