JP7066639B2 - 患者における抗ｃｄ１９治療の治療的有用性を予測するための方法 - Google Patents

患者における抗ｃｄ１９治療の治療的有用性を予測するための方法 Download PDF

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JP7066639B2
JP7066639B2 JP2018562324A JP2018562324A JP7066639B2 JP 7066639 B2 JP7066639 B2 JP 7066639B2 JP 2018562324 A JP2018562324 A JP 2018562324A JP 2018562324 A JP2018562324 A JP 2018562324A JP 7066639 B2 JP7066639 B2 JP 7066639B2
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lymphoma
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JP2019519770A (ja
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エンデル，ヤン
ヴィンダーリヒ，マルク
ボクスハマー，ライナー
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MorphoSys GmbH
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    • 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
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/575—Immunoassay; Biospecific binding assay; Materials therefor for cancer
    • G01N33/57505—Immunoassay; Biospecific binding assay; Materials therefor for cancer of the blood, e.g. leukaemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2896—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against molecules with a "CD"-designation, not provided for elsewhere
    • 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
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/575—Immunoassay; Biospecific binding assay; Materials therefor for cancer
    • G01N33/5758—Immunoassay; Biospecific binding assay; Materials therefor for cancer involving compounds serving as markers for tumours, cancers or neoplasias, e.g. cellular determinants, receptors, heat shock/stress proteins, A-protein, oligosaccharides or metabolites
    • G01N33/5759—Immunoassay; Biospecific binding assay; Materials therefor for cancer involving compounds serving as markers for tumours, cancers or neoplasias, e.g. cellular determinants, receptors, heat shock/stress proteins, A-protein, oligosaccharides or metabolites involving compounds localised on the membrane of tumour or cancer cells
    • 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
    • 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
    • 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
    • G01N2333/705—Assays involving receptors, cell surface antigens or cell surface determinants
    • G01N2333/70503—Immunoglobulin superfamily, e.g. VCAMs, PECAM, LFA-3
    • G01N2333/70535—Fc-receptors, e.g. CD16, CD32, CD64 (CD2314/705F)
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/52—Predicting or monitoring the response to treatment, e.g. for selection of therapy based on assay results in personalised medicine; Prognosis

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  • Health & Medical Sciences (AREA)
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  • Immunology (AREA)
  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Hematology (AREA)
  • Molecular Biology (AREA)
  • Urology & Nephrology (AREA)
  • Biomedical Technology (AREA)
  • General Health & Medical Sciences (AREA)
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  • Food Science & Technology (AREA)
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  • Pathology (AREA)
  • Biotechnology (AREA)
  • Oncology (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Genetics & Genomics (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Biophysics (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Peptides Or Proteins (AREA)
  • Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)
  • Investigating Or Analysing Biological Materials (AREA)
  • Micro-Organisms Or Cultivation Processes Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
JP2018562324A 2016-05-30 2017-05-30 患者における抗ｃｄ１９治療の治療的有用性を予測するための方法 Active JP7066639B2 (ja)

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JP2022072884A JP7511806B2 (ja) 2016-05-30 2022-04-27 患者における抗ｃｄ１９治療の治療的有用性を予測するための方法

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EP16171885 2016-05-30
EP16171885.3 2016-05-30
PCT/EP2017/063045 WO2017207574A1 (en) 2016-05-30 2017-05-30 Methods for predicting therapeutic benefit of anti-cd19 therapy in patients

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JP2019519770A5 JP2019519770A5 (https=) 2020-07-16
JP7066639B2 true JP7066639B2 (ja) 2022-05-13

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JP2022072884A Active JP7511806B2 (ja) 2016-05-30 2022-04-27 患者における抗ｃｄ１９治療の治療的有用性を予測するための方法

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US (2) US20190195879A1 (https=)
EP (2) EP3916392B1 (https=)
JP (2) JP7066639B2 (https=)
KR (1) KR102416144B1 (https=)
CN (2) CN115932265B (https=)
AU (1) AU2017272608B2 (https=)
CY (1) CY1124768T1 (https=)
DK (2) DK3916392T3 (https=)
EA (1) EA201892542A1 (https=)
ES (2) ES2981046T3 (https=)
FI (1) FI3916392T3 (https=)
HR (2) HRP20240670T1 (https=)
HU (2) HUE067450T2 (https=)
IL (1) IL263103B2 (https=)
LT (2) LT3916392T (https=)
MA (2) MA57021B1 (https=)
MD (2) MD3465214T2 (https=)
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PL (2) PL3916392T3 (https=)
PT (2) PT3916392T (https=)
RS (2) RS62155B1 (https=)
SG (2) SG10201911958SA (https=)
SI (2) SI3916392T1 (https=)
SM (2) SMT202400204T1 (https=)
WO (1) WO2017207574A1 (https=)
ZA (2) ZA201808647B (https=)

Families Citing this family (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
SMT202100541T1 (it) 2015-08-21 2021-11-12 Morphosys Ag Combinazioni e loro usi
IL301786B2 (en) 2016-10-28 2025-09-01 Morphosys Ag Combination of anti-CD19 antibody with BCL-2 inhibitor and their uses
KR20200030337A (ko) 2018-09-12 2020-03-20 주식회사 녹십자랩셀 종양 치료를 위한 항-cd 19 항체 및 자연살해세포를 포함하는 약학적 조합물
MX2021013101A (es) * 2019-05-03 2022-01-04 Morphosys Ag Terapia anti-cd19 en pacientes que tienen una cantidad limitada de células nk.
EP4051317A1 (en) * 2019-10-31 2022-09-07 MorphoSys AG Sequential anti-cd19 therapy
TWI865644B (zh) * 2019-10-31 2024-12-11 德商莫菲西斯公司 用於治療白血病或淋巴瘤之抗cd19療法與來那度胺(lenalidomide)的組合
US20230014026A1 (en) * 2020-06-22 2023-01-19 Morphosys Ag Anti-Tumor Combination Therapy comprising Anti-CD19 Antibody and Polypeptides Blocking the SIRPalpha-CD47 Innate Immune Checkpoint
US20220184208A1 (en) * 2020-12-04 2022-06-16 Morphosys Ag Anti-cd19 combination therapy
WO2026024668A1 (en) * 2024-07-22 2026-01-29 Abbott Laboratories Method of determining a volume of a liquid in a sample

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2002522511A (ja) 1998-08-11 2002-07-23 アイデック ファーマスーティカルズ コーポレイション 抗ｃｄ２０抗体の投与を含むｂ細胞リンパ腫の併用療法
US20100167315A1 (en) 2006-09-13 2010-07-01 Glycode Method for investigating the response to a treatment with a monoclonal antibody
JP2013543869A (ja) 2010-11-15 2013-12-09 メディミューン，エルエルシー Ｂ細胞リンパ腫のための併用療法
JP2014525926A (ja) 2011-08-16 2014-10-02 モルフォシス・アー・ゲー 抗ｃｄ１９抗体とナイトロゲンマスタードとの併用療法
WO2016005548A1 (en) 2014-07-11 2016-01-14 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods for diagnosing hematological cancers

Family Cites Families (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU2002306596B2 (en) 2001-02-27 2008-01-17 The Government Of The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services Analogs of thalidomide as potential angiogenesis inhibitors
WO2005016326A2 (en) 2003-07-11 2005-02-24 The Government Of The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services Analogs of thalidomide as potential angiogenesis inhibitors
EP2216342B1 (en) 2003-07-31 2015-04-22 Immunomedics, Inc. Anti-CD19 antibodies
US7902338B2 (en) 2003-07-31 2011-03-08 Immunomedics, Inc. Anti-CD19 antibodies
KR101335798B1 (ko) * 2005-02-15 2013-12-02 듀크 유니버시티 항-ｃｄ19 항체 및 종양학에서 이의 용도
WO2007002223A2 (en) 2005-06-20 2007-01-04 Medarex, Inc. Cd19 antibodies and their uses
AU2006332155B2 (en) 2005-12-30 2013-01-10 Cancer Research Technology Limited Anti-CD19 antibodies with reduced immunogenicity
PL2383297T3 (pl) 2006-08-14 2013-06-28 Xencor Inc Zoptymalizowane przeciwciała ukierunkowane na CD19
KR101456728B1 (ko) 2006-09-08 2014-10-31 메디뮨 엘엘씨 인간화 항-ｃｄ19 항체, 및 이것의 종양학, 이식 및 자가면역 질환의 치료에서의 용도
CA2693053C (en) 2007-05-30 2021-01-05 Xencor, Inc. Methods and compositions for inhibiting cd32b expressing cells
RU2476441C2 (ru) 2007-10-19 2013-02-27 Сиэтл Дженетикс, Инк. Cd19-связывающие средства и их применение
EP2398829A2 (en) 2009-02-23 2011-12-28 Glenmark Pharmaceuticals S.A. Humanized antibodies that bind to cd19 and their uses
WO2011147834A1 (en) 2010-05-26 2011-12-01 Roche Glycart Ag Antibodies against cd19 and uses thereof
EP2409712A1 (en) 2010-07-19 2012-01-25 International-Drug-Development-Biotech Anti-CD19 antibody having ADCC and CDC functions and improved glycosylation profile
EP2409993A1 (en) 2010-07-19 2012-01-25 International-Drug-Development-Biotech Anti-CD19 antibody having ADCC function with improved glycosylation profile
EP2524929A1 (en) 2011-05-17 2012-11-21 Sanofi Use of anti-CD19 maytansinoid immunoconjugate antibody for the treatment of CD19+ B-cell malignancies syptoms
HUE058855T2 (hu) * 2011-08-16 2022-09-28 Morphosys Ag Kombinációs terápia, CD19 elleni ellenanyag és purinanalóg alkalmazásával
EP2791165A4 (en) * 2011-12-12 2015-08-05 Pikamab Inc PREDICTING SENSITIVITY TO ANTIBODY MAINTENANCE THERAPY
US9139649B2 (en) * 2014-02-25 2015-09-22 Immunomedics, Inc. Humanized anti-CD22 antibody
JP2017519757A (ja) 2014-06-16 2017-07-20 ゼンコー・インコーポレイテッドＸｅｎｃｏｒ、 Ｉｎｃ． 慢性リンパ球性白血病（ｃｌｌ）の処置

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2002522511A (ja) 1998-08-11 2002-07-23 アイデック ファーマスーティカルズ コーポレイション 抗ｃｄ２０抗体の投与を含むｂ細胞リンパ腫の併用療法
US20100167315A1 (en) 2006-09-13 2010-07-01 Glycode Method for investigating the response to a treatment with a monoclonal antibody
JP2013543869A (ja) 2010-11-15 2013-12-09 メディミューン，エルエルシー Ｂ細胞リンパ腫のための併用療法
JP2014525926A (ja) 2011-08-16 2014-10-02 モルフォシス・アー・ゲー 抗ｃｄ１９抗体とナイトロゲンマスタードとの併用療法
WO2016005548A1 (en) 2014-07-11 2016-01-14 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods for diagnosing hematological cancers

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PL3465214T3 (pl) 2021-12-20
JP2019519770A (ja) 2019-07-11
EP3465214A1 (en) 2019-04-10
HRP20210938T1 (hr) 2021-09-03
IL263103B1 (en) 2023-06-01
CN115932265B (zh) 2026-04-14
SI3916392T1 (sl) 2024-10-30
EP3916392A1 (en) 2021-12-01
ZA201808647B (en) 2021-05-26
HRP20240670T1 (hr) 2024-09-27
DK3916392T3 (da) 2024-05-21
ZA202100296B (en) 2025-05-28
SMT202100291T1 (it) 2021-07-12
MX2018014702A (es) 2019-10-02
NZ748468A (en) 2025-05-30
MA45124B1 (fr) 2021-05-31
EP3465214B1 (en) 2021-04-28
PT3916392T (pt) 2024-06-04
RS65540B1 (sr) 2024-06-28
MA45124A (fr) 2017-12-07
KR20190013980A (ko) 2019-02-11
DK3465214T3 (da) 2021-05-31
FI3916392T3 (fi) 2024-06-03
PT3465214T (pt) 2021-06-30
ES2981046T3 (es) 2024-10-07
EP3916392B1 (en) 2024-05-01
PL3916392T3 (pl) 2024-09-23
BR112018074603A2 (pt) 2019-03-19
IL263103A (en) 2018-12-31
AU2017272608A1 (en) 2018-12-06
US20220283166A1 (en) 2022-09-08
US20190195879A1 (en) 2019-06-27
CN109313194B (zh) 2022-11-04
MX2021014963A (es) 2022-02-24
CN115932265A (zh) 2023-04-07
HUE054860T2 (hu) 2021-10-28
SG10201911958SA (en) 2020-02-27
MX388502B (es) 2025-03-20
ES2878156T3 (es) 2021-11-18
SG11201810159TA (en) 2018-12-28
MD3916392T2 (ro) 2024-10-31
MA57021B1 (fr) 2024-05-31
CA3025823A1 (en) 2017-12-07
RS62155B1 (sr) 2021-08-31
IL263103B2 (en) 2023-10-01
WO2017207574A1 (en) 2017-12-07
SMT202400204T1 (it) 2024-09-16
CN109313194A (zh) 2019-02-05
CY1124768T1 (el) 2022-11-25
HUE067450T2 (hu) 2024-10-28
MD3465214T2 (ro) 2021-09-30
JP2022119764A (ja) 2022-08-17
AU2017272608B2 (en) 2023-08-10
KR102416144B1 (ko) 2022-07-04
LT3916392T (lt) 2024-08-26
JP7511806B2 (ja) 2024-07-08
EA201892542A1 (ru) 2019-06-28
SI3465214T1 (sl) 2021-12-31
LT3465214T (lt) 2021-10-11

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