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ATE397661T1 - Bindungsdomänen des delta-proteins - Google Patents

Bindungsdomänen des delta-proteins

Info

Publication number
ATE397661T1
ATE397661T1 AT99101563T AT99101563T ATE397661T1 AT E397661 T1 ATE397661 T1 AT E397661T1 AT 99101563 T AT99101563 T AT 99101563T AT 99101563 T AT99101563 T AT 99101563T AT E397661 T1 ATE397661 T1 AT E397661T1
Authority
AT
Austria
Prior art keywords
binding domain
toporythmic protein
delta protein
fragment
protein
Prior art date
Application number
AT99101563T
Other languages
English (en)
Inventor
Spyridon Artavanis-Tsakonas
Marc Alan Telander Muskavitch
Richard Grant Fehon
Scott Shepard
Original Assignee
Univ Yale
Indiana University Foundation
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=27105529&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=ATE397661(T1) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Application filed by Univ Yale, Indiana University Foundation filed Critical Univ Yale
Application granted granted Critical
Publication of ATE397661T1 publication Critical patent/ATE397661T1/de

Links

Classifications

    • 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
    • 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
    • A61P37/04—Immunostimulants
    • 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
    • C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
    • 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
    • C07K2319/00—Fusion polypeptide
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10S530/00—Chemistry: natural resins or derivatives; peptides or proteins; lignins or reaction products thereof
    • Y10S530/827—Proteins from mammals or birds
    • Y10S530/839—Nerves; brain

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Organic Chemistry (AREA)
  • Immunology (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Zoology (AREA)
  • Toxicology (AREA)
  • Cell Biology (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Peptides Or Proteins (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)
  • Micro-Organisms Or Cultivation Processes Thereof (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Medicinal Preparation (AREA)
  • Use Of Switch Circuits For Exchanges And Methods Of Control Of Multiplex Exchanges (AREA)
  • Medicines Containing Material From Animals Or Micro-Organisms (AREA)
AT99101563T 1991-05-03 1992-05-01 Bindungsdomänen des delta-proteins ATE397661T1 (de)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US69518991A 1991-05-03 1991-05-03
US79192391A 1991-11-14 1991-11-14

Publications (1)

Publication Number Publication Date
ATE397661T1 true ATE397661T1 (de) 2008-06-15

Family

ID=27105529

Family Applications (4)

Application Number Title Priority Date Filing Date
AT99101563T ATE397661T1 (de) 1991-05-03 1992-05-01 Bindungsdomänen des delta-proteins
AT99101561T ATE473754T1 (de) 1991-05-03 1992-05-01 Verfahren zur manipulation der zelldifferenzierung
AT92911557T ATE226633T1 (de) 1991-05-03 1992-05-01 Bindungsdomänen in notch- und delta-proteinen
AT99101562T ATE386116T1 (de) 1991-05-03 1992-05-01 Bindungsdomänen des serrate-proteins

Family Applications After (3)

Application Number Title Priority Date Filing Date
AT99101561T ATE473754T1 (de) 1991-05-03 1992-05-01 Verfahren zur manipulation der zelldifferenzierung
AT92911557T ATE226633T1 (de) 1991-05-03 1992-05-01 Bindungsdomänen in notch- und delta-proteinen
AT99101562T ATE386116T1 (de) 1991-05-03 1992-05-01 Bindungsdomänen des serrate-proteins

Country Status (12)

Country Link
US (1) US5849869A (de)
EP (4) EP0933082B1 (de)
JP (7) JPH07503123A (de)
AT (4) ATE397661T1 (de)
AU (1) AU675203B2 (de)
CA (1) CA2102208C (de)
DE (4) DE69233791D1 (de)
DK (4) DK0930366T3 (de)
ES (4) ES2181674T5 (de)
IE (2) IE921367A1 (de)
IL (1) IL101728A (de)
WO (1) WO1992019734A1 (de)

Families Citing this family (75)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
IL101728A (en) * 1991-05-03 2007-08-19 Univ Yale Human Abandonment and Delta, Restrictive Areas of Effect in Tophoric Proteins, and Methods Based on Them
US5869282A (en) * 1991-12-11 1999-02-09 Imperial Cancer Research Technology, Ltd. Nucleotide and protein sequences of the serrate gene and methods based thereon
US6004924A (en) 1991-12-11 1999-12-21 Imperial Cancer Research Technology, Ltd. Protein sequences of serrate gene products
US5786158A (en) * 1992-04-30 1998-07-28 Yale University Therapeutic and diagnostic methods and compositions based on notch proteins and nucleic acids
US20050112121A1 (en) * 1992-04-30 2005-05-26 Yale University Therapeutic and diagnostic methods and compositions based on notch proteins and nucleic acids
US5750652A (en) * 1994-01-21 1998-05-12 Yale University Deltex proteins
CA2226087C (en) 1995-06-28 2012-01-31 Imperial Cancer Research Technology, Ltd. Nucleotide and protein sequences of vertebrate delta genes and methods based thereon
US20050158859A1 (en) * 1995-09-29 2005-07-21 Yale University Manipulation of non-terminally differentiated cells using the Notch pathway
US5780300A (en) * 1995-09-29 1998-07-14 Yale University Manipulation of non-terminally differentiated cells using the notch pathway
DE69635899T2 (de) 1995-11-17 2006-11-23 Asahi Kasei Kabushiki Kaisha Polypeptid, das die differenzierung unterdrueckt
AU728798B2 (en) * 1995-11-22 2001-01-18 Yale University Vertebrate deltex proteins, nucleic acids, and antibodies, and related methods and compositions
EP0913404B1 (de) * 1996-07-16 2006-06-14 Asahi Kasei Kabushiki Kaisha Differenzierungsinhibitor
US6887475B1 (en) 1996-11-07 2005-05-03 Lorantis Limited Notch
TR199901000T2 (xx) * 1996-11-07 1999-07-21 Lorantis Limited �entik.
US6121045A (en) * 1997-04-04 2000-09-19 Millennium Biotherapeutics, Inc. Human Delta3 nucleic acid molecules
ES2275304T3 (es) 1997-04-04 2007-06-01 Millennium Pharmaceuticals, Inc. Nuevas composiciones de delta-3 humana y usos diagnosticos y terapeuticos para las mismas.
US20060122373A1 (en) 1997-04-04 2006-06-08 Millennium Pharmaceuticals, Inc. Delta3, FTHMA-070, Tango85, Tango77, SPOIL,NEOKINE, Tango129 and integrin alpha subunit protein and nucleic acid molecules and uses thereof
US6664098B1 (en) 1997-05-14 2003-12-16 Asahi Kasei Kabushiki Kaisha Differentiation inhibitory agent
US6436650B1 (en) * 1997-07-23 2002-08-20 Yale University Activated forms of notch and methods based thereon
US6692919B1 (en) 1997-07-23 2004-02-17 Yale University Activated forms of notch and methods based thereon
US6392019B1 (en) 1997-11-22 2002-05-21 John Ford Antibodies specific for EGF motif proteins
US6808890B2 (en) 1999-07-28 2004-10-26 Nuvelo, Inc. Method of detecting a cancerous cell expressing EGFL6, and EGF mutif protein
AU763012B2 (en) 1997-11-22 2003-07-10 Arca Biopharma, Inc. A novel EGF motif protein obtained from a cDNA library of fetal liver-spleen
CA2329053A1 (en) * 1998-05-28 1999-12-02 Incyte Pharmaceuticals, Inc. Human socs proteins
US8084258B2 (en) 1999-07-12 2011-12-27 University Of Basel Manipulation of tissue of organ type using the notch pathway
GB9927328D0 (en) 1999-11-18 2000-01-12 Lorantis Ltd Immunotherapy
US6448197B1 (en) * 2000-07-13 2002-09-10 Exxonmobil Chemical Patents Inc. Method for making a metal containing small pore molecular sieve catalyst
US8044259B2 (en) * 2000-08-03 2011-10-25 The Regents Of The University Of Michigan Determining the capability of a test compound to affect solid tumor stem cells
US6984522B2 (en) 2000-08-03 2006-01-10 Regents Of The University Of Michigan Isolation and use of solid tumor stem cells
WO2002018544A2 (en) * 2000-08-31 2002-03-07 Loyola University Chicago Method and reagents for treatment of skin disorders by modulating the notch pathway
US7399633B2 (en) * 2000-10-27 2008-07-15 Fred Hutchinson Cancer Research Center Methods for immortalizing cells
GB0118155D0 (en) 2001-07-25 2001-09-19 Lorantis Ltd Superantigen
CA2469204A1 (en) * 2001-12-07 2003-06-19 Regents Of The University Of Michigan Prospective identification and characterization of breast cancer stem cells
EP1639090A4 (de) * 2003-06-09 2008-04-16 Univ Michigan Zusammensetzungen und verfahren zur behandlung und diagnose von krebs
AU2005209909B8 (en) * 2004-02-03 2009-01-15 The Regents Of The University Of Michigan Compositions and methods for characterizing, regulating, diagnosing, and treating cancer
US20060252073A1 (en) * 2005-04-18 2006-11-09 Regents Of The University Of Michigan Compositions and methods for the treatment of cancer
US20070099209A1 (en) * 2005-06-13 2007-05-03 The Regents Of The University Of Michigan Compositions and methods for treating and diagnosing cancer
WO2006138275A2 (en) * 2005-06-13 2006-12-28 The Regents Of The University Of Michigan Compositions and methods for treating and diagnosing cancer
US7723112B2 (en) * 2005-10-31 2010-05-25 The Regents Of The University Of Michigan Compositions and methods for treating and diagnosing cancer
US7723477B2 (en) 2005-10-31 2010-05-25 Oncomed Pharmaceuticals, Inc. Compositions and methods for inhibiting Wnt-dependent solid tumor cell growth
WO2007133250A2 (en) 2005-10-31 2007-11-22 Austin Gurney Compositions and methods for diagnosing and treating cancer
ES2413087T3 (es) 2006-06-13 2013-07-15 Oncomed Pharmaceuticals, Inc. Composiciones y métodos para el diagnóstico y tratamiento del cáncer
US7750124B2 (en) 2006-09-29 2010-07-06 Oncomed Pharmaceuticals, Inc. Anti-human DLL4 antibodies and compositions
RU2448979C2 (ru) * 2006-12-14 2012-04-27 Ридженерон Фармасьютикалз, Инк. Антитела человека к дельта-подобному лиганду-4 человека
MX2009006500A (es) 2006-12-18 2009-06-26 Genentech Inc Anticuerpos antagonistas anti-notch3 y su uso en la prevencion y el tratamiento de enfermedades relacionadas con el receptor notch3.
EP2125887A4 (de) 2007-01-24 2010-11-10 Oncomed Pharm Inc Zusammensetzungen und verfahren zur behandlung und diagnostizierung von krebs
US8148147B2 (en) * 2007-01-24 2012-04-03 The Regents Of The University Of Michigan Compositions and methods for treating and diagnosing pancreatic cancer
PE20090321A1 (es) 2007-06-04 2009-04-20 Genentech Inc Anticuerpos anti-notch1 nrr, metodo de preparacion y composicion farmaceutica
US8068607B2 (en) 2007-07-31 2011-11-29 Ricoh Company, Limited Information processing apparatus and information processing method
US8551659B2 (en) 2007-11-12 2013-10-08 Gs Yuasa International Ltd. Active material for lithium secondary battery, lithium secondary battery, and method for producing the same
PT2307459E (pt) 2008-07-08 2015-03-11 Oncomed Pharm Inc Agentes de ligação a receptor notch1 e métodos da sua utilização
US9132189B2 (en) 2008-07-08 2015-09-15 Oncomed Pharmaceuticals, Inc. Notch1 binding agents and methods of use thereof
TWI506037B (zh) 2008-09-26 2015-11-01 Oncomed Pharm Inc 捲曲結合劑類及彼等之用途
HUE029661T2 (en) 2009-10-16 2017-03-28 Oncomed Pharm Inc A therapeutic combination and use of DLL4 antagonist antibodies and antihypertensive agents
TWI535445B (zh) 2010-01-12 2016-06-01 安可美德藥物股份有限公司 Ｗｎｔ拮抗劑及治療和篩選方法
JP2013530929A (ja) 2010-04-01 2013-08-01 オンコメッド ファーマシューティカルズ インコーポレイテッド ｆｒｉｚｚｌｅｄ結合剤およびその使用
CA3090548A1 (en) 2010-04-09 2011-10-13 Fred Hutchinson Cancer Research Center Compositions and methods for providing hematopoietic function
JP6165627B2 (ja) 2010-04-09 2017-07-19 フレッド ハッチンソン キャンサー リサーチ センター Ｈｌａの適合なしに造血機能を提供するための組成物および方法
US8551479B2 (en) 2010-09-10 2013-10-08 Oncomed Pharmaceuticals, Inc. Methods for treating melanoma
TWI583699B (zh) 2011-09-23 2017-05-21 安可美德藥物股份有限公司 Ｖｅｇｆ／ｄｌｌ４結合劑類及彼等之用途
AU2012347534B2 (en) 2011-12-08 2018-01-25 Fred Hutchinson Cancer Research Center Compositions and methods for enhanced generation of hematopoietic stem/progenitor cells
WO2014066328A1 (en) 2012-10-23 2014-05-01 Oncomed Pharmaceuticals, Inc. Methods of treating neuroendocrine tumors using wnt pathway-binding agents
WO2014071018A1 (en) 2012-10-31 2014-05-08 Oncomed Pharmaceuticals, Inc. Methods and monitoring of treatment with a dll4 antagonist
EP2943566A1 (de) 2013-01-08 2015-11-18 Fred Hutchinson Cancer Research Center Zusammensetzungen und verfahren zur expansion von embryonalen hämatopoetischen stammzellen
WO2014121196A1 (en) 2013-02-04 2014-08-07 Oncomed Pharmaceuticals, Inc. Methods and monitoring of treatment with a wnt pathway inhibitor
US9168300B2 (en) 2013-03-14 2015-10-27 Oncomed Pharmaceuticals, Inc. MET-binding agents and uses thereof
MX2016005689A (es) 2013-10-31 2016-08-08 Hutchinson Fred Cancer Res Celulas no t efectoras y madre/progenitoras hematopoyeticas modificadas y usos de estas.
CA2949981C (en) 2014-06-04 2023-03-14 Fred Hutchinson Cancer Research Center Expansion and engraftment of stem cells using notch 1 and/or notch 2 agonists
WO2016070051A2 (en) 2014-10-31 2016-05-06 Oncomed Pharmaceuticals, Inc. Combination therapy for treatment of disease
WO2016176651A2 (en) 2015-04-29 2016-11-03 Fred Hutchinson Cancer Research Center Modified hematopoietic stem/progenitor and non-t effector cells, and uses thereof
EP3288570A4 (de) 2015-04-29 2018-11-21 Fred Hutchinson Cancer Research Center Modifizierte stammzellen und verwendungen davon
WO2017053705A1 (en) 2015-09-23 2017-03-30 Oncomed Pharmaceuticals, Inc. Methods and compositions for treatment of cancer
RU2747728C2 (ru) 2015-12-04 2021-05-13 Фред Хатчинсон Кэнсер Рисерч Сентер Применение размноженных популяций гематопоэтических стволовых клеток/клеток-предшественников
WO2020056170A1 (en) 2018-09-12 2020-03-19 Fred Hutchinson Cancer Research Center Reducing cd33 expression to selectively protect therapeutic cells
WO2023150393A2 (en) 2022-02-07 2023-08-10 Ensoma, Inc. Inhibitor-resistant mgmt modifications and modification of mgmt-encoding nucleic acids

Family Cites Families (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3884853A (en) * 1973-11-14 1975-05-20 Staley Mfg Co A E Alkali-curable cationic/anionic starch for paper coating binders
US5115096A (en) * 1988-04-15 1992-05-19 Oncogen Amphiregulin: a bifunctional growth modulating glycoprotein
US5098833A (en) * 1989-02-23 1992-03-24 Genentech, Inc. DNA sequence encoding a functional domain of a lymphocyte homing receptor
US5368712A (en) * 1989-11-02 1994-11-29 Synporin Technologies, Inc. Biologically mimetic synthetic ion channel transducers
WO1992010518A1 (en) * 1990-12-07 1992-06-25 Yale University Purified slit protein and sequence elements thereof
IL101728A (en) * 1991-05-03 2007-08-19 Univ Yale Human Abandonment and Delta, Restrictive Areas of Effect in Tophoric Proteins, and Methods Based on Them
WO1993012141A1 (en) * 1991-12-11 1993-06-24 Yale University Nucleotide and protein sequences of the serrate gene and methods based thereon
JPH08509358A (ja) * 1992-12-11 1996-10-08 アメリカ合衆国 神経内分泌腫瘍で発現されるδ様遺伝子

Also Published As

Publication number Publication date
IL101728A0 (en) 1992-12-30
ATE386116T1 (de) 2008-03-15
IE85350B1 (en) 2009-10-14
AU1919792A (en) 1992-12-21
JP4430891B2 (ja) 2010-03-10
WO1992019734A1 (en) 1992-11-12
DK0930365T3 (da) 2008-06-02
IL101728A (en) 2007-08-19
ES2181674T3 (es) 2003-03-01
EP0576623A4 (de) 1995-01-18
US5849869A (en) 1998-12-15
JP2011135886A (ja) 2011-07-14
JP2011155979A (ja) 2011-08-18
EP0930366A2 (de) 1999-07-21
ES2303363T3 (es) 2008-08-01
DE69233735D1 (de) 2008-07-17
CA2102208C (en) 2003-04-29
ES2310933T3 (es) 2009-01-16
EP0933082B1 (de) 2010-07-14
AU675203B2 (en) 1997-01-30
EP0576623B2 (de) 2007-10-03
JP2008005843A (ja) 2008-01-17
JP2007330259A (ja) 2007-12-27
EP0576623A1 (de) 1994-01-05
EP0930365A3 (de) 1999-07-28
DE69233791D1 (de) 2010-08-26
IE20030774A1 (en) 2003-12-10
DE69232832D1 (de) 2002-11-28
DK0933082T3 (da) 2010-10-25
DK0576623T3 (da) 2003-02-24
EP0930366B1 (de) 2008-06-04
ES2181674T5 (es) 2008-03-01
ATE473754T1 (de) 2010-07-15
JP4604228B2 (ja) 2011-01-05
CA2102208A1 (en) 1992-11-12
DK0930366T3 (da) 2008-10-13
JP2004065243A (ja) 2004-03-04
EP0933082A1 (de) 1999-08-04
DE69232832T2 (de) 2003-06-18
EP0576623B1 (de) 2002-10-23
EP0930366A3 (de) 1999-07-28
IE921367A1 (en) 1992-11-04
DE69232832T3 (de) 2008-02-28
JP2007330258A (ja) 2007-12-27
DE69233724T2 (de) 2009-04-02
JPH07503123A (ja) 1995-04-06
ATE226633T1 (de) 2002-11-15
DK0576623T4 (da) 2008-01-02
JP4604227B2 (ja) 2011-01-05
DE69233724D1 (de) 2008-03-27
EP0930365B1 (de) 2008-02-13
ES2348919T3 (es) 2010-12-16
EP0930365A2 (de) 1999-07-21

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