CN110799218A - 包含sting激动剂的抗体缀合物 - Google Patents

包含sting激动剂的抗体缀合物 Download PDF

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Publication number
CN110799218A
CN110799218A CN201880043438.4A CN201880043438A CN110799218A CN 110799218 A CN110799218 A CN 110799218A CN 201880043438 A CN201880043438 A CN 201880043438A CN 110799218 A CN110799218 A CN 110799218A
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China
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alkyl
alkenyl
alkynyl
phenyl
independently selected
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Pending
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CN201880043438.4A
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English (en)
Chinese (zh)
Inventor
T·W·小杜本斯基
J·R·布鲁姆
S·坎汉
C·Y·周
K·高蒂尔
L·H·格利克曼
郝学士
D·凯恩
S·卡斯布哈特拉
G·E·卡蒂巴
T·N·L·勒
J·莱昂
J·麦肯纳
S·麦克沃特
C·O·恩杜巴库
W·欧
L·宋
G·S·特里亚
宇野哲郎
T·Y-H·吴
万咏勤
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Novartis AG
Chinook Therapeutics Inc
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Novartis AG
Aduro Biotech Inc
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Publication of CN110799218A publication Critical patent/CN110799218A/zh
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6801—Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
    • A61K47/6803—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H21/00—Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K9/00—Peptides having up to 20 amino acids, containing saccharide radicals and having a fully defined sequence; Derivatives thereof
    • C07K9/001—Peptides having up to 20 amino acids, containing saccharide radicals and having a fully defined sequence; Derivatives thereof the peptide sequence having less than 12 amino acids and not being part of a ring structure
    • C07K9/003—Peptides being substituted by heterocyclic radicals, e.g. bleomycin, phleomycin

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Organic Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Immunology (AREA)
  • Epidemiology (AREA)
  • Biochemistry (AREA)
  • Molecular Biology (AREA)
  • Genetics & Genomics (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Biotechnology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Biophysics (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Peptides Or Proteins (AREA)
  • Saccharide Compounds (AREA)
  • Medicinal Preparation (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Medicines Containing Material From Animals Or Micro-Organisms (AREA)
CN201880043438.4A 2017-04-28 2018-04-26 包含sting激动剂的抗体缀合物 Pending CN110799218A (zh)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US201762491879P 2017-04-28 2017-04-28
US62/491,879 2017-04-28
PCT/US2018/029570 WO2018200812A1 (en) 2017-04-28 2018-04-26 Antibody conjugates comprising sting agonist

Publications (1)

Publication Number Publication Date
CN110799218A true CN110799218A (zh) 2020-02-14

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CN201880043438.4A Pending CN110799218A (zh) 2017-04-28 2018-04-26 包含sting激动剂的抗体缀合物

Country Status (5)

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EP (1) EP3615080A1 (https=)
JP (1) JP2020517700A (https=)
CN (1) CN110799218A (https=)
AR (1) AR113224A1 (https=)
WO (1) WO2018200812A1 (https=)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111592570A (zh) * 2020-05-15 2020-08-28 清华大学 新型sting激动剂及其制备方法和应用
CN115060902A (zh) * 2022-05-13 2022-09-16 上海市第十人民医院 可作为肿瘤诊断和预后分析标志物的cGAS甲基化修饰及其检测试剂和应用
CN115768485A (zh) * 2020-04-02 2023-03-07 梅尔莎纳医疗公司 包含sting激动剂的抗体药物缀合物
WO2024153127A1 (zh) * 2023-01-18 2024-07-25 泰励生物科技（上海）有限公司 抗体偶联药物及其用途
WO2025140587A1 (zh) * 2023-12-27 2025-07-03 上海迪诺医药科技有限公司 环状二核苷酸化合物、其偶联物及应用

Families Citing this family (46)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR102847350B1 (ko) 2015-11-25 2025-08-19 주식회사 리가켐바이오사이언스 분지된 링커를 포함하는 항체-약물 접합체 및 이의 제조방법
WO2018100558A2 (en) 2016-12-01 2018-06-07 Takeda Pharmaceutical Company Limited Cyclic dinucleotide
MX2019011655A (es) 2017-03-29 2019-12-19 Legochem Biosciences Inc Profarmaco de dimero de pirrolobenzodiazepina y compuesto conjugado ligando-conector de este.
WO2019051488A1 (en) 2017-09-11 2019-03-14 Sperovie Biosciences, Inc. COMPOUNDS, COMPOSITIONS AND METHODS OF TREATING DISEASE
WO2019051489A1 (en) 2017-09-11 2019-03-14 Sperovie Biosciences, Inc. COMPOUNDS, COMPOSITIONS AND METHODS OF TREATING DISEASE
JP7195317B2 (ja) 2017-11-10 2022-12-23 武田薬品工業株式会社 Ｓｔｉｎｇ調節剤化合物、ならびに製造及び使用する方法
EP3505188A1 (en) * 2017-12-29 2019-07-03 Invivogen Pro-cyclic dinucleotide conjugates for cytokine induction
JP7459063B2 (ja) 2018-05-09 2024-04-01 レゴケム バイオサイエンシズ， インク． 抗－ｃｄ１９抗体薬物複合体に関連する組成物および方法
MX2020012964A (es) * 2018-06-01 2021-02-16 Eisai R&D Man Co Ltd Metodos para el tratamiento de cancer de vejiga.
EP3820477A4 (en) 2018-07-10 2022-07-13 Sperovie Biosciences, Inc. COMPOUNDS, COMPOSITIONS AND METHODS FOR TREATMENT OF DISEASES
WO2020089815A1 (en) * 2018-10-31 2020-05-07 Novartis Ag Antibody conjugates comprising sting agonist
WO2020092617A1 (en) * 2018-10-31 2020-05-07 Novartis Ag Dc-sign antibody conjugates comprising sting agonists
JP7607564B2 (ja) * 2018-12-21 2024-12-27 ノバルティス アーゲー Ｐｍｅｌ１７に対する抗体及びその結合体
WO2020227159A2 (en) 2019-05-03 2020-11-12 Flagship Pioneering Innovations V, Inc. Methods of modulating immune activity
JP7621974B2 (ja) 2019-05-09 2025-01-27 アリゴス セラピューティクス インコーポレイテッド Ｓｔｉｎｇモジュレータとしての修飾環状ジヌクレオシド化合物
MX2021013657A (es) * 2019-05-10 2022-02-21 Takeda Pharmaceuticals Co Conjugados de anticuerpo y farmaco.
KR20220024106A (ko) 2019-05-20 2022-03-03 노파르티스 아게 Mcl-1 억제제 항체-약물 접합체 및 사용 방법
CN114269749B (zh) 2019-06-10 2024-10-01 苏特罗生物制药公司 5H-吡咯并[3,2-d]嘧啶-2,4-二氨基化合物及其抗体偶联物
WO2020248065A1 (en) * 2019-06-12 2020-12-17 Ontario Institute For Cancer Research (Oicr) Unsaturated heterocycloalkyl and heteroaromatic acyl hydrazone linkers, methods and uses thereof
US11033635B2 (en) 2019-07-19 2021-06-15 Immunesensor Therapeutics, Inc. Antibody-STING agonist conjugates and their use in immunotherapy
CA3149482A1 (en) 2019-08-02 2021-02-11 Mersana Therapeutics, Inc. Bis-[n-((5-carbamoyl)-1h-benzo[d]imidazol-2-yl)-pyrazol-5-carboxamide] derivatives and related compounds as sting (stimulator of interferon genes) agonists for the treatment of cancer
ES3055173T3 (en) * 2019-08-21 2026-02-10 Scripps Research Inst Bicyclic agonists of stimulator of interferon genes sting
KR20210028544A (ko) * 2019-09-04 2021-03-12 주식회사 레고켐 바이오사이언스 인간 ror1에 대한 항체를 포함하는 항체 약물 접합체 및 이의 용도
WO2021046426A1 (en) * 2019-09-06 2021-03-11 Sperovie Biosciences, Inc. Cyclic dinucleotide sting agonists tethered to a pd-1 or ctla-4 antibodies
US20230074385A1 (en) * 2019-12-23 2023-03-09 Eisai R&D Management Co., Ltd. Method for producing eribulin-based antibody-drug conjugate
CA3168368A1 (en) * 2020-03-06 2021-09-10 Masayuki Ishizaki Antibody-drug conjugate including novel cyclic dinucleotide derivative
BR112022019532A2 (pt) * 2020-03-31 2022-12-06 Orum Therapeutics Inc Conjugados de neodegrader
WO2021206158A1 (ja) 2020-04-10 2021-10-14 小野薬品工業株式会社 がん治療方法
WO2021216572A1 (en) 2020-04-20 2021-10-28 Massachusetts Institute Of Technology Lipid compositions for delivery of sting agonist compounds and uses thereof
JP2023533111A (ja) 2020-05-15 2023-08-02 イミューンセンサー セラピューティクス、インコーポレイテッド 免疫チェックポイント阻害剤とのｓｔｉｎｇアゴニスト併用治療
JP7397996B2 (ja) 2020-11-09 2023-12-13 武田薬品工業株式会社 抗体薬物コンジュゲート
JP7717832B2 (ja) 2021-04-10 2025-08-04 ジェンマブ エー／エス Ｆｏｌｒ１結合剤、そのコンジュゲートおよびこれを使用する方法
EP4326769A1 (en) 2021-04-20 2024-02-28 Institut Curie Compositions and methods for use in immunotherapy
WO2022226317A1 (en) 2021-04-23 2022-10-27 Profoundbio Us Co. Anti-cd70 antibodies, conjugates thereof and methods of using the same
TW202320857A (zh) 2021-07-06 2023-06-01 美商普方生物製藥美國公司 連接子、藥物連接子及其結合物及其使用方法
AU2022315305A1 (en) 2021-07-23 2024-02-01 Immunesensor Therapeutics, Inc. Sting agonist combination treatments with cytokines
CN118524854A (zh) * 2021-12-17 2024-08-20 北京加科思新药研发有限公司 包含可用作sting激动剂的新型化合物的化合物-连接基构建体及其用途
CA3261366A1 (en) 2022-07-21 2024-01-25 Firefly Bio, Inc. GLUCOCORTICOID RECEPTOR AGONISTS AND THEIR CONJUGATES
EP4615853A2 (en) * 2022-11-08 2025-09-17 LigaChem Biosciences Inc. Heterocyclic compounds as sting agonists
AU2024234194A1 (en) 2023-03-10 2025-08-07 Novartis Ag Panras inhibitor antibody-drug conjugates and methods of use thereof
GB202304385D0 (en) 2023-03-24 2023-05-10 Prostate Cancer Res Combinatorial IL-15 therapy
AU2024353316A1 (en) 2023-09-26 2026-03-26 Genmab A/S Ptk7 binding agents, conjugates thereof and methods of using the same
WO2025149661A1 (en) 2024-01-10 2025-07-17 Genmab A/S Slitrk6 binding agents, conjugates thereof and methods of using the same
WO2025181219A1 (en) 2024-02-29 2025-09-04 Genmab A/S Egfr and c-met bispecific binding agents, conjugates thereof and methods of using the same
WO2025233676A1 (en) * 2024-05-08 2025-11-13 Ligachem Biosciences Inc. Compositions and methods related to a combination therapy of sting agonists and immune checkpoint inhibitors
WO2025233679A1 (en) * 2024-05-08 2025-11-13 Ligachem Biosciences Inc. Compositions and methods related to a combination therapy of sting agonists and antibody drug conjugates

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016145102A1 (en) * 2015-03-10 2016-09-15 Aduro Biotech, Inc. Compositions and methods for activating "stimulator of interferon gene" -dependent signalling
WO2016161372A1 (en) * 2015-04-01 2016-10-06 President And Fellows Of Harvard College Immunoconjugates for programming or reprogramming of cells
WO2017100305A2 (en) * 2015-12-07 2017-06-15 Opi Vi - Ip Holdco Llc Composition of antibody construct-agonist conjugates and methods of use thereof

Family Cites Families (21)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1958962A3 (en) 1997-06-12 2013-05-01 Novartis International Pharmaceutical Ltd. Artificial antibody polypeptides
US8076303B2 (en) 2005-12-13 2011-12-13 Spring Bank Pharmaceuticals, Inc. Nucleotide and oligonucleotide prodrugs
KR20200058590A (ko) 2008-04-30 2020-05-27 이뮤노젠 아이엔씨 가교제 및 그 용도
ES2732574T3 (es) 2012-11-30 2019-11-25 Novartis Ag Métodos para preparar conjugados a partir de proteínas que contienen disulfuro
PL2931738T3 (pl) 2012-12-13 2019-07-31 Aduro Biotech, Inc. Kompozycje zawierające cykliczne dinukleotydy purynowe o zdefiniowanej stereochemii i sposoby ich otrzymywania i zastosowania
KR102447350B1 (ko) 2013-02-08 2022-09-23 노파르티스 아게 면역접합체의 제조를 위한 항체의 변형에 사용되는 특정 부위
WO2014179335A1 (en) 2013-04-29 2014-11-06 Memorial Sloan Kettering Cancer Center Compositions and methods for altering second messenger signaling
RS59500B1 (sr) * 2013-05-18 2019-12-31 Aduro Biotech Inc Sastavi i metode za aktiviranje signaliziranja koje je zavisno od „stimulatora gena za interferon“
US10092644B2 (en) 2013-11-22 2018-10-09 Brock University Use of fluorinated cyclic dinucleotides as oral vaccine adjuvants
US9315523B2 (en) 2013-12-06 2016-04-19 Rutgers, The State University Of New Jersey Cyclic dinucleosides
PE20170198A1 (es) 2014-06-04 2017-04-08 Glaxosmithkline Ip Dev Ltd Dinucleotidos ciclicos como moduladores de sting
EP3546473B1 (en) 2014-12-16 2025-12-10 Kayla Therapeutics Fluorinated cyclic [(2',5')p(3',5')p]-dinucleotides for cytokine induction
EP3317290A4 (en) 2015-07-02 2019-04-10 Spring Bank Pharmaceuticals, Inc. COMPOSITIONS AND METHOD FOR TREATING VIRUS INFECTION
TW201717968A (zh) 2015-07-14 2017-06-01 春季銀行製藥公司 誘導ｒｉｇ－ｉ和其他模式辨識受體之化合物及組成物
US20180222982A1 (en) * 2015-07-29 2018-08-09 Novartis Ag Combination therapies comprising antibody molecules to pd-1
CR20180101A (es) 2015-08-13 2018-04-12 Merck Sharp & Dohme Compuestos di-nucleóticos cíclicos como agonistas de sting
CN106540256A (zh) * 2016-03-27 2017-03-29 聊城市奥润生物医药科技有限公司 环二核苷酸-脂质体偶联单克隆抗体在抗肿瘤中的应用
WO2018009652A1 (en) 2016-07-06 2018-01-11 Sperovie Biosciences, Inc. Compounds, compositions, and methods for the treatment of disease
US11033569B2 (en) 2016-07-06 2021-06-15 Sperovie Biosciences, Inc. Compounds,Compositions, and methods for the treatment of disease
WO2018013887A1 (en) 2016-07-15 2018-01-18 Sperovie Biosciences, Inc. Compounds, compositions, and methods for the treatment of disease
MX2019000660A (es) 2016-07-15 2019-10-02 Sperovie Biosciences Inc Compuestos, composiciones y métodos para el tratamiento de enfermedades.

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016145102A1 (en) * 2015-03-10 2016-09-15 Aduro Biotech, Inc. Compositions and methods for activating "stimulator of interferon gene" -dependent signalling
WO2016161372A1 (en) * 2015-04-01 2016-10-06 President And Fellows Of Harvard College Immunoconjugates for programming or reprogramming of cells
WO2017100305A2 (en) * 2015-12-07 2017-06-15 Opi Vi - Ip Holdco Llc Composition of antibody construct-agonist conjugates and methods of use thereof

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
LAURENT DUCRY等: "Antibody-Drug Conjugates: Linking Cytotoxic Payloads to Monoclonal Antibodies" *

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115768485A (zh) * 2020-04-02 2023-03-07 梅尔莎纳医疗公司 包含sting激动剂的抗体药物缀合物
CN111592570A (zh) * 2020-05-15 2020-08-28 清华大学 新型sting激动剂及其制备方法和应用
CN111592570B (zh) * 2020-05-15 2022-04-29 清华大学 新型sting激动剂及其制备方法和应用
CN115060902A (zh) * 2022-05-13 2022-09-16 上海市第十人民医院 可作为肿瘤诊断和预后分析标志物的cGAS甲基化修饰及其检测试剂和应用
CN115060902B (zh) * 2022-05-13 2025-07-11 上海市第十人民医院 可作为肿瘤诊断和预后分析标志物的cGAS甲基化修饰及其检测试剂和应用
WO2024153127A1 (zh) * 2023-01-18 2024-07-25 泰励生物科技（上海）有限公司 抗体偶联药物及其用途
WO2025140587A1 (zh) * 2023-12-27 2025-07-03 上海迪诺医药科技有限公司 环状二核苷酸化合物、其偶联物及应用

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WO2018200812A1 (en) 2018-11-01
EP3615080A1 (en) 2020-03-04
JP2020517700A (ja) 2020-06-18
AR113224A1 (es) 2020-02-19

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