CY1124584T1 - Μεθοδοι προωθησης της αποκρισης τ κυτταρων - Google Patents

Μεθοδοι προωθησης της αποκρισης τ κυτταρων

Info

Publication number
CY1124584T1
CY1124584T1 CY20211100839T CY211100839T CY1124584T1 CY 1124584 T1 CY1124584 T1 CY 1124584T1 CY 20211100839 T CY20211100839 T CY 20211100839T CY 211100839 T CY211100839 T CY 211100839T CY 1124584 T1 CY1124584 T1 CY 1124584T1
Authority
CY
Cyprus
Prior art keywords
clec
promoting
cell
methods
cell response
Prior art date
Application number
CY20211100839T
Other languages
Greek (el)
English (en)
Inventor
Géraldine Teppaz
Nicolas Poirier
Bernard Vanhove
Vanessa GAUTTIER
Elise CHIFFOLEAU
Original Assignee
Inserm - Institut National De La Santé Et De La Recherche Médicale
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 Inserm - Institut National De La Santé Et De La Recherche Médicale filed Critical Inserm - Institut National De La Santé Et De La Recherche Médicale
Publication of CY1124584T1 publication Critical patent/CY1124584T1/el

Links

Classifications

    • 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
    • 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
    • C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • C07K14/4701—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals not used
    • C07K14/4726—Lectins
    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7088—Compounds having three or more nucleosides or nucleotides
    • 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
    • A61K38/1703—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • A61K38/1709—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • A61K38/1732—Lectins
    • 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
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/04—Immunostimulants
    • 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
    • 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
    • C07K14/7056—Lectin superfamily, e.g. CD23, CD72
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • 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
    • C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
    • C12N15/115—Aptamers, i.e. nucleic acids binding a target molecule specifically and with high affinity without hybridising therewith ; Nucleic acids binding to non-nucleic acids, e.g. aptamers
    • 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
    • C07K2317/70—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
    • 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

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Genetics & Genomics (AREA)
  • Immunology (AREA)
  • Engineering & Computer Science (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Molecular Biology (AREA)
  • Zoology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Biomedical Technology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Epidemiology (AREA)
  • Wood Science & Technology (AREA)
  • Biotechnology (AREA)
  • General Engineering & Computer Science (AREA)
  • Toxicology (AREA)
  • Plant Pathology (AREA)
  • Physics & Mathematics (AREA)
  • Microbiology (AREA)
  • Marine Sciences & Fisheries (AREA)
  • Cell Biology (AREA)
  • Peptides Or Proteins (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Medicines Containing Material From Animals Or Micro-Organisms (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
CY20211100839T 2016-10-21 2021-09-24 Μεθοδοι προωθησης της αποκρισης τ κυτταρων CY1124584T1 (el)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
EP16306381 2016-10-21
EP17305988 2017-07-24
PCT/EP2017/076911 WO2018073440A1 (en) 2016-10-21 2017-10-20 Methods for promoting t cells response

Publications (1)

Publication Number Publication Date
CY1124584T1 true CY1124584T1 (el) 2022-07-22

Family

ID=60293924

Family Applications (1)

Application Number Title Priority Date Filing Date
CY20211100839T CY1124584T1 (el) 2016-10-21 2021-09-24 Μεθοδοι προωθησης της αποκρισης τ κυτταρων

Country Status (21)

Country Link
US (3) US11365257B2 (https=)
EP (2) EP3529262B1 (https=)
JP (2) JP7032396B6 (https=)
KR (1) KR102646708B1 (https=)
CN (1) CN110291102A (https=)
AU (1) AU2017345286B2 (https=)
CA (1) CA3039348C (https=)
CY (1) CY1124584T1 (https=)
DK (1) DK3529262T3 (https=)
ES (2) ES2883678T3 (https=)
HR (1) HRP20211544T1 (https=)
HU (1) HUE056016T2 (https=)
IL (1) IL266111B (https=)
LT (1) LT3529262T (https=)
MA (1) MA46570B1 (https=)
MD (1) MD3529262T2 (https=)
PL (1) PL3529262T3 (https=)
RS (1) RS62463B1 (https=)
SI (1) SI3529262T1 (https=)
SM (1) SMT202100555T1 (https=)
WO (1) WO2018073440A1 (https=)

Families Citing this family (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ES2883678T3 (es) * 2016-10-21 2021-12-09 Inst Nat Sante Rech Med Métodos para promover la respuesta de linfocitos T
SG11201907870VA (en) 2017-02-28 2019-09-27 Vor Biopharma Inc Compositions and methods for inhibition of lineage specific proteins
CA3110837A1 (en) 2018-08-28 2020-03-05 Vor Biopharma Inc. Genetically engineered hematopoietic stem cells and uses thereof
CN115151309A (zh) * 2019-12-05 2022-10-04 Ose免疫疗法 抗clec-1a抗体及其抗原结合片段
CN113156140A (zh) * 2021-03-05 2021-07-23 青岛大学附属医院 C型凝集素样受体-1作为真菌性角膜炎的治疗标志物的应用
WO2022258714A1 (en) 2021-06-08 2022-12-15 Ose Immunotherapeutics Humanized anti-clec-1a antibodies and antigen-binding fragments thereof and mimetics thereof
WO2023083890A1 (en) * 2021-11-09 2023-05-19 Ose Immunotherapeutics Identification of clec-1 ligand and uses thereof
US20260035434A1 (en) 2022-08-01 2026-02-05 Ose Immunotherapeutics Heterodimeric fc-clec-1 fusion molecule and uses thereof
WO2025032213A1 (en) 2023-08-10 2025-02-13 Ose Immunotherapeutics Identification of hla-dra as a ligand of clec-1 and uses thereof

Family Cites Families (43)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4816567A (en) 1983-04-08 1989-03-28 Genentech, Inc. Recombinant immunoglobin preparations
US5225539A (en) 1986-03-27 1993-07-06 Medical Research Council Recombinant altered antibodies and methods of making altered antibodies
US5567610A (en) 1986-09-04 1996-10-22 Bioinvent International Ab Method of producing human monoclonal antibodies and kit therefor
GB8823869D0 (en) 1988-10-12 1988-11-16 Medical Res Council Production of antibodies
US5175384A (en) 1988-12-05 1992-12-29 Genpharm International Transgenic mice depleted in mature t-cells and methods for making transgenic mice
US5530101A (en) 1988-12-28 1996-06-25 Protein Design Labs, Inc. Humanized immunoglobulins
US5859205A (en) 1989-12-21 1999-01-12 Celltech Limited Humanised antibodies
US6150584A (en) 1990-01-12 2000-11-21 Abgenix, Inc. Human antibodies derived from immunized xenomice
US5229275A (en) 1990-04-26 1993-07-20 Akzo N.V. In-vitro method for producing antigen-specific human monoclonal antibodies
US5545806A (en) 1990-08-29 1996-08-13 Genpharm International, Inc. Ransgenic non-human animals for producing heterologous antibodies
ES2136092T3 (es) 1991-09-23 1999-11-16 Medical Res Council Procedimientos para la produccion de anticuerpos humanizados.
US5573905A (en) 1992-03-30 1996-11-12 The Scripps Research Institute Encoded combinatorial chemical libraries
AU701578B2 (en) 1992-08-21 1999-02-04 Vrije Universiteit Brussel Immunoglobulins devoid of light chains
US5618829A (en) 1993-01-28 1997-04-08 Mitsubishi Chemical Corporation Tyrosine kinase inhibitors and benzoylacrylamide derivatives
AU691820B2 (en) 1993-07-15 1998-05-28 Cancer Research Campaign Technology Limited Prodrugs of protein tyrosine kinase inhibitors
EP0690452A3 (en) 1994-06-28 1999-01-07 Advanced Micro Devices, Inc. Electrically erasable memory and method of erasure
US5804396A (en) 1994-10-12 1998-09-08 Sugen, Inc. Assay for agents active in proliferative disorders
EP0739981A1 (en) 1995-04-25 1996-10-30 Vrije Universiteit Brussel Variable fragments of immunoglobulins - use for therapeutic or veterinary purposes
US5639757A (en) 1995-05-23 1997-06-17 Pfizer Inc. 4-aminopyrrolo[2,3-d]pyrimidines as tyrosine kinase inhibitors
HU228446B1 (en) 1996-04-12 2013-03-28 Warner Lambert Co Kinazoline derivatives as irreversible inhibitors of protein-kinase, pharmaceutical compositions containing these compounds and use thereof
ZA986732B (en) 1997-07-29 1999-02-02 Warner Lambert Co Irreversible inhibitiors of tyrosine kinases
US6100254A (en) 1997-10-10 2000-08-08 Board Of Regents, The University Of Texas System Inhibitors of protein tyrosine kinases
US6740665B1 (en) 1999-02-10 2004-05-25 Ramachandran Murali Tyrosine kinase inhibitors and methods of using the same
US6245759B1 (en) 1999-03-11 2001-06-12 Merck & Co., Inc. Tyrosine kinase inhibitors
AU5636900A (en) 1999-06-30 2001-01-31 Merck & Co., Inc. Src kinase inhibitor compounds
JP2003503351A (ja) 1999-06-30 2003-01-28 メルク エンド カムパニー インコーポレーテッド Ｓｒｃキナーゼ阻害化合物
WO2001000214A1 (en) 1999-06-30 2001-01-04 Merck & Co., Inc. Src kinase inhibitor compounds
DE60023926T2 (de) 1999-09-10 2006-07-20 Merck & Co., Inc. Tyrosin kinase inhibitoren
US6794393B1 (en) 1999-10-19 2004-09-21 Merck & Co., Inc. Tyrosine kinase inhibitors
AU778042B2 (en) 1999-10-19 2004-11-11 Merck & Co., Inc. Tyrosine kinase inhibitors
HRP20020349A2 (en) 1999-10-19 2004-02-29 Merck & Co Inc Tyrosine kinase inhibitors
AU785198B2 (en) * 1999-11-15 2006-11-02 Miltenyi Biotec B.V. & Co. KG Antigen-binding fragments specific for dendritic cells, compositions and methods of use thereof antigens recognised thereby and cells obtained thereby
US6313138B1 (en) 2000-02-25 2001-11-06 Merck & Co., Inc. Tyrosine kinase inhibitors
US6420382B2 (en) 2000-02-25 2002-07-16 Merck & Co., Inc. Tyrosine kinase inhibitors
ATE316088T1 (de) 2001-06-22 2006-02-15 Merck & Co Inc Tyrosin-kinase inhibitoren
WO2003011836A1 (en) 2001-08-01 2003-02-13 Merck & Co., Inc. Tyrosine kinase inhibitors
WO2003020276A1 (en) 2001-08-30 2003-03-13 Merck & Co., Inc. Tyrosine kinase inhibitors
US8246959B1 (en) * 2003-08-01 2012-08-21 University Of Washington Dendritic cell-associated lectin-like molecules, compositions and methods of use
US7908091B2 (en) 2006-03-17 2011-03-15 Prometheus Laboratories Inc. Methods of predicting and monitoring tyrosine kinase inhibitor therapy
US20080254047A1 (en) * 2007-02-23 2008-10-16 Baylor Research Institute Activation of Human Antigen-Presenting Cells Through CLEC-6
JP5641508B2 (ja) * 2010-02-23 2014-12-17 国立大学法人 東京大学 樹状細胞免疫受容体刺激剤
KR20170037625A (ko) * 2014-07-21 2017-04-04 노파르티스 아게 Cll-1 키메라 항원 수용체를 사용한 암의 치료
ES2883678T3 (es) 2016-10-21 2021-12-09 Inst Nat Sante Rech Med Métodos para promover la respuesta de linfocitos T

Also Published As

Publication number Publication date
ES2978486T3 (es) 2024-09-13
JP7032396B2 (ja) 2022-03-08
MD3529262T2 (ro) 2022-01-31
IL266111B (en) 2022-09-01
CA3039348C (en) 2023-09-05
ES2883678T3 (es) 2021-12-09
US20220281983A1 (en) 2022-09-08
JP7404418B2 (ja) 2023-12-25
MA46570B1 (fr) 2021-10-29
JP2020503252A (ja) 2020-01-30
HRP20211544T1 (hr) 2022-01-07
US20240400695A1 (en) 2024-12-05
US12091464B2 (en) 2024-09-17
PL3529262T3 (pl) 2021-12-27
US20190309075A1 (en) 2019-10-10
CA3039348A1 (en) 2018-04-26
DK3529262T3 (da) 2021-09-20
EP3950709A1 (en) 2022-02-09
SMT202100555T1 (it) 2021-11-12
MA46570A (fr) 2021-03-31
US11365257B2 (en) 2022-06-21
LT3529262T (lt) 2021-11-10
CN110291102A (zh) 2019-09-27
KR102646708B1 (ko) 2024-03-12
JP7404418B6 (ja) 2024-01-26
WO2018073440A1 (en) 2018-04-26
JP7032396B6 (ja) 2022-03-22
HUE056016T2 (hu) 2022-01-28
EP3950709B1 (en) 2024-02-14
AU2017345286B2 (en) 2023-08-03
AU2017345286A1 (en) 2019-04-18
EP3529262A1 (en) 2019-08-28
JP2022065159A (ja) 2022-04-26
IL266111A (en) 2019-06-30
KR20190068605A (ko) 2019-06-18
EP3529262B1 (en) 2021-07-21
SI3529262T1 (sl) 2021-12-31
RS62463B1 (sr) 2021-11-30

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