JP6947642B2 - 抗がん性融合ポリペプチド - Google Patents

抗がん性融合ポリペプチド Download PDF

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JP6947642B2
JP6947642B2 JP2017560331A JP2017560331A JP6947642B2 JP 6947642 B2 JP6947642 B2 JP 6947642B2 JP 2017560331 A JP2017560331 A JP 2017560331A JP 2017560331 A JP2017560331 A JP 2017560331A JP 6947642 B2 JP6947642 B2 JP 6947642B2
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JP2018519803A (ja
JP2018519803A5 (enExample
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マーロン ヒンナー
マーロン ヒンナー
アイバ ラシダ シハム ベル
アイバ ラシダ シハム ベル
クリスティーヌ ローテ
クリスティーヌ ローテ
シェーン オルヴィル
シェーン オルヴィル
コリンナ シュロッサー
コリンナ シュロッサー
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ピエリス ファーマシューティカルズ ゲーエムベーハー
ピエリス ファーマシューティカルズ ゲーエムベーハー
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00Antineoplastic agents
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K14/00Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/46Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • C07K14/47Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K14/00Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/705Receptors; Cell surface antigens; Cell surface determinants
    • C07K14/70575NGF/TNF-superfamily, e.g. CD70, CD95L, CD153, CD154
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K16/00Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
    • C07K16/18Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2878Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the NGF-receptor/TNF-receptor superfamily, e.g. CD27, CD30, CD40, CD95
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K16/00Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
    • C07K16/18Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/32Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against translation products of oncogenes
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K2317/00Immunoglobulins specific features
    • C07K2317/90Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
    • C07K2317/92Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K2319/00Fusion polypeptide
    • C07K2319/33Fusion polypeptide fusions for targeting to specific cell types, e.g. tissue specific targeting, targeting of a bacterial subspecies

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Immunology (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Toxicology (AREA)
  • Zoology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Cell Biology (AREA)
  • Oncology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Peptides Or Proteins (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Micro-Organisms Or Cultivation Processes Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)
  • Medicinal Preparation (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
JP2017560331A 2015-05-18 2016-05-18 抗がん性融合ポリペプチド Active JP6947642B2 (ja)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
EP15167927.1 2015-05-18
EP15167927 2015-05-18
EP16150508 2016-01-08
EP16150508.6 2016-01-08
PCT/EP2016/061071 WO2016184882A1 (en) 2015-05-18 2016-05-18 Anti-cancer fusion polypeptide

Publications (3)

Publication Number Publication Date
JP2018519803A JP2018519803A (ja) 2018-07-26
JP2018519803A5 JP2018519803A5 (enExample) 2019-06-20
JP6947642B2 true JP6947642B2 (ja) 2021-10-13

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JP2017560331A Active JP6947642B2 (ja) 2015-05-18 2016-05-18 抗がん性融合ポリペプチド

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US (2) US10913778B2 (enExample)
EP (2) EP3298030B1 (enExample)
JP (1) JP6947642B2 (enExample)
KR (1) KR102685748B1 (enExample)
CN (1) CN108112253B (enExample)
AU (1) AU2016262845B2 (enExample)
CA (1) CA2980838A1 (enExample)
DK (1) DK3298030T5 (enExample)
ES (1) ES2938525T3 (enExample)
FI (1) FI3298030T3 (enExample)
HR (1) HRP20230145T1 (enExample)
HU (1) HUE061108T2 (enExample)
LT (1) LT3298030T (enExample)
MX (1) MX390894B (enExample)
PL (1) PL3298030T3 (enExample)
RS (1) RS64002B1 (enExample)
RU (2) RU2754466C2 (enExample)
SG (1) SG11201707426SA (enExample)
SI (1) SI3298030T1 (enExample)
SM (1) SMT202300026T1 (enExample)
WO (1) WO2016184882A1 (enExample)
ZA (1) ZA201706061B (enExample)

Families Citing this family (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015104406A2 (en) * 2014-01-13 2015-07-16 Pieris Ag Multi-specific polypeptide useful for localized tumor immunomodulation
RU2736312C2 (ru) * 2015-05-04 2020-11-13 ПИЕРИС ФАРМАСЬЮТИКАЛС ГмбХ Белки, специфичные в отношении cd137
KR20180029238A (ko) 2015-07-15 2018-03-20 피어이스 파마슈티컬즈 게엠베하 Lag-3에 특이적인 신규 단백질
AR106188A1 (es) 2015-10-01 2017-12-20 Hoffmann La Roche Anticuerpos anti-cd19 humano humanizados y métodos de utilización
EP3565843A1 (en) * 2017-01-03 2019-11-13 H. Hoffnabb-La Roche Ag Bispecific antigen binding molecules comprising anti-4-1bb clone 20h4.9
EP3565842A1 (en) 2017-01-06 2019-11-13 Crescendo Biologics Limited Single domain antibodies to programmed cell death (pd-1)
WO2018134279A1 (en) * 2017-01-18 2018-07-26 Pieris Pharmaceuticals Gmbh Novel fusion polypeptides specific for lag-3 and pd-1
WO2018134274A1 (en) 2017-01-18 2018-07-26 Pieris Pharmaceuticals Gmbh Lipocalin muteins with binding affinity for lag-3
JP7312168B2 (ja) * 2017-11-13 2023-07-20 クレッシェンド、バイオロジックス、リミテッド Cd137に結合するシングルドメイン抗体
GB201802573D0 (en) 2018-02-16 2018-04-04 Crescendo Biologics Ltd Therapeutic molecules that bind to LAG3
TW202003462A (zh) 2018-03-26 2020-01-16 德商4Sc製藥公司 用於癌症療法的包括hdac抑制劑和cd137激動劑之組合
HRP20230590T2 (hr) * 2018-07-31 2024-02-16 Pieris Pharmaceuticals Gmbh Novi fuzijski protein specifičan za cd137 i pd-l1
JP7476219B2 (ja) * 2019-02-26 2024-04-30 ピエリス ファーマシューティカルズ ゲーエムベーハー Cd137およびgpc3に特異的な新規融合タンパク質
KR20210146999A (ko) * 2019-03-29 2021-12-06 피어이스 파마슈티컬즈 게엠베하 리포칼린 뮤테인의 흡입 투여
EP3952996A1 (en) * 2019-04-12 2022-02-16 F. Hoffmann-La Roche AG Bispecific antigen binding molecules comprising lipocalin muteins
KR20200124176A (ko) * 2019-04-23 2020-11-02 주식회사 엘지화학 면역글로불린의 Fc 영역 및 GDF15를 포함하는 융합 폴리펩타이드
MX2021015452A (es) 2019-06-25 2022-02-11 Gilead Sciences Inc Proteinas de fusion flt3l-fc y metodos de uso.
TWI862640B (zh) * 2019-07-30 2024-11-21 英商拜西可泰克斯有限公司 異質雙環肽複合物
CN115960242B (zh) * 2021-09-09 2023-10-17 广东东阳光药业股份有限公司 抗癌结合分子及其应用
TW202428603A (zh) * 2022-09-21 2024-07-16 美商思進公司 新穎的cd137及cd228特異性融合蛋白

Family Cites Families (50)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3779221D1 (de) 1986-08-19 1992-06-25 Genentech Inc Einrichtung und dispersion zum intrapulmonalen eingeben von polypeptidwuchsstoffen und -zytokinen.
JPH01215289A (ja) 1988-02-22 1989-08-29 Toa Nenryo Kogyo Kk 遺伝子組換えによる正常ヒト血清アルブミンaの製造方法
FR2649991B2 (fr) 1988-08-05 1994-03-04 Rhone Poulenc Sante Utilisation de derives stables du plasmide pkd1 pour l'expression et la secretion de proteines heterologues dans les levures du genre kluyveromyces
US5728553A (en) 1992-09-23 1998-03-17 Delta Biotechnology Limited High purity albumin and method of producing
WO1995031479A1 (en) 1994-05-18 1995-11-23 Inhale Therapeutic Systems, Inc. Methods and compositions for the dry powder formulation of interferons
DE4417598A1 (de) 1994-05-19 1995-12-14 Max Planck Gesellschaft Verwendung des Tetracyclinpromotors zur stringent regulierten Produktion von rekombinanten Proteinen in prokaryontischen Zellen
AU5132096A (en) 1995-01-30 1996-08-21 Terrapin Technologies, Inc. Glubodies - multiplicities of proteins capable of binding a variety of small molecules
US5908621A (en) 1995-11-02 1999-06-01 Schering Corporation Polyethylene glycol modified interferon therapy
US6620413B1 (en) 1995-12-27 2003-09-16 Genentech, Inc. OB protein-polymer chimeras
DE19641876B4 (de) 1996-10-10 2011-09-29 Iba Gmbh Streptavidinmuteine
WO1998016873A1 (en) 1996-10-14 1998-04-23 Firm Forsat Ltd. Method for preparing dispersions of chromogenic components
DE19742706B4 (de) 1997-09-26 2013-07-25 Pieris Proteolab Ag Lipocalinmuteine
GB9722131D0 (en) 1997-10-20 1997-12-17 Medical Res Council Method
CA2233725A1 (en) 1998-03-31 1999-09-30 Hemosol Inc. Hemoglobin-hydroxyethyl starch complexes
TR200003635T2 (tr) 1998-06-08 2001-04-20 F.Hoffmann-La Roche Ag Peg-IFN-ALFA ve ribavirinin kronik hepatit C tedavisinde kullanılması.
US6403564B1 (en) 1998-10-16 2002-06-11 Schering Corporation Ribavirin-interferon alfa combination therapy for eradicating detectable HCV-RNA in patients having chronic hepatitis C infection
DE19926068C1 (de) 1999-06-08 2001-01-11 Arne Skerra Muteine des Bilin-Bindungsproteins
AU2001294617A1 (en) 2000-09-21 2002-04-02 University Of Massachusetts Method of inducing apoptosis in lymphoid cells
CA2440582A1 (en) 2001-03-09 2002-10-03 Dyax Corp. Serum albumin binding moieties
WO2003029462A1 (en) 2001-09-27 2003-04-10 Pieris Proteolab Ag Muteins of human neutrophil gelatinase-associated lipocalin and related proteins
EP1430136A1 (en) 2001-09-27 2004-06-23 Pieris ProteoLab AG Muteins of apolipoprotein d
AU2003275958A1 (en) 2003-08-25 2005-03-10 Pieris Proteolab Ag Muteins of tear lipocalin
AU2003264100A1 (en) 2003-08-25 2005-03-10 Pieris Proteolab Ag Muteins of a bilin-binding protein with affinity for a given target
US7288638B2 (en) * 2003-10-10 2007-10-30 Bristol-Myers Squibb Company Fully human antibodies against human 4-1BB
JP2007284351A (ja) 2004-07-27 2007-11-01 Osaka Bioscience Institute アミロイド蛋白質の凝集を抑制する物質とその作用
EP2899277A1 (en) 2004-11-26 2015-07-29 Pieris AG Compound with affinity for the cytotoxic T lymphocyte-associated antigen (CTLA-4)
JP2009509535A (ja) 2005-09-27 2009-03-12 アムニクス, インコーポレイテッド タンパク様薬剤およびその使用
US20070087005A1 (en) 2005-10-14 2007-04-19 Lazar Gregory A Anti-glypican-3 antibody
WO2007137170A2 (en) 2006-05-20 2007-11-29 Seattle Genetics, Inc. Anti-glypican-3 antibody drug conjugates
CN104650213A (zh) 2006-08-01 2015-05-27 皮里斯股份公司 泪液脂质运载蛋白的突变蛋白及其获得方法
ES2354653T3 (es) 2006-08-01 2011-03-16 Pieris Ag Muteínas de lipocalina lacrimal y procedimientos para obtener las mismas.
JP5868593B2 (ja) 2007-07-17 2016-02-24 メダレックス・リミテッド・ライアビリティ・カンパニーMedarex, L.L.C. Glypican−3に対するモノクローナル抗体
JP5848006B2 (ja) 2007-10-19 2016-01-27 アボット・ラボラトリーズAbbott Laboratories Ngalの検出用イムノアッセイ及びキット
CA2729322C (en) 2008-06-24 2020-05-26 Technische Universitaet Muenchen Muteins of hngal and related proteins with affinity for a given target
EP3660510A3 (en) 2009-12-07 2020-07-08 Pieris Pharmaceuticals GmbH Muteins of human lipocalin 2 (lcn2, hngal) with affinity for a given target
CA2808392C (en) 2010-08-16 2020-03-10 Pieris Pharmaceuticals Gmbh Binding proteins for hepcidin
CN103221428B (zh) * 2010-09-09 2016-02-10 辉瑞公司 4-1bb结合分子
EP2640740B1 (en) 2010-11-15 2017-03-15 Pieris Pharmaceuticals GmbH Muteins of human lipocalin 2 with affinity for glypican-3 (gpc3)
WO2013174783A1 (en) 2012-05-23 2013-11-28 Pieris Ag Lipocalin muteins with binding-affinity for glypican-3 (gpc-3) and use of lipocalin muteins for target-specific delivery to cells expressing gpc-3
JP2016505826A (ja) * 2012-12-10 2016-02-25 フレッド ハッチンソン キャンサー リサーチ センター スクリーニングの方法
WO2014116846A2 (en) * 2013-01-23 2014-07-31 Abbvie, Inc. Methods and compositions for modulating an immune response
CN104140974B (zh) * 2013-05-08 2017-09-29 科济生物医药(上海)有限公司 编码gpc‑3嵌合抗原受体蛋白的核酸及表达gpc‑3嵌合抗原受体蛋白的t淋巴细胞
WO2015104406A2 (en) 2014-01-13 2015-07-16 Pieris Ag Multi-specific polypeptide useful for localized tumor immunomodulation
ES2900898T3 (es) * 2014-04-07 2022-03-18 Chugai Pharmaceutical Co Ltd Anticuerpos biespecíficos inmunoactivadores
AU2016212087B2 (en) 2015-01-28 2019-11-07 Pieris Pharmaceuticals Gmbh Novel proteins specific for angiogenesis
BR112017017530A2 (pt) 2015-02-18 2018-04-17 Sanofi proteínas específicas para pioverdina e pioquelina
AU2016258977C1 (en) * 2015-05-04 2022-07-14 Pieris Pharmaceuticals Gmbh Anti-cancer fusion polypeptide
RU2736312C2 (ru) * 2015-05-04 2020-11-13 ПИЕРИС ФАРМАСЬЮТИКАЛС ГмбХ Белки, специфичные в отношении cd137
US10273275B2 (en) 2015-05-18 2019-04-30 Pieris Pharmaceuticals Gmbh Muteins of human lipocalin 2 with affinity for glypican-3 (GPC3) and methods of use thereof
TW201725212A (zh) 2015-12-10 2017-07-16 第一三共股份有限公司 特異性於降鈣素基因相關胜肽的新穎蛋白

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CN108112253B (zh) 2022-09-23
SI3298030T1 (sl) 2023-05-31
HRP20230145T1 (hr) 2023-04-28
RU2021119777A (ru) 2021-08-16
AU2016262845A1 (en) 2018-01-04
RS64002B1 (sr) 2023-03-31
RU2017135539A3 (enExample) 2019-11-29
EP3298030A1 (en) 2018-03-28
FI3298030T3 (fi) 2023-02-22
US20180148485A1 (en) 2018-05-31
SMT202300026T1 (it) 2023-03-17
ES2938525T3 (es) 2023-04-12
MX2017014716A (es) 2018-06-28
RU2017135539A (ru) 2019-06-18
AU2016262845B2 (en) 2020-07-23
WO2016184882A1 (en) 2016-11-24
MX390894B (es) 2025-03-21
DK3298030T5 (en) 2024-10-07
RU2754466C2 (ru) 2021-09-02
PL3298030T3 (pl) 2023-05-08
JP2018519803A (ja) 2018-07-26
US20210403516A1 (en) 2021-12-30
SG11201707426SA (en) 2017-10-30
CA2980838A1 (en) 2016-11-24
KR102685748B1 (ko) 2024-07-18
KR20180002855A (ko) 2018-01-08
LT3298030T (lt) 2023-02-27
ZA201706061B (en) 2022-05-25
US10913778B2 (en) 2021-02-09
CN108112253A (zh) 2018-06-01
US11919931B2 (en) 2024-03-05
EP4219535A1 (en) 2023-08-02
DK3298030T3 (en) 2023-02-06
BR112017020445A2 (pt) 2018-07-03
HUE061108T2 (hu) 2023-05-28
EP3298030B1 (en) 2023-01-18

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