KR20200010428A - Nkg2d, cd16, 및 ror1 또는 ror2에 결합하는 단백질 - Google Patents

Nkg2d, cd16, 및 ror1 또는 ror2에 결합하는 단백질 Download PDF

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KR20200010428A
KR20200010428A KR1020197037751A KR20197037751A KR20200010428A KR 20200010428 A KR20200010428 A KR 20200010428A KR 1020197037751 A KR1020197037751 A KR 1020197037751A KR 20197037751 A KR20197037751 A KR 20197037751A KR 20200010428 A KR20200010428 A KR 20200010428A
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그레고리 피. 창
앤 에프. 층
윌리엄 해니
브래들리 엠. 룬드
비앙카 프린츠
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드래곤플라이 쎄라퓨틱스, 인크.
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    • 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
    • C07K14/70503—Immunoglobulin superfamily
    • C07K14/70535—Fc-receptors, e.g. CD16, CD32, CD64 (CD2314/705F)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • C07K16/2803—Immunoglobulins [IG], 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
    • 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
    • C07K16/2803—Immunoglobulins [IG], 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
    • C07K16/283—Immunoglobulins [IG], 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 Fc-receptors, e.g. CD16, CD32, CD64
    • 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
    • C07K16/2851—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the lectin superfamily, e.g. CD23, CD72
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    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/63—Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
    • C12N15/79—Vectors or expression systems specially adapted for eukaryotic hosts
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    • C—CHEMISTRY; METALLURGY
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    • C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
    • C12N5/06—Animal cells or tissues; Human cells or tissues
    • C12N5/0602—Vertebrate cells
    • C12N5/0634—Cells from the blood or the immune system
    • C12N5/0646—Natural killers cells [NK], NKT 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
    • A61K2039/507—Comprising a combination of two or more separate antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • C—CHEMISTRY; METALLURGY
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    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
    • C07K2317/31—Immunoglobulins specific features characterized by aspects of specificity or valency multispecific
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
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    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/52—Constant or Fc region; Isotype
    • C07K2317/524—CH2 domain
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/52—Constant or Fc region; Isotype
    • C07K2317/53—Hinge
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/73—Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
    • C07K2317/94—Stability, e.g. half-life, pH, temperature or enzyme-resistance
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
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    • C12N2501/00—Active agents used in cell culture processes, e.g. differentation
    • C12N2501/50—Cell markers; Cell surface determinants
    • C12N2501/599—Cell markers; Cell surface determinants with CD designations not provided for elsewhere
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
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    • C12N2501/00—Active agents used in cell culture processes, e.g. differentation
    • C12N2501/998—Proteins not provided for elsewhere

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  • Proteomics, Peptides & Aminoacids (AREA)
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  • Animal Behavior & Ethology (AREA)
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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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  • Gastroenterology & Hepatology (AREA)
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  • Hematology (AREA)
  • Epidemiology (AREA)
  • Peptides Or Proteins (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Medicines Containing Material From Animals Or Micro-Organisms (AREA)
  • Micro-Organisms Or Cultivation Processes Thereof (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)
KR1020197037751A 2017-05-23 2018-05-22 Nkg2d, cd16, 및 ror1 또는 ror2에 결합하는 단백질 Ceased KR20200010428A (ko)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
US201762510135P 2017-05-23 2017-05-23
US62/510,135 2017-05-23
US201762549200P 2017-08-23 2017-08-23
US62/549,200 2017-08-23
PCT/US2018/033952 WO2018217799A1 (en) 2017-05-23 2018-05-22 A protein binding nkg2d, cd16 and ror1 or ror2

Publications (1)

Publication Number Publication Date
KR20200010428A true KR20200010428A (ko) 2020-01-30

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KR1020197037751A Ceased KR20200010428A (ko) 2017-05-23 2018-05-22 Nkg2d, cd16, 및 ror1 또는 ror2에 결합하는 단백질

Country Status (11)

Country Link
US (1) US20200157174A1 (https=)
EP (1) EP3630183A4 (https=)
JP (1) JP2020521448A (https=)
KR (1) KR20200010428A (https=)
CN (1) CN111263643A (https=)
AU (1) AU2018271872A1 (https=)
BR (1) BR112019024654A2 (https=)
CA (1) CA3064743A1 (https=)
IL (1) IL270794A (https=)
MX (1) MX2019013998A (https=)
WO (1) WO2018217799A1 (https=)

Families Citing this family (22)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU2018219887B2 (en) 2017-02-08 2024-08-15 Dragonfly Therapeutics, LLC Multi-specific binding proteins for activation of natural killer cells and therapeutic uses thereof to treat cancer
CN110944661A (zh) 2017-02-20 2020-03-31 蜻蜓疗法股份有限公司 结合her2、nkg2d和cd16的蛋白质
GB201710835D0 (en) 2017-07-05 2017-08-16 Ucl Business Plc ROR1 Antibodies
GB201710836D0 (en) 2017-07-05 2017-08-16 Ucl Business Plc ROR1 Car T-Cells
GB201710838D0 (en) 2017-07-05 2017-08-16 Ucl Business Plc Bispecific antibodies
GB201721802D0 (en) * 2017-12-22 2018-02-07 Almac Discovery Ltd Ror1-specific antigen binding molecules
BR112020015994A2 (pt) 2018-02-08 2020-12-15 Dragonfly Therapeutics, Inc. Terapia de combinação do câncer que envolve proteínas de ligação multiespecíficas que ativam células natural killer
CA3237846A1 (en) 2018-02-08 2019-08-15 Dragonfly Therapeutics, Inc. Antibody variable domains targeting the nkg2d receptor
WO2019164930A1 (en) 2018-02-20 2019-08-29 Dragonfly Therapeutics, Inc. Multi-specific binding proteins that bind cd33, nkg2d, and cd16, and methods of use
KR102835308B1 (ko) 2018-08-08 2025-07-21 드래곤플라이 쎄라퓨틱스, 인크. Nkg2d, cd16 및 종양 관련 항원에 결합하는 단백질
EA202091888A1 (ru) 2018-08-08 2020-10-23 Драгонфлай Терапьютикс, Инк. Вариабельные домены антител, нацеленные на рецептор nkg2d
EP3833392A4 (en) 2018-08-08 2022-05-18 Dragonfly Therapeutics, Inc. MULTISPECIFIC BINDING PROTEINS FOR BINDING CD33, NKG2D AND CD16 AND METHODS OF USE
CN111378039B (zh) * 2018-12-29 2021-08-24 深圳大学 治疗恶性肿瘤的抗体及其应用
CN111378040B (zh) * 2018-12-29 2021-08-10 深圳大学 检测多种恶性肿瘤细胞的抗体及其应用
JP7512394B2 (ja) 2020-05-06 2024-07-08 ドラゴンフライ セラピューティクス， インコーポレイテッド Ｎｋｇ２ｄ、ｃｄ１６及びｃｌｅｃ１２ａに結合するタンパク質
US12144827B2 (en) 2021-02-25 2024-11-19 Lyell Immunopharma, Inc. ROR1 targeting chimeric antigen receptor
EP4301774A4 (en) 2021-03-03 2025-08-13 Dragonfly Therapeutics Inc METHODS OF TREATING CANCER USING MULTI-SPECIFIC BINDING PROTEINS THAT BIND TO NKG2D, CD16, AND A TUMOR-ASSOCIATED ANTIGEN
IL312204A (en) 2021-10-28 2024-06-01 Lyell Immunopharma Inc Methods for culturing cells expressing ror1-binding protein
WO2024064952A1 (en) 2022-09-23 2024-03-28 Lyell Immunopharma, Inc. Methods for culturing nr4a-deficient cells overexpressing c-jun
WO2024064958A1 (en) 2022-09-23 2024-03-28 Lyell Immunopharma, Inc. Methods for culturing nr4a-deficient cells
WO2024077174A1 (en) 2022-10-05 2024-04-11 Lyell Immunopharma, Inc. Methods for culturing nr4a-deficient cells
WO2025217398A1 (en) 2024-04-10 2025-10-16 Lyell Immunopharma, Inc. Methods for culturing cells with improved culture medium

Family Cites Families (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
NZ573646A (en) * 2006-06-12 2012-04-27 Wyeth Llc Single-chain multivalent binding proteins with effector function
AU2008337517B2 (en) * 2007-12-14 2014-06-26 Novo Nordisk A/S Antibodies against human NKG2D and uses thereof
WO2010017103A2 (en) * 2008-08-04 2010-02-11 The United States Of America, As Represented By The Secretary, Department Of Health And Human Servic Fully human anti-human nkg2d monoclonal antibodies
US9242014B2 (en) * 2010-06-15 2016-01-26 The Regents Of The University Of California Receptor tyrosine kinase-like orphan receptor 1 (ROR1) single chain Fv antibody fragment conjugates and methods of use thereof
EP2714738B1 (en) * 2011-05-24 2018-10-10 Zyngenia, Inc. Multivalent and monovalent multispecific complexes and their uses
EA035419B9 (ru) * 2014-05-29 2020-08-07 Мэкроудженикс, Инк. Триспецифичные связывающие молекулы и способы их применения
CA2973720A1 (en) * 2015-01-14 2016-07-21 Compass Therapeutics Llc Multispecific immunomodulatory antigen-binding constructs
WO2016122701A1 (en) * 2015-01-26 2016-08-04 Macrogenics, Inc. Anti-dr5 antibodies and molecules comprising dr5-binding domains thereof
US11673957B2 (en) * 2015-03-10 2023-06-13 Eureka Therapeutics, Inc. Anti-ROR2 antibodies
WO2016187220A2 (en) * 2015-05-18 2016-11-24 Five Prime Therapeutics, Inc. Anti-ror1 antibodies
DK3313876T3 (da) * 2015-06-23 2025-04-22 Innate Pharma Multispecifikke antigenbindende proteiner
US20180327499A1 (en) * 2015-11-13 2018-11-15 INSERM (Institut National de la Santé et de la Recherche Médicale) Anti- nkg2d single domain antibodies and uses thereof
WO2017142928A1 (en) * 2016-02-17 2017-08-24 Macrogenics, Inc. Ror1-binding molecules, and methods of use thereof

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Publication number Publication date
CA3064743A1 (en) 2018-11-29
US20200157174A1 (en) 2020-05-21
BR112019024654A2 (pt) 2020-06-09
EP3630183A4 (en) 2021-03-03
WO2018217799A1 (en) 2018-11-29
AU2018271872A1 (en) 2019-12-12
IL270794A (en) 2020-01-30
JP2020521448A (ja) 2020-07-27
MX2019013998A (es) 2020-07-29
EP3630183A1 (en) 2020-04-08
CN111263643A (zh) 2020-06-09

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