AR094849A1 - Terapia combinada que involucra anticuerpos dirigidos contra claudina 18.2 para el tratamiento de cáncer - Google Patents
Terapia combinada que involucra anticuerpos dirigidos contra claudina 18.2 para el tratamiento de cáncerInfo
- Publication number
- AR094849A1 AR094849A1 ARP140100551A ARP140100551A AR094849A1 AR 094849 A1 AR094849 A1 AR 094849A1 AR P140100551 A ARP140100551 A AR P140100551A AR P140100551 A ARP140100551 A AR P140100551A AR 094849 A1 AR094849 A1 AR 094849A1
- Authority
- AR
- Argentina
- Prior art keywords
- dsm
- antibody
- agent
- expression
- stabilizes
- Prior art date
Links
- 206010028980 Neoplasm Diseases 0.000 title abstract 2
- 201000011510 cancer Diseases 0.000 title abstract 2
- 238000002648 combination therapy Methods 0.000 title 1
- 238000000034 method Methods 0.000 abstract 7
- 239000003795 chemical substances by application Substances 0.000 abstract 6
- 206010061902 Pancreatic neoplasm Diseases 0.000 abstract 2
- 239000000427 antigen Substances 0.000 abstract 2
- 102000036639 antigens Human genes 0.000 abstract 2
- 108091007433 antigens Proteins 0.000 abstract 2
- 210000004027 cell Anatomy 0.000 abstract 2
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 abstract 2
- 201000002528 pancreatic cancer Diseases 0.000 abstract 2
- 208000008443 pancreatic carcinoma Diseases 0.000 abstract 2
- 229940002612 prodrug Drugs 0.000 abstract 2
- 239000000651 prodrug Substances 0.000 abstract 2
- 150000003839 salts Chemical class 0.000 abstract 2
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 abstract 1
- 229930012538 Paclitaxel Natural products 0.000 abstract 1
- 229940123237 Taxane Drugs 0.000 abstract 1
- 125000003275 alpha amino acid group Chemical group 0.000 abstract 1
- 229940045985 antineoplastic platinum compound Drugs 0.000 abstract 1
- VSJKWCGYPAHWDS-FQEVSTJZSA-N camptothecin Chemical class C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-FQEVSTJZSA-N 0.000 abstract 1
- 229960002949 fluorouracil Drugs 0.000 abstract 1
- SDUQYLNIPVEERB-QPPQHZFASA-N gemcitabine Chemical compound O=C1N=C(N)C=CN1[C@H]1C(F)(F)[C@H](O)[C@@H](CO)O1 SDUQYLNIPVEERB-QPPQHZFASA-N 0.000 abstract 1
- 229960005277 gemcitabine Drugs 0.000 abstract 1
- 229960004768 irinotecan Drugs 0.000 abstract 1
- UWKQSNNFCGGAFS-XIFFEERXSA-N irinotecan Chemical compound C1=C2C(CC)=C3CN(C(C4=C([C@@](C(=O)OC4)(O)CC)C=4)=O)C=4C3=NC2=CC=C1OC(=O)N(CC1)CCC1N1CCCCC1 UWKQSNNFCGGAFS-XIFFEERXSA-N 0.000 abstract 1
- 239000002777 nucleoside Substances 0.000 abstract 1
- 150000003833 nucleoside derivatives Chemical class 0.000 abstract 1
- DWAFYCQODLXJNR-BNTLRKBRSA-L oxaliplatin Chemical compound O1C(=O)C(=O)O[Pt]11N[C@@H]2CCCC[C@H]2N1 DWAFYCQODLXJNR-BNTLRKBRSA-L 0.000 abstract 1
- 229960001756 oxaliplatin Drugs 0.000 abstract 1
- 229960001592 paclitaxel Drugs 0.000 abstract 1
- 150000003058 platinum compounds Chemical class 0.000 abstract 1
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 abstract 1
Classifications
-
- 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
- A61K38/19—Cytokines; Lymphokines; Interferons
- A61K38/20—Interleukins [IL]
- A61K38/2013—IL-2
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/555—Heterocyclic compounds containing heavy metals, e.g. hemin, hematin, melarsoprol
-
- 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
- A61K31/66—Phosphorus compounds
- A61K31/662—Phosphorus acids or esters thereof having P—C bonds, e.g. foscarnet, trichlorfon
- A61K31/663—Compounds having two or more phosphorus acid groups or esters thereof, e.g. clodronic acid, pamidronic acid
-
- 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
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
-
- 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
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
- A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
- A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
- A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
-
- 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
- A61K38/19—Cytokines; Lymphokines; Interferons
-
- 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
-
- 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
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/18—Drugs for disorders of the alimentary tract or the digestive system for pancreatic disorders, e.g. pancreatic enzymes
-
- 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
- A61P35/04—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
-
- 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
- C07K16/303—Liver or Pancreas
-
- 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
- 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
- C07K2317/10—Immunoglobulins specific features characterized by their source of isolation or production
- C07K2317/14—Specific host cells or culture conditions, e.g. components, pH or temperature
-
- 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
- C07K2317/32—Immunoglobulins specific features characterized by aspects of specificity or valency specific for a neo-epitope on a complex, e.g. antibody-antigen or ligand-receptor
-
- 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
- C07K2317/34—Identification of a linear epitope shorter than 20 amino acid residues or of a conformational epitope defined by amino acid residues
-
- 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
- C07K2317/73—Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
- C07K2317/734—Complement-dependent cytotoxicity [CDC]
-
- 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
- C07K2317/74—Inducing cell proliferation
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Immunology (AREA)
- Organic Chemistry (AREA)
- Epidemiology (AREA)
- Molecular Biology (AREA)
- Engineering & Computer Science (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Genetics & Genomics (AREA)
- Biophysics (AREA)
- Biochemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Gastroenterology & Hepatology (AREA)
- Cell Biology (AREA)
- Oncology (AREA)
- Microbiology (AREA)
- Mycology (AREA)
- Biomedical Technology (AREA)
- Zoology (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Peptides Or Proteins (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
Reivindicación 1: Un método para tratar o prevenir el cáncer pancreático en un paciente, caracterizado porque comprende administrar al paciente (i) un anticuerpo que tiene la capacidad de unirse a CLDN18.2 y (ii) un agente que estabiliza o aumenta la expresión de CLDN18.2. Reivindicación 2: El método de la reivindicación 1, caracterizado porque la expresión de CLDN18.2 es en la superficie celular de una célula cancerígena. Reivindicación 4: El método de cualquiera de las reivindicaciones 1 a 3, caracterizado porque el agente que estabiliza o aumenta la expresión de CLDN18.2 comprende un agente que se selecciona del grupo que consiste en análogos de nucleósidos, compuestos de platino, análogos de camptotecina, taxanos, profármacos de los mismos, sales de los mismos, y combinaciones de los mismos. Reivindicación 5: El método de cualquiera de las reivindicaciones 1 a 4, caracterizado porque el agente que estabiliza o aumenta la expresión de CLDN18.2 comprende un agente que se selecciona del grupo que consiste en gemcitabina, 5-fluorouracilo, oxaliplatino, irinotecan, paclitaxel, profármacos de los mismos, sales de los mismos, y combinaciones de los mismos. Reivindicación 19: El método de cualquiera de las reivindicaciones 1 a 18, caracterizado porque el anticuerpo que tiene la capacidad de unirse a CLDN18.2 es un anticuerpo que se selecciona del grupo que consiste en (i) un anticuerpo producido por y/o que se puede obtener a partir de un clon depositado bajo el Nº de acceso DSM ACC2737, DSM ACC2738, DSM ACC2739, DSM ACC2740, DSM ACC2741, DSM ACC2742, DSM ACC2743, DSM ACC2745, DSM ACC2746, DSM ACC2747, DSM ACC2748, DSM ACC2808, DSM ACC2809, o DSM ACC2810, (ii) un anticuerpo que es una forma quimerizada o humanizada del anticuerpo de (i), (iii) un anticuerpo que tiene la especificidad del anticuerpo de (i) y (iv) un anticuerpo que comprende la porción de unión a antígeno o sitio de unión a antígeno, en particular la región variable, del anticuerpo de (i) y preferentemente que tiene la especificidad del anticuerpo de (i). Reivindicación 20: El método de cualquiera de las reivindicaciones 1 a 19, caracterizado porque comprende administrar el anticuerpo que tiene la capacidad de unirse a CLDN18.2 a una dosis de hasta 1000 mg/m². Reivindicación 23: El método de cualquiera de las reivindicaciones 1 a 22, caracterizado porque CLDN18.2 tiene la secuencia de aminoácidos de acuerdo a SEQ ID Nº 1. Reivindicación 33: Una preparación médica para tratar o prevenir cáncer pancreático, caracterizada porque comprende (i) un anticuerpo que tiene la capacidad de unirse a CLDN18.2 y (ii) un agente que estabiliza o aumenta la expresión de CLDN18.2.
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
PCT/EP2013/000505 WO2014127785A1 (en) | 2013-02-20 | 2013-02-20 | Combination therapy involving antibodies against claudin 18.2 for treatment of cancer |
Publications (1)
Publication Number | Publication Date |
---|---|
AR094849A1 true AR094849A1 (es) | 2015-09-02 |
Family
ID=47843230
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
ARP140100551A AR094849A1 (es) | 2013-02-20 | 2014-02-20 | Terapia combinada que involucra anticuerpos dirigidos contra claudina 18.2 para el tratamiento de cáncer |
Country Status (23)
Country | Link |
---|---|
US (5) | US9770487B2 (es) |
JP (5) | JP6389478B2 (es) |
KR (3) | KR102385872B1 (es) |
CN (3) | CN115282269A (es) |
AR (1) | AR094849A1 (es) |
AU (1) | AU2014221035B2 (es) |
BR (1) | BR112015019995A2 (es) |
CA (1) | CA2899754C (es) |
DK (1) | DK2958945T3 (es) |
ES (1) | ES2930654T3 (es) |
HK (1) | HK1213925A1 (es) |
HU (1) | HUE060192T2 (es) |
IL (2) | IL239981B2 (es) |
LT (1) | LT2958945T (es) |
MX (3) | MX2015010724A (es) |
MY (1) | MY184332A (es) |
PL (1) | PL2958945T3 (es) |
PT (1) | PT2958945T (es) |
RU (1) | RU2699549C2 (es) |
SA (1) | SA515360926B1 (es) |
SG (2) | SG10201610412YA (es) |
UA (1) | UA118664C2 (es) |
WO (2) | WO2014127785A1 (es) |
Families Citing this family (37)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE10254601A1 (de) * | 2002-11-22 | 2004-06-03 | Ganymed Pharmaceuticals Ag | Differentiell in Tumoren exprimierte Genprodukte und deren Verwendung |
DE102004024617A1 (de) | 2004-05-18 | 2005-12-29 | Ganymed Pharmaceuticals Ag | Differentiell in Tumoren exprimierte Genprodukte und deren Verwendung |
WO2013174404A1 (en) | 2012-05-23 | 2013-11-28 | Ganymed Pharmaceuticals Ag | Combination therapy involving antibodies against claudin 18.2 for treatment of cancer |
CN105073776B (zh) | 2012-11-13 | 2019-04-12 | 拜恩科技股份公司 | 用于治疗表达紧密连接蛋白的癌症疾病的制剂 |
WO2014127785A1 (en) | 2013-02-20 | 2014-08-28 | Ganymed Pharmaceuticals Ag | Combination therapy involving antibodies against claudin 18.2 for treatment of cancer |
WO2014146672A1 (en) | 2013-03-18 | 2014-09-25 | Ganymed Pharmaceuticals Ag | Therapy involving antibodies against claudin 18.2 for treatment of cancer |
SG11201900171QA (en) * | 2016-07-08 | 2019-02-27 | Carsgen Therapeutics Co Ltd | Antibody for anti-claudin 18a2 and use thereof |
TWI710574B (zh) | 2017-05-16 | 2020-11-21 | 荷蘭商拜恩迪斯公司 | 抗訊號調節蛋白α(SIRPα)抗體 |
CA3089653A1 (en) | 2018-03-08 | 2019-09-12 | Phanes Therapeutics, Inc. | Anti-claudin 18.2 antibodies and uses thereof |
CN110577597B (zh) * | 2018-06-11 | 2021-10-22 | 康诺亚生物医药科技(成都)有限公司 | 一种阻断CD47和SIRPα相互作用的抗体 |
WO2020018852A2 (en) * | 2018-07-18 | 2020-01-23 | Askgene Pharma Inc. | Novel antibodies and methods for making and using the same |
JP2021535744A (ja) * | 2018-08-27 | 2021-12-23 | ナンジン・サンホーム・ファーマシューティカル・カンパニー・リミテッドNanjing Sanhome Pharmaceutical Co., Ltd. | 抗クローディン18.2抗体及びその使用 |
US20220033491A1 (en) * | 2018-09-30 | 2022-02-03 | Cafa Therapeutics Limited | Combination therapy of cldn18 antibody and chemotherapy drugs |
CN109402075A (zh) * | 2018-11-28 | 2019-03-01 | 深圳先进技术研究院 | 一种用于清除氧自由基的小分子蛋白质及其应用 |
AU2019415848A1 (en) * | 2018-12-28 | 2021-08-19 | Nanjing GenScript Biotech Co., Ltd. | Claudin18.2 binding moieties and uses thereof |
JP2022516505A (ja) * | 2018-12-28 | 2022-02-28 | スパークス・セラピューティクス・インコーポレイテッド | 癌および他の疾患の治療のための、クローディン18.2に特異的な結合分子、その組成物および方法 |
CN113271953A (zh) * | 2019-01-07 | 2021-08-17 | 科济生物医药(上海)有限公司 | 细胞免疫治疗的组合 |
CN109762067B (zh) * | 2019-01-17 | 2020-02-28 | 北京天广实生物技术股份有限公司 | 结合人Claudin 18.2的抗体及其用途 |
SG11202108398YA (en) | 2019-02-01 | 2021-08-30 | Novarock Biotherapeutics Ltd | Anti-claudin 18 antibodies and methods of use thereof |
US20220372112A1 (en) * | 2019-04-19 | 2022-11-24 | Keymed Biosciences Co., Ltd. | Tumor therapeutic agent and use thereof |
CN111944048B (zh) * | 2019-05-16 | 2023-10-03 | 启愈生物技术(上海)有限公司 | 抗cldn抗体及其药物组合物和检测方法 |
KR20220024010A (ko) * | 2019-05-16 | 2022-03-03 | 치루 파머수티컬 컴퍼니 리미티드 | 클라우딘 18a2에 대한 항체 및 그의 용도 |
AU2020281380B2 (en) * | 2019-05-30 | 2024-04-11 | Shandong Boan Biotechnology Co., Ltd. | Antibody or chimeric antigen receptor which targets claudin 18.2 |
WO2021024020A1 (en) * | 2019-08-06 | 2021-02-11 | Astellas Pharma Inc. | Combination therapy involving antibodies against claudin 18.2 and immune checkpoint inhibitors for treatment of cancer |
CN114630840A (zh) * | 2019-08-20 | 2022-06-14 | 苏州创胜医药集团有限公司 | 新型抗cldn18.2抗体 |
CN114981303B (zh) * | 2019-09-13 | 2024-01-23 | 安徽俊义医疗管理咨询有限公司 | 人源化抗Claudin18.2(CLDN18.2)抗体 |
WO2021111003A1 (en) | 2019-12-06 | 2021-06-10 | SOTIO a.s. | Humanized cldn18.2 antibodies |
CN114761433A (zh) * | 2019-12-11 | 2022-07-15 | 上海复宏汉霖生物技术股份有限公司 | 一种抗Claudin18.2单克隆抗体、其制备方法及用途 |
MX2022007849A (es) | 2019-12-23 | 2022-07-19 | Sotio Biotech A S | Anticuerpos especificos contra la claudina 18.2 tumoral. |
WO2021160154A1 (zh) * | 2020-02-10 | 2021-08-19 | 上海诗健生物科技有限公司 | Cldn18.2抗体及其用途 |
CN113854234B (zh) * | 2020-06-30 | 2023-09-08 | 江苏奥赛康生物医药有限公司 | 一种小鼠胰腺癌模型及其构建方法和应用 |
EP4214233A1 (en) | 2020-09-16 | 2023-07-26 | Amgen Inc. | Methods for administering therapeutic doses of bispecific t-cell engaging molecules for the treatment of cancer |
WO2022100590A1 (zh) * | 2020-11-10 | 2022-05-19 | 齐鲁制药有限公司 | 针对密蛋白18a2的adcc增强型人源化抗体及其应用 |
WO2022122709A1 (en) | 2020-12-07 | 2022-06-16 | Sotio Biotech A.S. | Antibody-drug conjugates based on humanized cldn18.2 antibodies |
EP4267194A1 (en) | 2020-12-23 | 2023-11-01 | SOTIO Biotech a.s. | Tumor-specific claudin 18.2 antibody-drug conjugates |
WO2023161457A1 (en) | 2022-02-27 | 2023-08-31 | Evobright Gmbh | Bispecific antibodies against cd277 and a tumor-antigen |
CN116536274B (zh) * | 2023-06-20 | 2023-09-19 | 上海精翰生物科技有限公司 | Claudin18.2表达稳转细胞株、制备方法及应用 |
Family Cites Families (48)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB8601597D0 (en) | 1986-01-23 | 1986-02-26 | Wilson R H | Nucleotide sequences |
GB8717430D0 (en) | 1987-07-23 | 1987-08-26 | Celltech Ltd | Recombinant dna product |
GB8809129D0 (en) | 1988-04-18 | 1988-05-18 | Celltech Ltd | Recombinant dna methods vectors and host cells |
CA2339043A1 (en) | 1998-09-01 | 2000-03-09 | Genentech, Inc. | Further pro polypeptides and sequences thereof |
EP1144629A3 (en) | 1998-09-01 | 2001-11-28 | Genentech, Inc. | Further pro polypeptides and sequences thereof |
EP1112364A2 (en) | 1998-09-16 | 2001-07-04 | ZymoGenetics, Inc. | Stomach polypeptide zsig28 |
WO2000020447A2 (en) | 1998-10-06 | 2000-04-13 | Curagen Corporation | Polynucleotides coding for secreted polypeptides, some having similarity to syncollin or claudin or cytokine, their therapeutic uses |
US6146304A (en) | 1998-12-22 | 2000-11-14 | Caterpillar Inc. | Vehicle differential |
KR20010109275A (ko) | 1998-12-23 | 2001-12-08 | 로저 에이. 윌리암스 | 종양치료의 병용치료로서 사이클로옥시게나제-2 억제제와기질 금속단백분해효소 억제제를 사용하는 방법 |
WO2000058473A2 (en) | 1999-03-31 | 2000-10-05 | Curagen Corporation | Nucleic acids including open reading frames encoding polypeptides; 'orfx' |
AU2883700A (en) | 1999-06-23 | 2001-01-09 | Genentech Inc. | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
AU7573000A (en) | 1999-09-01 | 2001-03-26 | Genentech Inc. | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
US6493119B1 (en) | 1999-09-07 | 2002-12-10 | Chien-Yu Kuo | Scalable DWDM network switch architecture with wavelength tunable sources |
US6380362B1 (en) | 1999-12-23 | 2002-04-30 | Genesis Research & Development Corporation Ltd. | Polynucleotides, polypeptides expressed by the polynucleotides and methods for their use |
DE10003939A1 (de) | 2000-01-29 | 2001-08-02 | Cognis Deutschland Gmbh | Verfahren zur Herstellung radikalisch nachvernetzter Polymere unter Einsatz von reaktiven Anhydriden |
WO2001055326A2 (en) | 2000-01-31 | 2001-08-02 | Human Genome Sciences, Inc. | Nucleic acids, proteins, and antibodies |
CA2396719A1 (en) | 2000-01-31 | 2001-08-02 | Human Genome Sciences, Inc. | 22 human secreted proteins |
EP1261703A1 (en) | 2000-01-31 | 2002-12-04 | Human Genome Sciences, Inc. | Nucleic acids, proteins, and antibodies |
WO2001055355A1 (en) | 2000-01-31 | 2001-08-02 | Human Genome Sciences, Inc. | Nucleic acids, proteins, and antibodies |
AU6802801A (en) | 2000-03-01 | 2001-09-24 | Genentech Inc | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
US6436703B1 (en) | 2000-03-31 | 2002-08-20 | Hyseq, Inc. | Nucleic acids and polypeptides |
AU2001260847A1 (en) | 2000-05-24 | 2001-12-03 | Genesis Research And Development Corporation Limited | Compositions isolated from skin cells and methods for their use |
AU8497701A (en) | 2000-08-15 | 2002-02-25 | Immunex Corp | Claudin polypeptides |
AU2001286810A1 (en) | 2000-08-28 | 2002-03-13 | Diadexus, Inc. | Compositions and methods relating to lung specific genes |
EP2298789B1 (en) | 2000-09-08 | 2012-03-14 | Schering Corporation | Mammalian genes; related reagents and methods |
ES2295228T3 (es) | 2000-11-30 | 2008-04-16 | Medarex, Inc. | Roedores transcromosomicos transgenicos para la preparacion de anticuerpos humanos. |
US20030133939A1 (en) | 2001-01-17 | 2003-07-17 | Genecraft, Inc. | Binding domain-immunoglobulin fusion proteins |
US7754208B2 (en) | 2001-01-17 | 2010-07-13 | Trubion Pharmaceuticals, Inc. | Binding domain-immunoglobulin fusion proteins |
SI1549344T1 (sl) * | 2002-10-10 | 2015-05-29 | Merck Patent Gmbh | FARMACEVTSKI SESTAVKI PROTI RECEPTORJEM ErbB1 |
PL216630B1 (pl) | 2002-10-17 | 2014-04-30 | Genmab As | Izolowane ludzkie przeciwciało monoklonalne wiążące ludzki CD20, związane z tym przeciwciałem transfektoma, komórka gospodarza, transgeniczne zwierzę lub roślina, kompozycja, immunokoniugat, cząsteczka bispecyficzna, wektor ekspresyjny, kompozycja farmaceutyczna, zastosowanie medyczne, zestaw oraz przeciwciało antyidiotypowe i jego zastosowanie |
DE10254601A1 (de) | 2002-11-22 | 2004-06-03 | Ganymed Pharmaceuticals Ag | Differentiell in Tumoren exprimierte Genprodukte und deren Verwendung |
WO2004063355A2 (en) | 2003-01-10 | 2004-07-29 | Protein Design Labs, Inc. | Novel methods of diagnosis of metastatic cancer, compositions and methods of screening for modulators of matastatic cancer |
DE102004024617A1 (de) | 2004-05-18 | 2005-12-29 | Ganymed Pharmaceuticals Ag | Differentiell in Tumoren exprimierte Genprodukte und deren Verwendung |
DE102004042822A1 (de) | 2004-08-31 | 2006-03-16 | Technische Universität Dresden | Verbindungen und Methoden zur Behandlung, Diagnose und Prognose bei Pankreaserkrankungen |
EP2182057A1 (en) | 2005-08-31 | 2010-05-05 | Cell Signaling Technology, Inc. | Antibody agains phosphorylated Tyrosine for the detection of protein phosphorylation in carcinoma signaling pathways |
DK2402758T3 (da) | 2005-09-19 | 2014-11-03 | Janssen Diagnostics Llc | Fremgangsmåder og anvendelser til identificering af oprindelsen af et karcinom med ukendt primær oprindelse |
EP1790664A1 (en) * | 2005-11-24 | 2007-05-30 | Ganymed Pharmaceuticals AG | Monoclonal antibodies against claudin-18 for treatment of cancer |
WO2008013948A2 (en) | 2006-07-27 | 2008-01-31 | Cell Signaling Technology, Inc. | Tyrosine phosphorylation sites |
CA2677118A1 (en) | 2007-02-01 | 2008-08-07 | Veridex, Llc | Methods and materials for identifying the origin of a carcinoma of unknown primary origin |
EP2145902A3 (en) | 2007-04-19 | 2010-09-29 | Peter Hornbeck | Tyrosine phosphorylation sites and antibodies specific for them |
EP1997832A1 (en) | 2007-05-29 | 2008-12-03 | Ganymed Pharmaceuticals AG | Monoclonal antibodies against Claudin-18 for treatment of cancer |
WO2008152822A1 (ja) | 2007-06-15 | 2008-12-18 | Medinet Co., Ltd. | 医薬 |
EP2036987A1 (en) | 2007-09-17 | 2009-03-18 | Siemens Healthcare Diagnostics GmbH | Molecular markers for tumor cell content in tissue samples |
WO2010141093A2 (en) * | 2009-06-04 | 2010-12-09 | The University Of Maryland, Baltimore | Co-signaling methods for treating cancers |
WO2013167153A1 (en) | 2012-05-09 | 2013-11-14 | Ganymed Pharmaceuticals Ag | Antibodies useful in cancer diagnosis |
WO2013174403A1 (en) | 2012-05-23 | 2013-11-28 | Ganymed Pharmaceuticals Ag | Combination therapy involving antibodies against claudin 18.2 for treatment of cancer |
WO2013174404A1 (en) | 2012-05-23 | 2013-11-28 | Ganymed Pharmaceuticals Ag | Combination therapy involving antibodies against claudin 18.2 for treatment of cancer |
WO2014127785A1 (en) | 2013-02-20 | 2014-08-28 | Ganymed Pharmaceuticals Ag | Combination therapy involving antibodies against claudin 18.2 for treatment of cancer |
-
2013
- 2013-02-20 WO PCT/EP2013/000505 patent/WO2014127785A1/en active Application Filing
-
2014
- 2014-02-18 BR BR112015019995A patent/BR112015019995A2/pt not_active Application Discontinuation
- 2014-02-18 KR KR1020157022627A patent/KR102385872B1/ko active IP Right Grant
- 2014-02-18 MY MYPI2015002055A patent/MY184332A/en unknown
- 2014-02-18 PL PL14707647.5T patent/PL2958945T3/pl unknown
- 2014-02-18 ES ES14707647T patent/ES2930654T3/es active Active
- 2014-02-18 JP JP2015558372A patent/JP6389478B2/ja active Active
- 2014-02-18 CN CN202210591156.6A patent/CN115282269A/zh active Pending
- 2014-02-18 LT LTEPPCT/EP2014/000433T patent/LT2958945T/lt unknown
- 2014-02-18 US US14/769,046 patent/US9770487B2/en active Active
- 2014-02-18 SG SG10201610412YA patent/SG10201610412YA/en unknown
- 2014-02-18 HU HUE14707647A patent/HUE060192T2/hu unknown
- 2014-02-18 SG SG11201506317PA patent/SG11201506317PA/en unknown
- 2014-02-18 AU AU2014221035A patent/AU2014221035B2/en active Active
- 2014-02-18 KR KR1020237032247A patent/KR20230143186A/ko not_active Application Discontinuation
- 2014-02-18 CN CN202210595828.0A patent/CN115177733A/zh active Pending
- 2014-02-18 PT PT147076475T patent/PT2958945T/pt unknown
- 2014-02-18 MX MX2015010724A patent/MX2015010724A/es active IP Right Grant
- 2014-02-18 UA UAA201508994A patent/UA118664C2/uk unknown
- 2014-02-18 IL IL239981A patent/IL239981B2/en unknown
- 2014-02-18 WO PCT/EP2014/000433 patent/WO2014127906A1/en active Application Filing
- 2014-02-18 DK DK14707647.5T patent/DK2958945T3/da active
- 2014-02-18 IL IL302093A patent/IL302093A/en unknown
- 2014-02-18 KR KR1020227011583A patent/KR20220050230A/ko not_active Application Discontinuation
- 2014-02-18 CN CN201480009127.8A patent/CN105073777B/zh active Active
- 2014-02-18 RU RU2015139901A patent/RU2699549C2/ru active
- 2014-02-18 CA CA2899754A patent/CA2899754C/en active Active
- 2014-02-20 AR ARP140100551A patent/AR094849A1/es not_active Application Discontinuation
-
2015
- 2015-08-19 MX MX2020011772A patent/MX2020011772A/es unknown
- 2015-08-19 SA SA515360926A patent/SA515360926B1/ar unknown
- 2015-08-19 MX MX2020011783A patent/MX2020011783A/es unknown
-
2016
- 2016-02-22 HK HK16101942.9A patent/HK1213925A1/zh unknown
-
2017
- 2017-08-23 US US15/684,168 patent/US10314890B2/en active Active
-
2018
- 2018-08-17 JP JP2018153591A patent/JP6694926B2/ja active Active
-
2019
- 2019-05-02 US US16/401,931 patent/US10946069B2/en active Active
-
2020
- 2020-04-20 JP JP2020074760A patent/JP7051931B2/ja active Active
- 2020-10-08 US US17/066,232 patent/US11826402B2/en active Active
-
2022
- 2022-03-30 JP JP2022055122A patent/JP7299369B2/ja active Active
-
2023
- 2023-06-15 JP JP2023098630A patent/JP2023123596A/ja active Pending
- 2023-08-24 US US18/455,469 patent/US20240091312A1/en active Pending
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
AR094849A1 (es) | Terapia combinada que involucra anticuerpos dirigidos contra claudina 18.2 para el tratamiento de cáncer | |
AR125906A2 (es) | Terapia combinada que involucra anticuerpos dirigidos contra claudina 18.2 para el tratamiento del cáncer | |
AR091131A1 (es) | Terapia combinada que involucra anticuerpos dirigidos contra claudina 18.2 para el tratamiento del cancer | |
CY1119433T1 (el) | Αμινο-υποκατεστημενες ιμιδαζοπυριδαζινες | |
CY1119676T1 (el) | Συνθεσεις και μεθοδοι για τη θεραπεια του καρκινου | |
CY1120334T1 (el) | Υποκατεστημενης 3-αλλογονοαλυλαμινης αναστολεις ssao και χρησεις αυτων | |
AR091220A1 (es) | Metodos para tratar cancer usando antagonistas de union a pd-1 axis y antagonistas de vegf | |
SG10201811841UA (en) | Methods of treating cancer using tigit inhibitors and anti-cancer agents | |
EA201690905A1 (ru) | Специфические антитела против cd38 для лечения злокачественных новообразований у человека | |
NI201400024A (es) | Agentes de ligación al factor de crecimiento endotelial vascular/ligando 4 similar a delta ( vegf/dll4) y usos de los mismos. | |
EA201792066A1 (ru) | Оптимизированная комбинированная терапия и ее применение для лечения злокачественной опухоли и аутоиммунного заболевания | |
UA117098C2 (uk) | Сполука, що містить модифікований олігонуклеотид | |
EA201691590A1 (ru) | Бензимидазол-2-амины в качестве ингибиторов midhi | |
EA201490647A1 (ru) | Производные бензотиазол-6-илуксусной кислоты и их применение для лечения вич-инфекции | |
PE20142242A1 (es) | Anticuerpos humanos anti-cd27, metodos, y usos | |
EA201490891A1 (ru) | Пиридопиразины, обладающие противораковой активностью через ингибирование fgfr киназ | |
EA201500019A1 (ru) | Способ лечения gd2-положительного рака | |
PE20141560A1 (es) | Anticuerpo anti-epirregulina humanizado y agente terapeutico contra el cancer que comprende dicho anticuerpo como ingrediente activo | |
AR086051A1 (es) | Metodo para tratar el cancer colorrectal, composicion que comprende aflibercept, acido folinico, 5-fluorouracilo (5-fu) e irinotecano (folfiri), articulo manufacturado, kit | |
EA201791535A1 (ru) | Новое соединение 4'-тионуклеозида, а также способ его получения, его фармацевтическая композиция и применение | |
EA202091514A1 (ru) | СПОСОБЫ ЛЕЧЕНИЯ РАКА ТОЛСТОЙ КИШКИ С ИСПОЛЬЗОВАНИЕМ КОМБИНИРОВАННОЙ ТЕРАПИИ НАНОЧАСТИЦАМИ С ИНГИБИТОРОМ mTOR | |
EA201492148A1 (ru) | Способ лечения немелкоклеточного рака легких | |
EA201591687A1 (ru) | Индукционная терапия ритуксимабом с последующим лечением с использованием глатирамера ацетата | |
JP2015516496A5 (es) | ||
EA201490395A1 (ru) | Способ получения фармацевтических композиций, содержащих финголимод |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
FC | Refusal |