TW202547879A - 抗轉鐵蛋白受體抗體及其用途 - Google Patents

抗轉鐵蛋白受體抗體及其用途

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Publication number
TW202547879A
TW202547879A TW114129782A TW114129782A TW202547879A TW 202547879 A TW202547879 A TW 202547879A TW 114129782 A TW114129782 A TW 114129782A TW 114129782 A TW114129782 A TW 114129782A TW 202547879 A TW202547879 A TW 202547879A
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Taiwan
Prior art keywords
cases
seq
sequence
region
receptor antibody
Prior art date
Application number
TW114129782A
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English (en)
Chinese (zh)
Inventor
碧翠絲 黛安娜 達利曼特
文卡塔 拉瑪那 多帕拉普迪
瑞秋 瓊斯
Original Assignee
美商亞維代堤生物科學公司 美國加州聖地牙哥市凱倫路 3020 號
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Application filed by 美商亞維代堤生物科學公司 美國加州聖地牙哥市凱倫路 3020 號 filed Critical 美商亞維代堤生物科學公司 美國加州聖地牙哥市凱倫路 3020 號
Publication of TW202547879A publication Critical patent/TW202547879A/zh

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    • 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
    • C07K16/2881—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against CD71
    • 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
    • A61K47/6807—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates the drug or compound being a sugar, nucleoside, nucleotide, nucleic acid, e.g. RNA antisense
    • 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
    • A61K47/6811—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates the drug being a protein or peptide, e.g. transferrin or bleomycin
    • 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
    • A61K47/6835—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 the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
    • A61K47/6849—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 the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a receptor, a cell surface antigen or a cell surface determinant
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • 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
    • 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
    • C12N15/113—Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing
    • 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
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/24—Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
    • 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
    • C07K2317/33—Crossreactivity, e.g. for species or epitope, or lack of said crossreactivity
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/51—Complete heavy chain or Fd fragment, i.e. VH + CH1
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/52—Constant or Fc region; Isotype
    • 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
    • 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
    • C07K2317/71—Decreased effector function due to an Fc-modification
    • 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
    • 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
    • C07K2317/94—Stability, e.g. half-life, pH, temperature or enzyme-resistance
    • 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
    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/10—Type of nucleic acid
    • C12N2310/14—Type of nucleic acid interfering nucleic acids [NA]
    • 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
    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/30—Chemical structure
    • C12N2310/35—Nature of the modification
    • C12N2310/351—Conjugate
    • C12N2310/3513—Protein; Peptide

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical & Material Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Chemistry (AREA)
  • Immunology (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • Biochemistry (AREA)
  • Epidemiology (AREA)
  • Biomedical Technology (AREA)
  • Biophysics (AREA)
  • Biotechnology (AREA)
  • Zoology (AREA)
  • Wood Science & Technology (AREA)
  • General Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Cell Biology (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Plant Pathology (AREA)
  • Microbiology (AREA)
  • Neurology (AREA)
  • Physics & Mathematics (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Peptides Or Proteins (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
TW114129782A 2018-12-21 2019-12-20 抗轉鐵蛋白受體抗體及其用途 TW202547879A (zh)

Applications Claiming Priority (2)

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US201862784181P 2018-12-21 2018-12-21
US62/784,181 2018-12-21

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TW108147094A TWI894134B (zh) 2018-12-21 2019-12-20 抗轉鐵蛋白受體抗體及其用途

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US (4) US10913800B2 (OSRAM)
EP (1) EP3898693A4 (OSRAM)
JP (3) JP2022513482A (OSRAM)
KR (2) KR20240015162A (OSRAM)
CN (1) CN113508136A (OSRAM)
AU (1) AU2019406199A1 (OSRAM)
IL (4) IL319265A (OSRAM)
MX (1) MX2021007368A (OSRAM)
SG (1) SG11202106593UA (OSRAM)
TW (2) TW202547879A (OSRAM)
WO (1) WO2020132584A1 (OSRAM)

Families Citing this family (54)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR102775461B1 (ko) 2016-04-01 2025-02-28 어비디티 바이오사이언시스 인크. 핵산-폴리펩타이드 조성물 및 이의 용도
CN110381980A (zh) 2017-01-06 2019-10-25 艾维迪提生物科学有限责任公司 核酸-多肽组合物以及诱导外显子跳读的方法
GB201711809D0 (en) 2017-07-21 2017-09-06 Governors Of The Univ Of Alberta Antisense oligonucleotide
WO2019136180A2 (en) * 2018-01-04 2019-07-11 Avidity Biosciences Llc Heteroduplex nucleic acid molecules and uses thereof
US12097263B2 (en) 2018-08-02 2024-09-24 Dyne Therapeutics, Inc. Muscle targeting complexes and uses thereof for treating myotonic dystrophy
JP7611825B2 (ja) 2018-08-02 2025-01-10 ダイン セラピューティクス,インコーポレーテッド ジストロフィン異常症を処置するための筋標的化複合体およびそれらの使用
US12018087B2 (en) 2018-08-02 2024-06-25 Dyne Therapeutics, Inc. Muscle-targeting complexes comprising an anti-transferrin receptor antibody linked to an oligonucleotide and methods of delivering oligonucleotide to a subject
US12370264B1 (en) 2018-08-02 2025-07-29 Dyne Therapeutics, Inc. Complexes comprising an anti-transferrin receptor antibody linked to an oligonucleotide and method of delivering oligonucleotide to a subject
US20220193250A1 (en) 2018-08-02 2022-06-23 Dyne Therapeutics, Inc. Muscle targeting complexes and uses thereof for treating facioscapulohumeral muscular dystrophy
US11168141B2 (en) 2018-08-02 2021-11-09 Dyne Therapeutics, Inc. Muscle targeting complexes and uses thereof for treating dystrophinopathies
US11911484B2 (en) 2018-08-02 2024-02-27 Dyne Therapeutics, Inc. Muscle targeting complexes and uses thereof for treating myotonic dystrophy
IL319265A (en) * 2018-12-21 2025-04-01 Avidity Biosciences Inc Anti-transferrin receptor antibodies and their uses
CA3137715A1 (en) 2019-04-25 2020-10-29 Avidity Biosciences, Inc. Nucleic acid compositions and methods of multi-exon skipping
KR20220125802A (ko) * 2020-01-10 2022-09-14 다인 세라퓨틱스, 인크. 근육 표적화 복합체 및 디스트로핀병증을 치료하기 위한 그의 용도
US12624120B2 (en) 2020-01-31 2026-05-12 Dyne Therapeutics, Inc. Anti-transferrin receptor (TfR) antibody and uses thereof
WO2021188390A1 (en) 2020-03-19 2021-09-23 Avidity Biosciences, Inc. Compositions and methods of treating facioscapulohumeral muscular dystrophy
WO2021195469A1 (en) 2020-03-27 2021-09-30 Avidity Biosciences, Inc. Compositions and methods of treating muscle dystrophy
KR20230043115A (ko) * 2020-06-24 2023-03-30 사프렘 테크놀로지스 비.브이. 히드라존에 기반한 사포닌 유도체
WO2022020105A1 (en) * 2020-07-23 2022-01-27 Dyne Therapeutics, Inc. Anti-transferrin receptor (tfr) antibody and uses thereof
CN116348139A (zh) * 2020-07-23 2023-06-27 达因疗法公司 肌肉靶向复合物及其用于治疗面肩肱型肌营养不良的用途
US20230346966A1 (en) * 2020-07-23 2023-11-02 Dyne Therapeutics, Inc. Muscle-targeting complexes and uses thereof in treating muscle atrophy
IL299663A (en) * 2020-07-23 2023-03-01 Dyne Therapeutics Inc Muscle targeting complexes and their uses for the treatment of myotonic dystrophy
CN117980006A (zh) 2021-07-09 2024-05-03 达因疗法公司 用于治疗肌养蛋白病的肌肉靶向复合物和制剂
US11633498B2 (en) 2021-07-09 2023-04-25 Dyne Therapeutics, Inc. Muscle targeting complexes and uses thereof for treating myotonic dystrophy
US11969475B2 (en) 2021-07-09 2024-04-30 Dyne Therapeutics, Inc. Muscle targeting complexes and uses thereof for treating facioscapulohumeral muscular dystrophy
US11638761B2 (en) 2021-07-09 2023-05-02 Dyne Therapeutics, Inc. Muscle targeting complexes and uses thereof for treating Facioscapulohumeral muscular dystrophy
US11771776B2 (en) * 2021-07-09 2023-10-03 Dyne Therapeutics, Inc. Muscle targeting complexes and uses thereof for treating dystrophinopathies
WO2023283619A2 (en) * 2021-07-09 2023-01-12 Dyne Therapeutics, Inc. Muscle targeting complexes and uses thereof for treating dystrophinopathies
US11672872B2 (en) 2021-07-09 2023-06-13 Dyne Therapeutics, Inc. Anti-transferrin receptor antibody and uses thereof
WO2023287238A1 (ko) * 2021-07-15 2023-01-19 한양대학교 산학협력단 뇌혈관장벽 통과 효율이 향상된 항 인간 트랜스페린 수용체 항체, 및 이를 이용한 다중특이적 항체 및 약학 조성물
MX2024003266A (es) 2021-09-16 2024-04-03 Avidity Biosciences Inc Composiciones y metodos de tratamiento de la distrofia muscular facioescapulohumeral.
US12071621B2 (en) 2022-04-05 2024-08-27 Avidity Biosciences, Inc. Anti-transferrin receptor antibody-PMO conjugates for inducing DMD exon 44 skipping
US20250249117A1 (en) * 2022-04-15 2025-08-07 Dyne Therapeutics, Inc. Dosing of muscle targeting complexes for treating myotonic dystrophy
KR20250004770A (ko) 2022-04-15 2025-01-08 다인 세라퓨틱스, 인크. 근긴장성 이영양증을 치료하기 위한 근육 표적화 복합체 및 제제
KR102638322B1 (ko) 2022-05-30 2024-02-19 주식회사 유기지능스튜디오 1인칭 실감형 오디오 컨텐츠를 제작하기 위한 장치, 방법
KR20250031159A (ko) * 2022-07-01 2025-03-06 데날리 테라퓨틱스 인크. 세포에 올리고뉴클레오타이드를 전달하기 위한 트랜스페린 수용체 결합 분자 접합체
WO2024097851A1 (en) * 2022-11-02 2024-05-10 Vanderbilt University Cd71-blocking antibodies for treating autoimmune and inflammatory diseases
WO2024155066A1 (ko) * 2023-01-16 2024-07-25 주식회사 시그널바이오 뇌혈관장벽 통과 효율이 향상된 항 인간 트랜스페린 수용체 항체, 및 이를 이용한 다중특이적 항체 및 약학 조성물
UY40699A (es) 2023-04-05 2024-08-30 Ionis Pharmaceuticals Inc Compuestos y métodos para reducir la expresión de pln
EP4735602A2 (en) * 2023-06-27 2026-05-06 Atrium Therapeutics, Inc. Compositions and methods of using prkag2-targeting antibody-oligonucleotide conjugates abstract
CN121793987A (zh) 2023-06-30 2026-04-03 艾维迪提生物科学公司 使用pln靶向性抗体-寡核苷酸缀合物的组合物和方法
KR20260044219A (ko) 2023-07-21 2026-04-01 매로우 테라퓨틱스, 인크. 조혈 세포 표적화 접합체 및 관련 방법
CN116735864B (zh) * 2023-08-15 2023-11-10 迦进生物医药(上海)有限公司 评估TfR1抗体血液安全性的试剂盒
WO2025076006A2 (en) * 2023-10-02 2025-04-10 Avidity Biosciences, Inc. Antibody-oligonucleotide conjugate compositions and methods of inducing dmd exon 45 skipping
WO2025085352A1 (en) 2023-10-18 2025-04-24 Eli Lilly And Company Transferrin receptor binding proteins and uses thereof
TW202517685A (zh) * 2023-10-26 2025-05-01 美商百健Ma公司 抗運鐵蛋白受體抗體及其用途
WO2025133132A1 (en) * 2023-12-20 2025-06-26 Institut National De La Sante Et De La Recherche Medicale Novel anti-tfr1 (cd71) antibodies for cancer treatment
WO2025149667A1 (en) 2024-01-12 2025-07-17 Pheon Therapeutics Ltd Antibody drug conjugates and uses thereof
WO2025160275A1 (en) 2024-01-24 2025-07-31 Arrowhead Pharmaceuticals, Inc. Anti-transferrin receptor antibodies, conjugates thereof, and uses thereof
CN120648680A (zh) * 2024-03-15 2025-09-16 迦进生物医药(上海)有限公司 治疗杜兴型肌营养不良症和贝克型肌营养不良症的药物
US20250325693A1 (en) * 2024-04-03 2025-10-23 Avidity Biosciences, Inc. Antibody-oligonucleotide conjugate compositions and methods of inducing dmd exon 50 skipping
KR20250160320A (ko) * 2024-05-03 2025-11-12 한양대학교 산학협력단 엔도좀 탈출 효율이 향상된 항 인간 트랜스페린 수용체 항체, 및 이를 이용한 다중특이적 항체 및 약학 조성물
CN119161483B (zh) * 2024-10-16 2026-02-06 中国人民解放军军事科学院军事医学研究院 人源抗转铁蛋白受体1抗体及其应用
CN119913155B (zh) * 2025-04-01 2025-06-20 佑嘉(杭州)生物医药科技有限公司 一种siRNA及其抗体偶联物、产品和应用

Family Cites Families (125)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5892644A (ja) 1981-11-26 1983-06-02 Taiho Yakuhin Kogyo Kk 新規なニトロ安息香酸アミド誘導体およびそれを含有する放射線増感剤
US4694778A (en) 1984-05-04 1987-09-22 Anicon, Inc. Chemical vapor deposition wafer boat
US5185444A (en) 1985-03-15 1993-02-09 Anti-Gene Deveopment Group Uncharged morpolino-based polymers having phosphorous containing chiral intersubunit linkages
WO1986005519A1 (en) 1985-03-15 1986-09-25 James Summerton Polynucleotide assay reagent and method
US4866132A (en) 1986-04-17 1989-09-12 The Research Foundation Of State University Of New York Novel radiopaque barium polymer complexes, compositions of matter and articles prepared therefrom
US5624925A (en) 1986-09-25 1997-04-29 Sri International 1,2,4-benzotriazine oxides as radiosensitizers and selective cytotoxic agents
US4921963A (en) 1987-04-13 1990-05-01 British Columbia Cancer Foundation Platinum complexes with one radiosensitizing ligand
JPH0819111B2 (ja) 1987-10-22 1996-02-28 ポーラ化成工業株式会社 2―ニトロイミダゾール誘導体及びこれを有効成分とする放射線増感剤
US4828971A (en) 1988-03-24 1989-05-09 Eastman Kodak Company Thermally processable element comprising a backing layer
CA1251835A (en) 1988-04-05 1989-03-28 Wai-Cheung Tang Dielectric image-resonator multiplexer
US5256334A (en) 1988-09-08 1993-10-26 The Research Foundation Of The State University Of New York Homogeneous radiopaque polymer-organobismuth composites
WO1991004753A1 (en) 1989-10-02 1991-04-18 Cetus Corporation Conjugates of antisense oligonucleotides and therapeutic uses thereof
US5208020A (en) 1989-10-25 1993-05-04 Immunogen Inc. Cytotoxic agents comprising maytansinoids and their therapeutic use
DE4216134A1 (de) 1991-06-20 1992-12-24 Europ Lab Molekularbiolog Synthetische katalytische oligonukleotidstrukturen
CA2123307A1 (en) * 1991-11-26 1993-06-10 Phillip M. Friden Process for the preparation of transferrin receptor specific antibody-neuro-pharmaceutical or diagnostic agent conjugates
US5652094A (en) 1992-01-31 1997-07-29 University Of Montreal Nucleozymes
WO1994004147A1 (en) 1992-08-17 1994-03-03 Quadra Logic Technologies, Inc. Method for destroying or inhibiting growth of unwanted cells or tissues
US5346981A (en) 1993-01-13 1994-09-13 Miles Inc. Radiopaque polyurethanes
US5599796A (en) 1993-12-02 1997-02-04 Emory University Treatment of urogenital cancer with boron neutron capture therapy
US5627053A (en) 1994-03-29 1997-05-06 Ribozyme Pharmaceuticals, Inc. 2'deoxy-2'-alkylnucleotide containing nucleic acid
US5736557A (en) 1994-06-17 1998-04-07 Hoffman-La Roche, Inc. N,N-bis (quinolin-4-yl)-diamine derivatives, their preparation and their use as antimalarials
US5716824A (en) 1995-04-20 1998-02-10 Ribozyme Pharmaceuticals, Inc. 2'-O-alkylthioalkyl and 2-C-alkylthioalkyl-containing enzymatic nucleic acids (ribozymes)
US5939045A (en) 1994-12-22 1999-08-17 Nissan Chemical Industries, Ltd. Organic bismuth derivatives for X-ray imaging
US5700825A (en) 1995-03-31 1997-12-23 Florida State University Radiosensitizing diamines and their pharmaceutical preparations
US5889136A (en) 1995-06-09 1999-03-30 The Regents Of The University Of Colorado Orthoester protecting groups in RNA synthesis
DE69637256T2 (de) 1996-01-16 2008-06-19 Sirna Therapeutics, Inc., Boulder Synthese von Methoxynukleoside und enzymatische Nukleisäure Moleküle
ATE279947T1 (de) 1996-03-18 2004-11-15 Univ Texas Immunglobulinähnliche domäne mit erhöhten halbwertszeiten
US5849902A (en) 1996-09-26 1998-12-15 Oligos Etc. Inc. Three component chimeric antisense oligonucleotides
US6111086A (en) 1998-02-27 2000-08-29 Scaringe; Stephen A. Orthoester protecting groups
WO1999054459A2 (en) 1998-04-20 1999-10-28 Ribozyme Pharmaceuticals, Inc. Nucleic acid molecules with novel chemical compositions capable of modulating gene expression
GB9816575D0 (en) 1998-07-31 1998-09-30 Zeneca Ltd Novel compounds
GB9818730D0 (en) 1998-08-27 1998-10-21 Univ Portsmouth Collections of compounds
PT1109812E (pt) 1998-08-27 2005-09-30 Spirogen Ltd Pirrolobenzodiazepinas
GB9818731D0 (en) 1998-08-27 1998-10-21 Univ Portsmouth Compounds
CA2328356A1 (en) 1999-12-22 2001-06-22 Itty Atcravi Recreational vehicles
ES2274823T3 (es) 1999-12-29 2007-06-01 Immunogen, Inc. Agentes cototoxicos que comprenden doxorrubicinas y daunorrubicinas y su utilizacion terapeutica.
US8273866B2 (en) 2002-02-20 2012-09-25 Merck Sharp & Dohme Corp. RNA interference mediated inhibition of gene expression using chemically modified short interfering nucleic acid (SINA)
US7833992B2 (en) 2001-05-18 2010-11-16 Merck Sharpe & Dohme Conjugates and compositions for cellular delivery
US8202979B2 (en) 2002-02-20 2012-06-19 Sirna Therapeutics, Inc. RNA interference mediated inhibition of gene expression using chemically modified short interfering nucleic acid
US6884869B2 (en) 2001-04-30 2005-04-26 Seattle Genetics, Inc. Pentapeptide compounds and uses related thereto
MXPA05000511A (es) 2001-07-12 2005-09-30 Jefferson Foote Anticuepros super humanizados.
US6716821B2 (en) 2001-12-21 2004-04-06 Immunogen Inc. Cytotoxic agents bearing a reactive polyethylene glycol moiety, cytotoxic conjugates comprising polyethylene glycol linking groups, and methods of making and using the same
AU2003207708A1 (en) 2002-02-20 2003-09-09 Sirna Therapeutics, Inc. Rna interference mediated inhibition of map kinase genes
US9181551B2 (en) 2002-02-20 2015-11-10 Sirna Therapeutics, Inc. RNA interference mediated inhibition of gene expression using chemically modified short interfering nucleic acid (siNA)
US9657294B2 (en) 2002-02-20 2017-05-23 Sirna Therapeutics, Inc. RNA interference mediated inhibition of gene expression using chemically modified short interfering nucleic acid (siNA)
US20040023220A1 (en) 2002-07-23 2004-02-05 Lawrence Greenfield Integrated method for PCR cleanup and oligonucleotide removal
ES2544527T3 (es) 2002-07-31 2015-09-01 Seattle Genetics, Inc. Conjugados de fármacos y su uso para tratar el cáncer, una enfermedad autoinmune o una enfermedad infecciosa
ES2280826T5 (es) 2002-08-05 2017-08-03 Silence Therapeutics Gmbh Nuevas formas adicionales de moléculas de ARN de interferencia
US7923547B2 (en) 2002-09-05 2011-04-12 Sirna Therapeutics, Inc. RNA interference mediated inhibition of gene expression using chemically modified short interfering nucleic acid (siNA)
US7250496B2 (en) 2002-11-14 2007-07-31 Rosetta Genomics Ltd. Bioinformatically detectable group of novel regulatory genes and uses thereof
JP2006507841A (ja) 2002-11-14 2006-03-09 ダーマコン, インコーポレイテッド 機能的siRNAおよび超機能的siRNA
US7276497B2 (en) 2003-05-20 2007-10-02 Immunogen Inc. Cytotoxic agents comprising new maytansinoids
GB0416511D0 (en) 2003-10-22 2004-08-25 Spirogen Ltd Pyrrolobenzodiazepines
EP3434275A1 (en) 2003-11-06 2019-01-30 Seattle Genetics, Inc. Assay for cancer cells based on the use of auristatin conjugates with antibodies
EP1723152B1 (en) 2004-03-09 2015-02-11 Spirogen Sàrl Pyrrolobenzodiazepines
JP2008519863A (ja) 2004-11-12 2008-06-12 シアトル ジェネティクス インコーポレイティッド N末端にアミノ安息香酸単位を有するオーリスタチン
EP1879901B1 (en) 2005-04-21 2009-12-23 Spirogen Limited Pyrrolobenzodiazepines
WO2007008848A2 (en) 2005-07-07 2007-01-18 Seattle Genetics, Inc. Monomethylvaline compounds having phenylalanine carboxy modifications at the c-terminus
ATE527262T1 (de) 2006-01-25 2011-10-15 Sanofi Sa Neue tomaymycin derivate enhaltende zytotoxische mittel
US7750116B1 (en) 2006-02-18 2010-07-06 Seattle Genetics, Inc. Antibody drug conjugate metabolites
ES2645410T3 (es) 2006-05-10 2017-12-05 Sarepta Therapeutics, Inc. Análogos de oligonucleótidos que tienen enlaces intersubunitarios catiónicos
JP6047270B2 (ja) 2006-08-11 2016-12-21 バイオマリン テクノロジーズ ベー.フェー. Dnaリピートの不安定性に関連した遺伝的障害を治療するための方法及び手段
EP2532673A3 (en) 2007-05-10 2014-01-08 R & D Biopharmaceuticals Gmbh Tubulysine derivatives
SI2019104T1 (sl) 2007-07-19 2013-12-31 Sanofi Citotoksična sredstva, ki obsegajo nove tomaimicinske derivate, in njihova terapevtska uporaba
US20110065774A1 (en) 2008-01-31 2011-03-17 Alnylam Pharmaceuticals Chemically modified oligonucleotides and uses thereof
WO2009099991A2 (en) 2008-01-31 2009-08-13 The Brigham And Women's Hospital, Inc. Treatment of cancer
EP2265283B1 (en) 2008-03-18 2014-09-03 Seattle Genetics, Inc. Auristatin drug linker conjugates
EP3604533A1 (en) 2008-04-11 2020-02-05 Arbutus Biopharma Corporation Site-specific delivery of nucleic acids by combining targeting ligands with endosomolytic components
GB0813432D0 (en) 2008-07-22 2008-08-27 Spirogen Ltd Pyrrolobenzodiazepines
SG171914A1 (en) 2008-12-02 2011-07-28 Chiralgen Ltd Method for the synthesis of phosphorus atom modified nucleic acids
CN102365021B (zh) 2009-02-05 2015-07-15 伊缪诺金公司 新型苯并二氮杂*衍生物
WO2010115033A2 (en) 2009-04-02 2010-10-07 Regents Of The University Of Minnesota Nucleotide repeat expansion-associated polypeptides and uses thereof
JP2012526130A (ja) 2009-05-05 2012-10-25 アルテルムネ テクフノロジエス,エルエルシー 化学的にプログラム可能な免疫
US20110269665A1 (en) 2009-06-26 2011-11-03 Avi Biopharma, Inc. Compound and method for treating myotonic dystrophy
IT1394860B1 (it) 2009-07-22 2012-07-20 Kemotech S R L Composti farmaceutici
JP5870400B2 (ja) 2010-04-15 2016-03-01 シアトル ジェネティクス,インコーポレーテッド 標的化ピロロベンゾジアゼピンコンジュゲート
ES2623057T3 (es) 2010-04-15 2017-07-10 Medimmune Limited Pirrolobenzodiazepinas usadas para tratar enfermedades proliferativas
KR102182663B1 (ko) 2010-05-28 2020-11-25 사렙타 쎄러퓨틱스, 인코퍼레이티드 변형된 서브유니트간 결합 및/또는 말단 그룹을 갖는 올리고뉴클레오타이드 유사체
AU2011263642B2 (en) 2010-06-11 2014-09-04 Isarna Therapeutics Gmbh Method for selective oligonucleotide modification
EP3489360A3 (en) 2010-07-19 2019-08-28 Ionis Pharmaceuticals, Inc. Modulation of nuclear-retained rna
EP2409983A1 (en) 2010-07-19 2012-01-25 Leibniz-Institut für Pflanzenbiochemie (IPB) Tubulysin analogues
EP3766975A1 (en) 2010-10-29 2021-01-20 Sirna Therapeutics, Inc. Rna interference mediated inhibition of gene expression using short interfering nucleic acid (sina)
JP2013542958A (ja) 2010-11-03 2013-11-28 イミュノジェン・インコーポレーテッド アンサマイトシン誘導体を含む細胞傷害性剤
US8501930B2 (en) 2010-12-17 2013-08-06 Arrowhead Madison Inc. Peptide-based in vivo siRNA delivery system
MX348071B (es) * 2011-03-16 2017-05-26 Amgen Inc Variantes de fc.
MX350954B (es) 2011-06-21 2017-09-26 Immunogen Inc Derivados de maitansinoides novedosos con enlazador de peptido y conjugados de estos.
EP2732035A2 (en) 2011-07-15 2014-05-21 Sarepta Therapeutics, Inc. Methods and compositions for manipulating translation of protein isoforms from alternative initiation start sites
US9605019B2 (en) 2011-07-19 2017-03-28 Wave Life Sciences Ltd. Methods for the synthesis of functionalized nucleic acids
US9526798B2 (en) 2011-10-14 2016-12-27 Seattle Genetics, Inc. Pyrrolobenzodiazepines and targeted conjugates
IL303831A (en) 2011-11-18 2023-08-01 Alnylam Pharmaceuticals Inc Adapted RNAI factors
AU2012348017A1 (en) 2011-12-05 2014-07-03 Igenica Biotherapeutics, Inc. Antibody-drug conjugates and related compounds, compositions, and methods
US10010623B2 (en) 2012-02-16 2018-07-03 Ucl Business Plc Lysosome-cleavable linker
AR090905A1 (es) 2012-05-02 2014-12-17 Merck Sharp & Dohme Conjugados que contienen tetragalnac y peptidos y procedimientos para la administracion de oligonucleotidos, composicion farmaceutica
US9504756B2 (en) 2012-05-15 2016-11-29 Seattle Genetics, Inc. Self-stabilizing linker conjugates
EP3925627A1 (en) 2012-05-15 2021-12-22 Concortis Biosystems, Corp Drug-conjugates and uses thereof
CN112007045B (zh) 2012-07-13 2026-01-06 波涛生命科学有限公司 手性控制
KR102058381B1 (ko) * 2012-08-24 2019-12-24 강원대학교산학협력단 인간 l1cam에 대한 인간화 항체 및 그의 제조 방법
ES2738310T3 (es) 2012-10-12 2020-01-21 Medimmune Ltd Pirrolobenzodiazepinas y conjugados de las mismas
AU2012395148B2 (en) 2012-11-24 2016-10-27 Hangzhou Dac Biotech Co., Ltd. Hydrophilic linkers and their uses for conjugation of drugs to cell binding molecules
KR20150119848A (ko) 2012-12-21 2015-10-26 바이오얼라이언스 씨.브이. 친수성 자기-희생 링커 및 그것의 포합체
AU2014244245C1 (en) 2013-03-13 2018-04-19 Genentech, Inc. Pyrrolobenzodiazepines and conjugates thereof
EP3964237B1 (en) 2013-03-15 2026-02-18 Regeneron Pharmaceuticals, Inc. Biologically active molecules, conjugates thereof, and therapeutic uses
EP2777714A1 (en) 2013-03-15 2014-09-17 NBE-Therapeutics LLC Method of producing an immunoligand/payload conjugate by means of a sequence-specific transpeptidase enzyme
US9295731B2 (en) 2013-04-01 2016-03-29 Mark Quang Nguyen Cleavable drug conjugates, compositions thereof and methods of use
GB2529356B (en) 2013-04-28 2020-12-23 Genequantum Healthcare Co Ltd Novel linkers, coupling intermediates, conjugates, preparation method and application thereof
EA038367B1 (ru) * 2013-05-20 2021-08-16 Дженентек, Инк. АНТИТЕЛА ПРОТИВ РЕЦЕПТОРА ТРАНСФЕРРИНА (TfR) И СПОСОБЫ ИХ ИСПОЛЬЗОВАНИЯ
US20140363454A1 (en) 2013-06-06 2014-12-11 Igenica Biotherapeutics, Inc. Antibody-Drug Conjugates, Compositions and Methods of Use
WO2014197854A1 (en) 2013-06-06 2014-12-11 Igenica Biotherapeutics, Inc. Novel linkers for antibody-drug conjugates and related compounds, compositions, and methods of use
TW201536329A (zh) 2013-08-09 2015-10-01 Isis Pharmaceuticals Inc 用於調節失養性肌強直蛋白質激酶(dmpk)表現之化合物及方法
WO2015038426A1 (en) 2013-09-13 2015-03-19 Asana Biosciences, Llc Self-immolative linkers containing mandelic acid derivatives, drug-ligand conjugates for targeted therapies and uses thereof
EP3057610B1 (en) 2013-10-15 2021-09-22 Sorrento Therapeutics, Inc. Drug-conjugates with a targeting molecule and two different drugs
AU2014337555C1 (en) 2013-10-15 2021-01-28 Seagen Inc. PEGylated drug-linkers for improved Ligand-Drug Conjugate pharmacokinetics
EP3610884B1 (en) 2013-11-06 2021-08-18 Merck Sharp & Dohme Corp. Peptide containing conjugates for dual molecular delivery of oligonucleotides
KR102423317B1 (ko) 2014-01-16 2022-07-22 웨이브 라이프 사이언시스 리미티드 키랄 디자인
JP6779876B2 (ja) * 2014-11-19 2020-11-04 ジェネンテック, インコーポレイテッド 抗トランスフェリン受容体抗体及びその使用方法
US20180305689A1 (en) 2015-04-22 2018-10-25 Mina Therapeutics Limited Sarna compositions and methods of use
CR20210429A (es) * 2015-06-24 2021-09-24 Hoffmann La Roche ANTICUERPOS ANTI-RECEPTOR DE TRANSFERRINA CON AFINIDAD DISEÑADA (Divisional 2017-0562)
KR102775461B1 (ko) 2016-04-01 2025-02-28 어비디티 바이오사이언시스 인크. 핵산-폴리펩타이드 조성물 및 이의 용도
WO2018002812A1 (en) 2016-06-29 2018-01-04 Crispr Therapeutics Ag Materials and methods for treatment of myotonic dystrophy type 1 (dm1) and other related disorders
CN110381980A (zh) 2017-01-06 2019-10-25 艾维迪提生物科学有限责任公司 核酸-多肽组合物以及诱导外显子跳读的方法
JOP20190187A1 (ar) 2017-02-03 2019-08-01 Novartis Ag مترافقات عقار جسم مضاد لـ ccr7
US11110180B2 (en) 2017-10-04 2021-09-07 Avidity Biosciences Inc. Nucleic acid-polypeptide compositions and uses thereof
CN118638788A (zh) 2017-12-06 2024-09-13 艾维迪提生物科学公司 治疗肌萎缩和强直性肌营养不良的组合物和方法
JP7611825B2 (ja) 2018-08-02 2025-01-10 ダイン セラピューティクス,インコーポレーテッド ジストロフィン異常症を処置するための筋標的化複合体およびそれらの使用
IL319265A (en) 2018-12-21 2025-04-01 Avidity Biosciences Inc Anti-transferrin receptor antibodies and their uses

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