CL2020002305A1 - Uso de anticuerpos sirpa v1 antihumanos y procedimiento de producción de anticuerpos anti-sirpa v1 - Google Patents

Uso de anticuerpos sirpa v1 antihumanos y procedimiento de producción de anticuerpos anti-sirpa v1

Info

Publication number
CL2020002305A1
CL2020002305A1 CL2020002305A CL2020002305A CL2020002305A1 CL 2020002305 A1 CL2020002305 A1 CL 2020002305A1 CL 2020002305 A CL2020002305 A CL 2020002305A CL 2020002305 A CL2020002305 A CL 2020002305A CL 2020002305 A1 CL2020002305 A1 CL 2020002305A1
Authority
CL
Chile
Prior art keywords
sirpa
human
antibodies
antibody production
isoforms
Prior art date
Application number
CL2020002305A
Other languages
English (en)
Inventor
Nicolas Poirier
Vanessa Gauttier
Caroline Mary
Sabrina Pengam
Bernard Vanhove
Original Assignee
Ose Immunotherapeutics
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 Ose Immunotherapeutics filed Critical Ose Immunotherapeutics
Publication of CL2020002305A1 publication Critical patent/CL2020002305A1/es

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803—Immunoglobulins [IGs], 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
    • 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
    • C07K16/2896—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against molecules with a "CD"-designation, not provided for elsewhere
    • 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
    • C07K14/70503—Immunoglobulin superfamily
    • 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
    • C07K14/70503—Immunoglobulin superfamily
    • C07K14/70532—B7 molecules, e.g. CD80, CD86
    • 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
    • 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
    • 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
    • C07K2317/50—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
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/74—Inducing 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
    • C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/80—Immunoglobulins specific features remaining in the (producing) cell, i.e. intracellular antibodies or intrabodies
    • 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
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Immunology (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Zoology (AREA)
  • Toxicology (AREA)
  • Cell Biology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Peptides Or Proteins (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

La invención pertenece al campo de la inmunoterapia. La presente invención proporciona anticuerpos útiles en aplicaciones terapéuticas y diagnósticas dirigidas a SIRPa humano, dichos anticuerpos mejoran la presentación cruzada de antígenos a células T. La invención también proporciona anticuerpos contra isoformas específicas de SIRPa y capaces de interrumpir la interacción entre esas isoformas de SIRPa y CD47 humano para su uso en el tratamiento o prevención de una enfermedad, o aplicaciones de diagnóstico, y procedimientos de producción y/o de selección de anticuerpos SIRPa antihumanos que se unen con diferentes afinidades a varias isoformas de miembros de SIRP humano.
CL2020002305A 2018-03-13 2020-09-07 Uso de anticuerpos sirpa v1 antihumanos y procedimiento de producción de anticuerpos anti-sirpa v1 CL2020002305A1 (es)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
EP18305271 2018-03-13

Publications (1)

Publication Number Publication Date
CL2020002305A1 true CL2020002305A1 (es) 2021-02-12

Family

ID=61972458

Family Applications (1)

Application Number Title Priority Date Filing Date
CL2020002305A CL2020002305A1 (es) 2018-03-13 2020-09-07 Uso de anticuerpos sirpa v1 antihumanos y procedimiento de producción de anticuerpos anti-sirpa v1

Country Status (13)

Country Link
US (1) US11884723B2 (es)
EP (1) EP3765512A1 (es)
JP (1) JP2021517130A (es)
KR (1) KR20210006338A (es)
CN (1) CN112105646A (es)
AU (1) AU2019233577A1 (es)
BR (1) BR112020017709A2 (es)
CA (1) CA3091468A1 (es)
CL (1) CL2020002305A1 (es)
EA (1) EA202091859A1 (es)
MX (1) MX2020009121A (es)
PH (1) PH12020551491A1 (es)
WO (1) WO2019175218A1 (es)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11779642B2 (en) 2016-12-09 2023-10-10 Alector Llc Anti-SIRP-alpha antibodies and methods of use thereof
US11976119B2 (en) 2018-05-25 2024-05-07 Alector Llc Anti-SIRPa antibodies and methods of use thereof

Families Citing this family (29)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
UA126658C2 (uk) 2016-04-14 2023-01-11 Осе Іммьюнотерапьютікс НОВІ АНТИТІЛА ДО SIRPa ТА ВАРІАНТИ ЇХ ТЕРАПЕВТИЧНОГО ЗАСТОСУВАННЯ
KR20230149857A (ko) 2016-07-07 2023-10-27 더 보드 어브 트러스티스 어브 더 리랜드 스탠포드 주니어 유니버시티 항체-애쥬번트 접합체
WO2019073080A1 (en) 2017-10-13 2019-04-18 Ose Immunotherapeutics ANTI-SIRPA MODIFIED ANTIBODIES AND USES THEREOF
WO2020190725A1 (en) 2019-03-15 2020-09-24 Bolt Biotherapeutics, Inc. Immunoconjugates targeting her2
EP3990476A1 (en) 2019-06-25 2022-05-04 Gilead Sciences, Inc. Flt3l-fc fusion proteins and methods of use
CN118178645A (zh) 2019-10-18 2024-06-14 四十七公司 用于治疗骨髓增生异常综合征和急性髓系白血病的联合疗法
JP2022552748A (ja) 2019-10-31 2022-12-19 フォーティ セブン， インコーポレイテッド 抗ｃｄ４７及び抗ｃｄ２０による血液癌の治療
PE20230376A1 (es) 2019-12-24 2023-03-06 Carna Biosciences Inc Compuestos moduladores de la diacilglicerol quinasa
US11692038B2 (en) 2020-02-14 2023-07-04 Gilead Sciences, Inc. Antibodies that bind chemokine (C-C motif) receptor 8 (CCR8)
CN111635458A (zh) * 2020-03-20 2020-09-08 上海健信生物医药科技有限公司 靶向Sirpα的抗体或其抗原结合片段及其制备和应用
TW202302145A (zh) 2021-04-14 2023-01-16 美商基利科學股份有限公司 ＣＤ４７／ＳＩＲＰα結合及ＮＥＤＤ８活化酶Ｅ１調節次單元之共抑制以用於治療癌症
WO2022245671A1 (en) 2021-05-18 2022-11-24 Gilead Sciences, Inc. Methods of using flt3l-fc fusion proteins
WO2022271650A1 (en) 2021-06-23 2022-12-29 Gilead Sciences, Inc. Diacylglyercol kinase modulating compounds
CN117480155A (zh) 2021-06-23 2024-01-30 吉利德科学公司 二酰基甘油激酶调节化合物
CA3222439A1 (en) 2021-06-23 2022-12-29 Gilead Sciences, Inc. Diacylglyercol kinase modulating compounds
EP4359415A1 (en) 2021-06-23 2024-05-01 Gilead Sciences, Inc. Diacylglyercol kinase modulating compounds
KR20240025597A (ko) 2021-06-29 2024-02-27 씨젠 인크. 비푸코실화 항-cd70 항체 및 cd47 길항제의 조합으로 암을 치료하는 방법
CN113583979B (zh) * 2021-08-03 2022-11-22 杭州荣谷生物科技有限公司 一种重组溶瘤痘苗病毒、制备方法及其用途
WO2023076983A1 (en) 2021-10-28 2023-05-04 Gilead Sciences, Inc. Pyridizin-3(2h)-one derivatives
CA3235986A1 (en) 2021-10-29 2023-05-04 Gilead Science, Inc. Cd73 compounds
AU2022417491A1 (en) 2021-12-22 2024-05-23 Gilead Sciences, Inc. Ikaros zinc finger family degraders and uses thereof
AU2022419982A1 (en) 2021-12-22 2024-06-06 Gilead Sciences, Inc. Ikaros zinc finger family degraders and uses thereof
TW202340168A (zh) 2022-01-28 2023-10-16 美商基利科學股份有限公司 Ｐａｒｐ７抑制劑
TW202346277A (zh) 2022-03-17 2023-12-01 美商基利科學股份有限公司 Ｉｋａｒｏｓ鋅指家族降解劑及其用途
US20230355796A1 (en) 2022-03-24 2023-11-09 Gilead Sciences, Inc. Combination therapy for treating trop-2 expressing cancers
TW202345901A (zh) 2022-04-05 2023-12-01 美商基利科學股份有限公司 用於治療結腸直腸癌之組合療法
TW202400138A (zh) 2022-04-21 2024-01-01 美商基利科學股份有限公司 Ｋｒａｓ ｇ１２ｄ調節化合物
WO2024006929A1 (en) 2022-07-01 2024-01-04 Gilead Sciences, Inc. Cd73 compounds
WO2024064668A1 (en) 2022-09-21 2024-03-28 Gilead Sciences, Inc. FOCAL IONIZING RADIATION AND CD47/SIRPα DISRUPTION ANTICANCER COMBINATION THERAPY

Family Cites Families (24)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2259122A1 (en) 1996-06-17 1997-12-24 Max Planck Gesellschaft Zur Forderung Der Wissenschaften E.V. Novel ptp-20, pcp-2, bdp1, clk and sirp proteins and related products and methods
DE19742706B4 (de) 1997-09-26 2013-07-25 Pieris Proteolab Ag Lipocalinmuteine
US8613922B2 (en) 2003-04-24 2013-12-24 The University Of North Carolina At Chapel Hill Methods for inhibiting diabetic retinopathy with an antibody against integrin associated protein (IAP)
US20100215640A1 (en) 2003-04-24 2010-08-26 The University Of North Carolina At Chapel Hill Method for inhibiting cellular activation by insulin-like growth factor-1
JP3936673B2 (ja) 2003-06-02 2007-06-27 国立大学法人群馬大学 Ｃｄ４７部分ペプチドと抗ｓｈｐｓ−１モノクロナール抗体
SI1907424T1 (sl) 2005-07-01 2015-12-31 E. R. Squibb & Sons, L.L.C. Humana monoklonska protitelesa proti programiranem smrtnem ligandu 1 (PD-L1)
EP1930342B1 (en) 2006-12-04 2012-01-25 Institut Pasteur OB-fold used as scaffold for engineering new specific binders
US20100239578A1 (en) 2007-10-11 2010-09-23 University Health Network Modulation of sirp-alpha - cd47 interaction for increasing human hematopoietic stem cell engraftment and compounds therefor
AU2008314647B2 (en) 2007-10-12 2013-03-21 Massachusetts Institute Of Technology Vaccine nanotechnology
EP2111869A1 (en) 2008-04-23 2009-10-28 Stichting Sanquin Bloedvoorziening Compositions and methods to enhance the immune system
CN108997498A (zh) 2008-12-09 2018-12-14 霍夫曼-拉罗奇有限公司 抗-pd-l1抗体及它们用于增强t细胞功能的用途
EP2995315B1 (en) 2009-05-15 2023-12-27 University Health Network Compositions and methods for treating hematologic cancers targeting the sirp alpha- cd47 interaction
GB201015765D0 (en) 2010-09-21 2010-10-27 Immatics Biotechnologies Gmbh Use of myeloid cell biomarkers for the diagnosis of cancer
US8883497B2 (en) 2011-04-28 2014-11-11 University Of Southern California Human myeloid derived suppressor cell cancer markers
US20140242095A1 (en) 2011-10-19 2014-08-28 University Health Network Antibodies and antibody fragments targeting sirp-alpha and their use in treating hematologic cancers
KR101981873B1 (ko) 2011-11-28 2019-05-23 메르크 파텐트 게엠베하 항-ｐｄ-ｌ1 항체 및 그의 용도
EP3766511A1 (en) 2012-01-17 2021-01-20 The Board of Trustees of the Leland Stanford Junior University High affinity sirp-alpha reagents
US10570204B2 (en) 2013-09-26 2020-02-25 The Medical College Of Wisconsin, Inc. Methods for treating hematologic cancers
EP3116544A4 (en) * 2014-03-11 2017-08-23 The Board of Trustees of the Leland Stanford Junior University Anti sirp-alpha antibodies and bi-specific macrophage enhancing antibodies
EP3012271A1 (en) 2014-10-24 2016-04-27 Effimune Method and compositions for inducing differentiation of myeloid derived suppressor cell to treat cancer and infectious diseases
US20180312600A1 (en) 2015-10-21 2018-11-01 Ose Immunotherapeutics Methods and compositions for modifying macrophage polarization into pro-inflammatory cells to treat cancer
UA126658C2 (uk) 2016-04-14 2023-01-11 Осе Іммьюнотерапьютікс НОВІ АНТИТІЛА ДО SIRPa ТА ВАРІАНТИ ЇХ ТЕРАПЕВТИЧНОГО ЗАСТОСУВАННЯ
SG11201808465UA (en) 2016-04-14 2018-10-30 Ose Immunotherapeutics NEW ANTI-SIRPa ANTIBODIES AND THEIR THERAPEUTIC APPLICATIONS
WO2019073080A1 (en) 2017-10-13 2019-04-18 Ose Immunotherapeutics ANTI-SIRPA MODIFIED ANTIBODIES AND USES THEREOF

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11779642B2 (en) 2016-12-09 2023-10-10 Alector Llc Anti-SIRP-alpha antibodies and methods of use thereof
US11976119B2 (en) 2018-05-25 2024-05-07 Alector Llc Anti-SIRPa antibodies and methods of use thereof

Also Published As

Publication number Publication date
EA202091859A1 (ru) 2021-02-04
US20210040206A1 (en) 2021-02-11
KR20210006338A (ko) 2021-01-18
WO2019175218A1 (en) 2019-09-19
JP2021517130A (ja) 2021-07-15
PH12020551491A1 (en) 2021-09-06
AU2019233577A1 (en) 2020-09-03
CN112105646A (zh) 2020-12-18
CA3091468A1 (en) 2019-09-19
US11884723B2 (en) 2024-01-30
BR112020017709A2 (pt) 2020-12-29
EP3765512A1 (en) 2021-01-20
MX2020009121A (es) 2020-10-01

Similar Documents

Publication Publication Date Title
CL2020002305A1 (es) Uso de anticuerpos sirpa v1 antihumanos y procedimiento de producción de anticuerpos anti-sirpa v1
DOP2023000165A (es) Anticuerpos de unión a cd3
CO2019012210A2 (es) Anticuerpos anti-trem2 y métodos para utilizarlos
BR112018076767A2 (pt) anticorpos de ligação a cd3
ECSP20082648A (es) Anticuerpos anti-sirpa y métodos de utilización de los mismos
MX2020006715A (es) Anticuerpos especificos del heterodimero de cd3-delta/epsilon.
EA201792221A1 (ru) Антитела против сортилина и способы их применения
UY37127A (es) Moléculas de unión a ror1, y métodos de uso de las mismas
PE20171324A1 (es) Anticuerpos heterodimericos que se unen a cd3 y a antigenos tumorales
CY1124153T1 (el) Αντισωματα και πολυπεπτιδια που κατευθυνονται εναντι cd127
CO2019012200A2 (es) Anticuerpos anti-cd33 y métodos para utilizarlos
PE20181054A1 (es) Anticuerpos anti-cd19 humano humanizados y metodos de utilizacion
AR069290A1 (es) Anticuerpos monoclonales que se unen al hgm -csf (factor estimulante de la colonia de granulocitos-macrofagos) y las composiciones medicas que los comprenden
PE20140673A1 (es) Nuevos moduladores y metodos para su uso
EA202092085A1 (ru) ТЕРАПЕВТИЧЕСКИЕ АНТИТЕЛА ПРОТИВ sPLA2-GIB И ИХ ПРИМЕНЕНИЕ
BR112016024214B8 (pt) Anticorpo monoclonal parcialmente humanizado, composição farmacêutica e uso de um anticorpo monoclonal
CL2020002600A1 (es) Anticuerpo anti-muerte programada-ligando 1 y su uso
UY39436A (es) Proteínas de unión específicas y sus usos
CO2021000386A2 (es) Anticuerpos humanizados contra psma
CO2023017609A2 (es) Anticuerpos multiespecíficos anti-cea y anti-cd137 y métodos de uso
EP4032550A3 (en) Humanized anti-cd19 antibody and use thereof with chimeric antigen receptor
EA202092595A1 (ru) Антитела к siglec-7 и способы их применения
AR108451A1 (es) Anticuerpos anti-tenascina modificados y métodos de utilización
EA202191139A1 (ru) АНТИТЕЛА К EpCAM, АКТИВИРУЕМЫЕ АНТИТЕЛА И ИММУНОКОНЪЮГАТЫ И ИХ ПРИМЕНЕНИЕ
EA202092279A1 (ru) Антитела к mica и/или micb и их применение