MX390849B - Anticuerpos antagonistas anti-axl. - Google Patents

Anticuerpos antagonistas anti-axl.

Info

Publication number
MX390849B
MX390849B MX2017007941A MX2017007941A MX390849B MX 390849 B MX390849 B MX 390849B MX 2017007941 A MX2017007941 A MX 2017007941A MX 2017007941 A MX2017007941 A MX 2017007941A MX 390849 B MX390849 B MX 390849B
Authority
MX
Mexico
Prior art keywords
axl
antagonist antibodies
antibodies
axl antagonist
gas6
Prior art date
Application number
MX2017007941A
Other languages
English (en)
Spanish (es)
Other versions
MX2017007941A (es
Inventor
David Robert Micklem
James Bradley Lorens
Lavina Ahmed
Linn Hodneland Nilsson
Sergej Kiprijanov
Tone Sandal
Original Assignee
Bergenbio Asa
Bergen Teknologioverfoering 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 Bergenbio Asa, Bergen Teknologioverfoering As filed Critical Bergenbio Asa
Publication of MX2017007941A publication Critical patent/MX2017007941A/es
Publication of MX390849B publication Critical patent/MX390849B/es

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
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2863—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against receptors for growth factors, growth regulators
    • 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
    • A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
    • A61K39/39558—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against tumor tissues, cells, antigens
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/30—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants from tumour cells
    • 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
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/30—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants from tumour cells
    • C07K16/3015—Breast
    • 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
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/30—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants from tumour cells
    • C07K16/3023—Lung
    • 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
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/30—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants from tumour cells
    • C07K16/3061—Blood cells
    • 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
    • G01N33/574—Immunoassay; Biospecific binding assay; Materials therefor for cancer
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/24—Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
    • 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
    • C07K2317/33—Crossreactivity, e.g. for species or epitope, or lack of said crossreactivity
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/40—Immunoglobulins specific features characterized by post-translational modification
    • C07K2317/41—Glycosylation, sialylation, or fucosylation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
    • C07K2317/565—Complementarity determining region [CDR]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
    • C07K2317/567—Framework region [FR]
    • 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
    • C07K2317/73—Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
    • C07K2317/732—Antibody-dependent cellular cytotoxicity [ADCC]
    • 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
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/77—Internalization into the cell
    • 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
    • C07K2317/92—Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
    • 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
    • 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
    • G01N2333/71—Assays involving receptors, cell surface antigens or cell surface determinants for growth factors; for growth regulators

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Immunology (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Molecular Biology (AREA)
  • Biochemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Genetics & Genomics (AREA)
  • Biophysics (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • Cell Biology (AREA)
  • Oncology (AREA)
  • Biomedical Technology (AREA)
  • Hematology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Microbiology (AREA)
  • Epidemiology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Urology & Nephrology (AREA)
  • Mycology (AREA)
  • Biotechnology (AREA)
  • Hospice & Palliative Care (AREA)
  • Food Science & Technology (AREA)
  • Physics & Mathematics (AREA)
  • Analytical Chemistry (AREA)
  • General Physics & Mathematics (AREA)
  • Pathology (AREA)
  • Peptides Or Proteins (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)
  • Micro-Organisms Or Cultivation Processes Thereof (AREA)
MX2017007941A 2014-12-18 2015-12-18 Anticuerpos antagonistas anti-axl. MX390849B (es)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB201422605 2014-12-18
PCT/EP2015/080654 WO2016097370A2 (en) 2014-12-18 2015-12-18 Anti-axl antagonistic antibodies

Publications (2)

Publication Number Publication Date
MX2017007941A MX2017007941A (es) 2018-01-30
MX390849B true MX390849B (es) 2025-03-21

Family

ID=55080088

Family Applications (1)

Application Number Title Priority Date Filing Date
MX2017007941A MX390849B (es) 2014-12-18 2015-12-18 Anticuerpos antagonistas anti-axl.

Country Status (9)

Country Link
US (3) US10208121B2 (OSRAM)
EP (1) EP3233119A2 (OSRAM)
JP (2) JP6931609B2 (OSRAM)
KR (1) KR102453227B1 (OSRAM)
CN (2) CN107531786B (OSRAM)
AU (1) AU2015366213B2 (OSRAM)
CA (1) CA2969879A1 (OSRAM)
MX (1) MX390849B (OSRAM)
WO (1) WO2016097370A2 (OSRAM)

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB201410826D0 (en) * 2014-06-18 2014-07-30 Bergenbio As Anti-axl antibodies
GB201410825D0 (en) * 2014-06-18 2014-07-30 Bergenbio As Anti-axl antibodies
WO2016097370A2 (en) * 2014-12-18 2016-06-23 Bergen Teknologioverføring As Anti-axl antagonistic antibodies
GB201506411D0 (en) 2015-04-15 2015-05-27 Bergenbio As Humanized anti-axl antibodies
GB201509338D0 (en) 2015-05-29 2015-07-15 Bergenbio As Combination therapy
GB201610902D0 (en) * 2016-06-22 2016-08-03 Bergen Teknologioverforing As And Bergenbio As Anti-Axl Antagonistic Antibodies
US11912775B2 (en) * 2017-07-18 2024-02-27 Kyowa Kirin Co., Ltd. Anti-human CCR1 monoclonal antibody
CN112218895A (zh) * 2018-04-10 2021-01-12 健玛保 用于癌症治疗的axl特异性抗体
US20210215697A1 (en) * 2018-05-14 2021-07-15 Bergenbio Asa Serum Biomarkers
CN110540592B (zh) 2018-05-29 2022-08-09 杭州尚健生物技术有限公司 结合axl蛋白的抗体及其应用
CN109206489A (zh) * 2018-09-29 2019-01-15 未名生物医药有限公司 蛋白序列12g12及其用途
CN109206490A (zh) * 2018-09-29 2019-01-15 未名生物医药有限公司 蛋白序列11b09及其用途
US12331320B2 (en) 2018-10-10 2025-06-17 The Research Foundation For The State University Of New York Genome edited cancer cell vaccines
US20220177593A1 (en) * 2019-03-29 2022-06-09 Celldex Therapeutics, Inc. Anti-axl antibodies and methods of use thereof
GB201912059D0 (en) 2019-08-22 2019-10-09 Bergenbio As Combaination therapy of a patient subgroup
WO2021154156A1 (en) * 2020-01-31 2021-08-05 Agency For Science, Technology And Research Anti-axl antibody and uses thereof
WO2021171257A1 (en) 2020-02-28 2021-09-02 Symphogen A/S Anti-axl antibodies and compositions
GB202004189D0 (en) 2020-03-23 2020-05-06 Bergenbio As Combination therapy
WO2021204713A1 (en) 2020-04-08 2021-10-14 Bergenbio Asa Axl inhibitors for antiviral therapy
GB202006072D0 (en) 2020-04-24 2020-06-10 Bergenbio Asa Method of selecting patients for treatment with cmbination therapy
CN116635064A (zh) 2020-12-18 2023-08-22 世纪治疗股份有限公司 具有适应性受体特异性的嵌合抗原受体系统
MX2023008744A (es) 2021-01-29 2023-10-02 Illimis Therapeutics Inc Molecula de fusion que tiene actividad no inflamatoria inductora de la fagocitosis.
GB202104037D0 (en) 2021-03-23 2021-05-05 Bergenbio Asa Combination therapy
AU2021451307A1 (en) * 2021-06-16 2024-02-01 Shanghai Sinobay Biotechnology Co., Ltd. Antibody targeting axl protein and antigen binding fragment thereof, preparation method therefor and use thereof
US12173081B2 (en) 2023-03-21 2024-12-24 Biograph 55, Inc. CD19/CD38 multispecific antibodies

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EP1382969A1 (en) 2002-07-17 2004-01-21 Max-Planck-Gesellschaft zur Förderung der Wissenschaften e.V. Diagnosis and prevention of cancer cell invasion
ES2556214T3 (es) * 2007-11-12 2016-01-14 U3 Pharma Gmbh Anticuerpos para AXL
EP2853544A1 (en) * 2007-11-15 2015-04-01 Chugai Seiyaku Kabushiki Kaisha Monoclonal antibody capable of binding to anexelekto, and use thereof
KR20120035145A (ko) 2009-05-11 2012-04-13 우드라이 파마 게엠베하 인간화 ａｘｌ 항체
TW201106972A (en) 2009-07-27 2011-03-01 Genentech Inc Combination treatments
TW201204388A (en) * 2010-06-18 2012-02-01 Genentech Inc Anti-Axl antibodies and methods of use
JP5753905B2 (ja) 2011-05-06 2015-07-22 チョンシャン ホスピタル フダン ユニバーシティ 血漿ｍｉｃｒｏＲＮＡの組合せからなる肝細胞がん診断マーカーを含む、肝細胞がんの診断キット
JP6033293B2 (ja) * 2011-06-22 2016-11-30 インサーム（インスティテュ ナシオナル ドゥ ラ サンテ エ ドゥ ラ ルシェルシェ メディカル）Ｉｎｓｅｒｍ（Ｉｎｓｔｉｔｕｔ Ｎａｔｉｏｎａｌ Ｄｅｌａ Ｓａｎｔｅ Ｅｔ Ｄｅ Ｌａ Ｒｅｃｈｅｒｃｈｅ Ｍｅｄｉｃａｌｅ） 抗Ａｘｌ抗体及びその使用
KR20140104945A (ko) * 2011-06-22 2014-08-29 인쎄름 (엥스띠뛰 나씨오날 드 라 쌍떼 에 드 라 흐쉐르슈 메디깔) 항-ａｘｌ 항체 및 그의 용도
EP2589609A1 (en) * 2011-11-03 2013-05-08 Pierre Fabre Medicament Antigen binding protein and its use as addressing product for the treatment of cancer
US9879061B2 (en) * 2011-12-15 2018-01-30 The Board Of Trustees Of The Leland Stanford Junior University Inhibition of AXL/GAS6 signaling in the treatment of liver fibrosis
EP2868644B1 (en) 2012-06-29 2018-08-01 Mitsubishi Gas Chemical Company, Inc. Method and apparatus for separating alkyl aromatic hydrocarbon
DK2914630T3 (da) * 2012-11-05 2021-04-26 Pf Medicament Hidtil ukendte antigen-bindende proteiner og deres anvendelse som adresseringsprodukt til behandling af kræft
GB201410825D0 (en) * 2014-06-18 2014-07-30 Bergenbio As Anti-axl antibodies
GB201410826D0 (en) * 2014-06-18 2014-07-30 Bergenbio As Anti-axl antibodies
US9986723B2 (en) * 2014-10-22 2018-06-05 The Board Of Regents Of The University Of Texas System Screen and use of therapeutics for pancreatic ductal adenocarcinoma
WO2016097370A2 (en) * 2014-12-18 2016-06-23 Bergen Teknologioverføring As Anti-axl antagonistic antibodies
GB201610902D0 (en) * 2016-06-22 2016-08-03 Bergen Teknologioverforing As And Bergenbio As Anti-Axl Antagonistic Antibodies

Also Published As

Publication number Publication date
KR102453227B1 (ko) 2022-10-11
JP2018506961A (ja) 2018-03-15
WO2016097370A2 (en) 2016-06-23
EP3233119A2 (en) 2017-10-25
KR20170099918A (ko) 2017-09-01
MX2017007941A (es) 2018-01-30
CN116410318A (zh) 2023-07-11
US20230406941A1 (en) 2023-12-21
AU2015366213A1 (en) 2017-06-22
CN107531786A (zh) 2018-01-02
US20170349658A1 (en) 2017-12-07
US20190177419A1 (en) 2019-06-13
US11584796B2 (en) 2023-02-21
AU2015366213B2 (en) 2021-10-07
JP6931609B2 (ja) 2021-09-08
WO2016097370A3 (en) 2016-08-11
JP2021101707A (ja) 2021-07-15
CA2969879A1 (en) 2016-06-23
CN107531786B (zh) 2023-01-13
US10208121B2 (en) 2019-02-19

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