AU2015366213B2 - Anti-Axl antagonistic antibodies - Google Patents

Anti-Axl antagonistic antibodies Download PDF

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Publication number
AU2015366213B2
AU2015366213B2 AU2015366213A AU2015366213A AU2015366213B2 AU 2015366213 B2 AU2015366213 B2 AU 2015366213B2 AU 2015366213 A AU2015366213 A AU 2015366213A AU 2015366213 A AU2015366213 A AU 2015366213A AU 2015366213 B2 AU2015366213 B2 AU 2015366213B2
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AU
Australia
Prior art keywords
antibody
seq
domain
antibodies
axi
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Ceased
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AU2015366213A
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English (en)
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AU2015366213A1 (en
Inventor
Lavina AHMED
Sergej Kiprijanov
James Bradley Lorens
David Robert Micklem
Linn Hodneland NILSSON
Tone Sandal
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
BerGenBio ASA
Vestlandets Innovasjonsselskap AS
Original Assignee
Bergen Teknologioverforing AS
BerGenBio ASA
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Publication of AU2015366213A1 publication Critical patent/AU2015366213A1/en
Assigned to BERGEN TEKNOLOGIOVERFØRING AS, BERGENBIO ASA reassignment BERGEN TEKNOLOGIOVERFØRING AS Amend patent request/document other than specification (104) Assignors: BERGEN TEKNOLOGIOVERFØRING AS, BERGENBIO AS
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    • 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
    • C07K16/2863—Immunoglobulins [IG], 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 [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
    • C07K16/30—Immunoglobulins [IG], 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 [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
    • C07K16/30—Immunoglobulins [IG], 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 [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
    • C07K16/30—Immunoglobulins [IG], 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 [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
    • C07K16/30—Immunoglobulins [IG], 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
    • G01N33/575—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

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  • 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)
  • Biophysics (AREA)
  • Genetics & Genomics (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Cell Biology (AREA)
  • Oncology (AREA)
  • Biomedical Technology (AREA)
  • Hematology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Epidemiology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Microbiology (AREA)
  • Mycology (AREA)
  • Urology & Nephrology (AREA)
  • Biotechnology (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)
  • Hospice & Palliative Care (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)
  • Micro-Organisms Or Cultivation Processes Thereof (AREA)
AU2015366213A 2014-12-18 2015-12-18 Anti-Axl antagonistic antibodies Ceased AU2015366213B2 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
GB1422605.4 2014-12-18
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
AU2015366213A1 AU2015366213A1 (en) 2017-06-22
AU2015366213B2 true AU2015366213B2 (en) 2021-10-07

Family

ID=55080088

Family Applications (1)

Application Number Title Priority Date Filing Date
AU2015366213A Ceased AU2015366213B2 (en) 2014-12-18 2015-12-18 Anti-Axl antagonistic antibodies

Country Status (9)

Country Link
US (3) US10208121B2 (enExample)
EP (1) EP3233119A2 (enExample)
JP (2) JP6931609B2 (enExample)
KR (1) KR102453227B1 (enExample)
CN (2) CN116410318A (enExample)
AU (1) AU2015366213B2 (enExample)
CA (1) CA2969879A1 (enExample)
MX (1) MX390849B (enExample)
WO (1) WO2016097370A2 (enExample)

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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
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
EP3774904A1 (en) * 2018-04-10 2021-02-17 Genmab A/S Axl-specific antibodies for cancer treatment
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
EP3946453A4 (en) * 2019-03-29 2022-12-07 Celldex Therapeutics, Inc. ANTI-AXL ANTIBODIES AND THEIR METHODS OF USE
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
US11807688B2 (en) 2020-02-28 2023-11-07 Les Laboratoires Servier 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
TW202241935A (zh) 2020-12-18 2022-11-01 美商世紀治療股份有限公司 具有可調適受體專一性之嵌合抗原受體系統
WO2022164288A1 (ko) 2021-01-29 2022-08-04 한국과학기술원 비염증성 식세포작용 유도 활성을 갖는 융합분자
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
TW202440636A (zh) 2023-03-21 2024-10-16 美商傳記55有限公司 Cd19/cd38多特異性抗體

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WO2009062690A1 (en) * 2007-11-12 2009-05-22 U3 Pharma Gmbh Axl antibodies
WO2011159980A1 (en) * 2010-06-18 2011-12-22 Genentech, Inc. Anti-axl antibodies and methods of use
WO2012175691A1 (en) * 2011-06-22 2012-12-27 INSERM (Institut National de la Santé et de la Recherche Médicale) Anti-axl antibodies and uses thereof
WO2012175692A1 (en) * 2011-06-22 2012-12-27 INSERM (Institut National de la Santé et de la Recherche Médicale) Anti-axl antibodies and uses thereof
WO2013064685A1 (en) * 2011-11-03 2013-05-10 Pierre Fabre Medicament Antigen binding protein and its use as addressing product for the treatment cancer
WO2014068139A1 (en) * 2012-11-05 2014-05-08 Pierre Fabre Medicament Novel antigen binding proteins and their use as addressing product for the treatment of cancer

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EA014640B1 (ru) * 2003-07-21 2010-12-30 Иммьюноджен, Инк. Антитело или его эпитоп-связывающий фрагмент, которые связываются с гликотопом са6, и способы их применения
CN101918452A (zh) * 2007-11-15 2010-12-15 中外制药株式会社 与Anexelekto结合的单克隆抗体及其利用
AR076564A1 (es) 2009-05-11 2011-06-22 U3 Pharma Gmbh Anticuerpos humanizados de axl(receptor de tirosina quinasa)
TW201106972A (en) 2009-07-27 2011-03-01 Genentech Inc Combination treatments
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IN2015DN00188A (enExample) 2012-06-29 2015-06-12 Mitsubishi Gas Chemical Co
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
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

Patent Citations (6)

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Publication number Priority date Publication date Assignee Title
WO2009062690A1 (en) * 2007-11-12 2009-05-22 U3 Pharma Gmbh Axl antibodies
WO2011159980A1 (en) * 2010-06-18 2011-12-22 Genentech, Inc. Anti-axl antibodies and methods of use
WO2012175691A1 (en) * 2011-06-22 2012-12-27 INSERM (Institut National de la Santé et de la Recherche Médicale) Anti-axl antibodies and uses thereof
WO2012175692A1 (en) * 2011-06-22 2012-12-27 INSERM (Institut National de la Santé et de la Recherche Médicale) Anti-axl antibodies and uses thereof
WO2013064685A1 (en) * 2011-11-03 2013-05-10 Pierre Fabre Medicament Antigen binding protein and its use as addressing product for the treatment cancer
WO2014068139A1 (en) * 2012-11-05 2014-05-08 Pierre Fabre Medicament Novel antigen binding proteins and their use as addressing product for the treatment of cancer

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Publication number Publication date
US20170349658A1 (en) 2017-12-07
MX390849B (es) 2025-03-21
US20190177419A1 (en) 2019-06-13
CN116410318A (zh) 2023-07-11
JP2021101707A (ja) 2021-07-15
CA2969879A1 (en) 2016-06-23
JP2018506961A (ja) 2018-03-15
MX2017007941A (es) 2018-01-30
US20230406941A1 (en) 2023-12-21
WO2016097370A2 (en) 2016-06-23
JP6931609B2 (ja) 2021-09-08
WO2016097370A3 (en) 2016-08-11
KR20170099918A (ko) 2017-09-01
AU2015366213A1 (en) 2017-06-22
US10208121B2 (en) 2019-02-19
US11584796B2 (en) 2023-02-21
CN107531786A (zh) 2018-01-02
CN107531786B (zh) 2023-01-13
KR102453227B1 (ko) 2022-10-11
EP3233119A2 (en) 2017-10-25

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