EA037890B1 - Способы и композиции, включающие комбинацию антагониста vegf и анти-ctla-4 антитела - Google Patents

Способы и композиции, включающие комбинацию антагониста vegf и анти-ctla-4 антитела Download PDF

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Publication number
EA037890B1
EA037890B1 EA201690633A EA201690633A EA037890B1 EA 037890 B1 EA037890 B1 EA 037890B1 EA 201690633 A EA201690633 A EA 201690633A EA 201690633 A EA201690633 A EA 201690633A EA 037890 B1 EA037890 B1 EA 037890B1
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EA
Eurasian Patent Office
Prior art keywords
antibody
ctla
subject
vegf
tumor
Prior art date
Application number
EA201690633A
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English (en)
Russian (ru)
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EA201690633A1 (ru
Inventor
Элла Иоффе
Израэль Лови
Гэвин ТЕРСТОН
Елена Бурова
Original Assignee
Ридженерон Фармасьютикалз, Инк.
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Application filed by Ридженерон Фармасьютикалз, Инк. filed Critical Ридженерон Фармасьютикалз, Инк.
Publication of EA201690633A1 publication Critical patent/EA201690633A1/ru
Publication of EA037890B1 publication Critical patent/EA037890B1/ru

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    • 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
    • A61K39/3955—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against proteinaceous materials, e.g. enzymes, hormones, lymphokines
    • 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
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/177—Receptors; Cell surface antigens; Cell surface determinants
    • A61K38/179—Receptors; Cell surface antigens; Cell surface determinants for growth factors; for growth regulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/177—Receptors; Cell surface antigens; Cell surface determinants
    • A61K38/1793—Receptors; Cell surface antigens; Cell surface determinants for cytokines; for lymphokines; for interferons
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • 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
    • 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
    • C07K14/71—Receptors; Cell surface antigens; Cell surface determinants for growth factors; for growth regulators
    • 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
    • C07K16/22—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against growth factors ; against growth regulators
    • 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
    • C07K16/2818—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 CD28 or CD152
    • 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
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • 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
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
    • 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
    • C07K2319/00—Fusion polypeptide
    • C07K2319/30—Non-immunoglobulin-derived peptide or protein having an immunoglobulin constant or Fc region, or a fragment thereof, attached thereto

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Immunology (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Molecular Biology (AREA)
  • Genetics & Genomics (AREA)
  • Biophysics (AREA)
  • Biochemistry (AREA)
  • Zoology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Cell Biology (AREA)
  • Microbiology (AREA)
  • Mycology (AREA)
  • Biomedical Technology (AREA)
  • Oncology (AREA)
  • Dermatology (AREA)
  • Endocrinology (AREA)
  • Toxicology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Peptides Or Proteins (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
EA201690633A 2013-10-18 2014-10-17 Способы и композиции, включающие комбинацию антагониста vegf и анти-ctla-4 антитела EA037890B1 (ru)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
US201361892601P 2013-10-18 2013-10-18
US201361901596P 2013-11-08 2013-11-08
US201461952923P 2014-03-14 2014-03-14
US201462055734P 2014-09-26 2014-09-26
PCT/US2014/061071 WO2015058048A1 (en) 2013-10-18 2014-10-17 Methods and compositions comprising a combination of a vegf antagonist and an anti-ctla-4 antibody

Publications (2)

Publication Number Publication Date
EA201690633A1 EA201690633A1 (ru) 2016-08-31
EA037890B1 true EA037890B1 (ru) 2021-06-01

Family

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EA201690633A EA037890B1 (ru) 2013-10-18 2014-10-17 Способы и композиции, включающие комбинацию антагониста vegf и анти-ctla-4 антитела

Country Status (11)

Country Link
US (2) US9968674B2 (https=)
EP (1) EP3057990B1 (https=)
JP (1) JP6607850B2 (https=)
KR (1) KR102338453B1 (https=)
CN (1) CN105636986B (https=)
AU (1) AU2014337135B2 (https=)
CA (1) CA2926853C (https=)
EA (1) EA037890B1 (https=)
IL (1) IL244599B (https=)
MX (1) MX377714B (https=)
WO (1) WO2015058048A1 (https=)

Families Citing this family (24)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RU2494108C2 (ru) 2006-04-07 2013-09-27 Аерпио Терапетикс, Инк. Антитела, которые связывают человеческий белок бета-тирозин фосфатазу (нртрвета), и их использование
WO2013056240A1 (en) 2011-10-13 2013-04-18 Aerpio Therapeutics, Inc. Methods for treating vascular leak syndrome and cancer
EP3800191B1 (en) 2014-03-17 2025-08-20 Adverum Biotechnologies, Inc. Compositions and methods for enhanced gene expression in cone cells
US9840553B2 (en) 2014-06-28 2017-12-12 Kodiak Sciences Inc. Dual PDGF/VEGF antagonists
US11021519B2 (en) 2015-03-02 2021-06-01 Adverum Biotechnologies, Inc. Compositions and methods for intravitreal delivery of polynucleotides to retinal cones
MA53355A (fr) 2015-05-29 2022-03-16 Agenus Inc Anticorps anti-ctla-4 et leurs procédés d'utilisation
WO2017106462A1 (en) * 2015-12-18 2017-06-22 Biogen Ma Inc. Bispecific antibody platform
KR20250057128A (ko) 2015-12-30 2025-04-28 코디악 사이언시스 인코포레이티드 항체 및 이의 접합체
JP7069032B2 (ja) 2016-03-24 2022-05-17 ミレニアム ファーマシューティカルズ， インコーポレイテッド がん免疫治療における胃腸の免疫関連有害事象の治療方法
US11542332B2 (en) 2016-03-26 2023-01-03 Bioatla, Inc. Anti-CTLA4 antibodies, antibody fragments, their immunoconjugates and uses thereof
ES2840059T3 (es) * 2016-06-16 2021-07-06 Adverum Biotechnologies Inc Tratamiento de la DMRE mediante el uso de la variante AAV2 con aflibercept
BR112019001206A2 (pt) 2016-07-20 2019-06-25 Aerpio Therapeutics Inc anticorpos monoclonais humanizados que visam ve-ptp (hptp-ss)
DK3551660T5 (da) 2016-12-07 2024-09-02 Agenus Inc Anti-ctla-4-antistoffer og fremgangsmåder til anvendelse deraf
WO2018144587A1 (en) * 2017-01-31 2018-08-09 Research Development Foundation Steap2 inhibitors for the treatment of liver cancers
MX2020005170A (es) 2017-11-17 2020-10-16 Amgen Inc Formulaciones de proteinas de fusion vegfr-fc.
KR102834864B1 (ko) * 2018-02-02 2025-07-16 온코씨4, 아이앤씨. 개선된 면역치료 효과를 갖지만 약화된 부작용을 갖는 돌연변이 항-ctla-4 항체
WO2019152413A1 (en) * 2018-02-02 2019-08-08 Oncoimmune, Inc. Methods of selecting and designing safer and more effective anti-ctla-4 antibodies for cancer therapy
EP3758737A4 (en) * 2018-03-02 2022-10-12 Kodiak Sciences Inc. IL-6 ANTIBODIES AND FUSION CONSTRUCTS AND CONJUGATES THEREOF
AU2019269361C1 (en) 2018-05-14 2025-06-12 Children's Research Institute, Children's National Medical Center Anti-CD24 compositions and uses thereof
WO2020068653A1 (en) 2018-09-24 2020-04-02 Aerpio Pharmaceuticals, Inc. MULTISPECIFIC ANTIBODIES THAT TARGET HPTP - β (VE-PTP) AND VEGF
BR112021008060A2 (pt) * 2018-10-31 2021-11-23 Bioatla Inc Polipeptídeo, anticorpo anti-ctla4 ou fragmento de anticorpo, imunoconjugado, composição farmacêutica, dose única de composição farmacêutica, método de tratar câncer, e, kit para diagnóstico ou tratamento
CN111378044B (zh) * 2018-12-28 2022-07-15 长春金赛药业有限责任公司 抗体融合蛋白、制备方法及其应用
JP2022523063A (ja) * 2019-01-30 2022-04-21 アムジエン・インコーポレーテツド アフリベルセプトの属性、並びにその特性決定及び修飾方法
CA3157509A1 (en) 2019-10-10 2021-04-15 Kodiak Sciences Inc. Methods of treating an eye disorder

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007113648A2 (en) * 2006-04-05 2007-10-11 Pfizer Products Inc. Ctla4 antibody combination therapy

Family Cites Families (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE19802753A1 (de) * 1998-01-26 1999-07-29 Merck Patent Gmbh Coreaktive Trägermaterialien zur Heterogenisierung von Katalysatoren, Cokatalysatoren und Liganden
US7109003B2 (en) 1998-12-23 2006-09-19 Abgenix, Inc. Methods for expressing and recovering human monoclonal antibodies to CTLA-4
US6682736B1 (en) 1998-12-23 2004-01-27 Abgenix, Inc. Human monoclonal antibodies to CTLA-4
US7396664B2 (en) 1999-06-08 2008-07-08 Regeneron Pharmaceuticals, Inc. VEGF-binding fusion proteins and nucleic acids encoding the same
US7070959B1 (en) 1999-06-08 2006-07-04 Regeneron Pharmaceuticals, Inc. Modified chimeric polypeptides with improved pharmacokinetic properties
US7303746B2 (en) * 1999-06-08 2007-12-04 Regeneron Pharmaceuticals, Inc. Methods of treating eye disorders with modified chimeric polypeptides
US7605238B2 (en) 1999-08-24 2009-10-20 Medarex, Inc. Human CTLA-4 antibodies and their uses
EP1212422B1 (en) 1999-08-24 2007-02-21 Medarex, Inc. Human ctla-4 antibodies and their uses
IL149701A0 (en) * 2001-05-23 2002-11-10 Pfizer Prod Inc Use of anti-ctla-4 antibodies
WO2006048749A1 (en) * 2004-11-04 2006-05-11 Pfizer Products Inc. Ctla-4 antibody and aromatase inhibitor or combination treatment for breast cancer
RU2448979C2 (ru) 2006-12-14 2012-04-27 Ридженерон Фармасьютикалз, Инк. Антитела человека к дельта-подобному лиганду-4 человека
JP2011500086A (ja) * 2007-10-22 2011-01-06 シェーリング コーポレイション 完全ヒト抗ｖｅｇｆ抗体および使用方法
WO2009100140A1 (en) 2008-02-04 2009-08-13 Medarex, Inc. Anti-clta-4 antibodies with reduced blocking of binding of ctla-4 to b7 and uses thereof
JO3182B1 (ar) 2009-07-29 2018-03-08 Regeneron Pharma مضادات حيوية بشرية عالية الالفة مع تولد الاوعية البشرية - 2

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007113648A2 (en) * 2006-04-05 2007-10-11 Pfizer Products Inc. Ctla4 antibody combination therapy

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
F. S. HODI, D. LAWRENCE, C. LEZCANO, X. WU, J. ZHOU, T. SASADA, W. ZENG, A. GIOBBIE-HURDER, M. B. ATKINS, N. IBRAHIM, P. FRIEDLAND: "Bevacizumab plus Ipilimumab in Patients with Metastatic Melanoma", CANCER IMMUNOLOGY RESEARCH, vol. 2, no. 7, 1 July 2014 (2014-07-01), pages 632 - 642, XP055163152, ISSN: 23266066, DOI: 10.1158/2326-6066.CIR-14-0053 *
H. M. KANTARJIAN, T. FOJO, M. MATHISEN, L. A. ZWELLING: "Cancer Drugs in the United States: Justum Pretium--The Just Price", JOURNAL OF CLINICAL ONCOLOGY, vol. 31, no. 28, 1 October 2013 (2013-10-01), pages 3600 - 3604, XP055163218, ISSN: 0732183X, DOI: 10.1200/JCO.2013.49.1845 *
LOCKHART, TZU-FEI WANG: "Aflibercept in the Treatment of Metastatic Colorectal Cancer", CLINICAL MEDICINE INSIGHTS: ONCOLOGY, LIBERTAS ACADEMICA, 1 January 2012 (2012-01-01), pages 19, XP055163219, DOI: 10.4137/CMO.S7432 *

Also Published As

Publication number Publication date
IL244599A0 (en) 2016-04-21
US20160243225A1 (en) 2016-08-25
MX377714B (es) 2025-03-11
JP2016539096A (ja) 2016-12-15
US10532096B2 (en) 2020-01-14
EP3057990A1 (en) 2016-08-24
CA2926853C (en) 2022-04-26
KR102338453B1 (ko) 2021-12-13
US9968674B2 (en) 2018-05-15
EP3057990B1 (en) 2019-09-04
CN105636986B (zh) 2020-05-12
EA201690633A1 (ru) 2016-08-31
KR20160067978A (ko) 2016-06-14
CN105636986A (zh) 2016-06-01
WO2015058048A1 (en) 2015-04-23
IL244599B (en) 2019-10-31
AU2014337135B2 (en) 2019-09-19
CA2926853A1 (en) 2015-04-23
US20180236070A1 (en) 2018-08-23
JP6607850B2 (ja) 2019-11-20
MX2016004736A (es) 2016-07-26

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