CN119487069A - 结合剂及其使用方法 - Google Patents

结合剂及其使用方法 Download PDF

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Publication number
CN119487069A
CN119487069A CN202380043410.1A CN202380043410A CN119487069A CN 119487069 A CN119487069 A CN 119487069A CN 202380043410 A CN202380043410 A CN 202380043410A CN 119487069 A CN119487069 A CN 119487069A
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CN
China
Prior art keywords
seq
cll
cdr2
antibody
antigen
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Pending
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CN202380043410.1A
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English (en)
Chinese (zh)
Inventor
J·舍雷尔
N·法兹鲁拉赛拉尔汗
M·阿劳乔阿尔维斯马丁斯达西尔瓦
T·查克拉博蒂
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Vor Biopharma Inc
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Vor Biopharma Inc
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Publication of CN119487069A publication Critical patent/CN119487069A/zh
Pending legal-status Critical Current

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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K16/00Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
    • C07K16/18Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2851Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the lectin superfamily, e.g. CD23, CD72
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/12Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
    • A61K35/14Blood; Artificial blood
    • A61K35/17Lymphocytes; B-cells; T-cells; Natural killer cells; Interferon-activated or cytokine-activated lymphocytes
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K40/00Cellular immunotherapy
    • A61K40/10Cellular immunotherapy characterised by the cell type used
    • A61K40/15Natural-killer [NK] cells; Natural-killer T [NKT] cells
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K40/00Cellular immunotherapy
    • A61K40/30Cellular immunotherapy characterised by the recombinant expression of specific molecules in the cells of the immune system
    • A61K40/31Chimeric antigen receptors [CAR]
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00Antineoplastic agents
    • A61P35/02Antineoplastic agents specific for leukemia
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K14/00Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/705Receptors; Cell surface antigens; Cell surface determinants
    • C07K14/70503Immunoglobulin superfamily
    • C07K14/7051T-cell receptor (TcR)-CD3 complex
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K14/00Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/705Receptors; Cell surface antigens; Cell surface determinants
    • C07K14/70503Immunoglobulin superfamily
    • C07K14/70521CD28, CD152
    • CCHEMISTRY; METALLURGY
    • C12BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
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    • C12N5/00Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
    • C12N5/06Animal cells or tissues; Human cells or tissues
    • C12N5/0602Vertebrate cells
    • C12N5/0634Cells from the blood or the immune system
    • C12N5/0646Natural killers cells [NK], NKT cells
    • CCHEMISTRY; METALLURGY
    • C12BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
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    • C12N9/00Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
    • C12N9/14Hydrolases (3)
    • C12N9/16Hydrolases (3) acting on ester bonds (3.1)
    • C12N9/22Ribonucleases [RNase]; Deoxyribonucleases [DNase]
    • C12N9/222Clustered regularly interspaced short palindromic repeats [CRISPR]-associated [CAS] enzymes
    • C12N9/226Class 2 CAS enzyme complex, e.g. single CAS protein
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2239/00Indexing codes associated with cellular immunotherapy of group A61K40/00
    • A61K2239/10Indexing codes associated with cellular immunotherapy of group A61K40/00 characterized by the structure of the chimeric antigen receptor [CAR]
    • A61K2239/11Antigen recognition domain
    • A61K2239/13Antibody-based
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2239/00Indexing codes associated with cellular immunotherapy of group A61K40/00
    • A61K2239/10Indexing codes associated with cellular immunotherapy of group A61K40/00 characterized by the structure of the chimeric antigen receptor [CAR]
    • A61K2239/21Transmembrane domain
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2239/00Indexing codes associated with cellular immunotherapy of group A61K40/00
    • A61K2239/10Indexing codes associated with cellular immunotherapy of group A61K40/00 characterized by the structure of the chimeric antigen receptor [CAR]
    • A61K2239/22Intracellular domain
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K2317/00Immunoglobulins specific features
    • C07K2317/20Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/22Immunoglobulins specific features characterized by taxonomic origin from camelids, e.g. camel, llama or dromedary
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K2317/00Immunoglobulins specific features
    • C07K2317/20Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/24Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K2317/00Immunoglobulins specific features
    • C07K2317/50Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/52Constant or Fc region; Isotype
    • C07K2317/524CH2 domain
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K2317/00Immunoglobulins specific features
    • C07K2317/50Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/52Constant or Fc region; Isotype
    • C07K2317/526CH3 domain
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K2317/00Immunoglobulins specific features
    • C07K2317/50Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/56Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
    • C07K2317/565Complementarity determining region [CDR]
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K2317/00Immunoglobulins specific features
    • C07K2317/50Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/56Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
    • C07K2317/569Single domain, e.g. dAb, sdAb, VHH, VNAR or nanobody®
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K2317/00Immunoglobulins specific features
    • C07K2317/60Immunoglobulins specific features characterized by non-natural combinations of immunoglobulin fragments
    • C07K2317/62Immunoglobulins specific features characterized by non-natural combinations of immunoglobulin fragments comprising only variable region components
    • C07K2317/622Single chain antibody (scFv)
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K2319/00Fusion polypeptide
    • C07K2319/01Fusion polypeptide containing a localisation/targetting motif
    • C07K2319/03Fusion polypeptide containing a localisation/targetting motif containing a transmembrane segment
    • CCHEMISTRY; METALLURGY
    • C12BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
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    • C12N2310/00Structure or type of the nucleic acid
    • C12N2310/10Type of nucleic acid
    • C12N2310/20Type of nucleic acid involving clustered regularly interspaced short palindromic repeats [CRISPR]
    • CCHEMISTRY; METALLURGY
    • C12BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12NMICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2510/00Genetically modified cells

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Immunology (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Genetics & Genomics (AREA)
  • Engineering & Computer Science (AREA)
  • Zoology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Molecular Biology (AREA)
  • Animal Behavior & Ethology (AREA)
  • Biochemistry (AREA)
  • Biomedical Technology (AREA)
  • Cell Biology (AREA)
  • Biotechnology (AREA)
  • Wood Science & Technology (AREA)
  • Epidemiology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biophysics (AREA)
  • Hematology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Microbiology (AREA)
  • Toxicology (AREA)
  • General Engineering & Computer Science (AREA)
  • Gastroenterology & Hepatology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Oncology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Virology (AREA)
  • Developmental Biology & Embryology (AREA)
  • Peptides Or Proteins (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Medicinal Preparation (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Medicines Containing Material From Animals Or Micro-Organisms (AREA)
CN202380043410.1A 2022-04-11 2023-04-11 结合剂及其使用方法 Pending CN119487069A (zh)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
US202263329664P 2022-04-11 2022-04-11
US63/329,664 2022-04-11
US202263399588P 2022-08-19 2022-08-19
US63/399,588 2022-08-19
PCT/US2023/065642 WO2023201238A1 (en) 2022-04-11 2023-04-11 Binding agents and methods of use thereof

Publications (1)

Publication Number Publication Date
CN119487069A true CN119487069A (zh) 2025-02-18

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ID=86328509

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Application Number Title Priority Date Filing Date
CN202380043410.1A Pending CN119487069A (zh) 2022-04-11 2023-04-11 结合剂及其使用方法

Country Status (7)

Country Link
US (1) US20250333515A1 (https=)
EP (1) EP4507794A1 (https=)
JP (1) JP2025513855A (https=)
CN (1) CN119487069A (https=)
AU (1) AU2023254830A1 (https=)
CA (1) CA3248167A1 (https=)
WO (1) WO2023201238A1 (https=)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2025030010A1 (en) 2023-08-01 2025-02-06 Vor Biopharma Inc. Compositions comprising genetically engineered hematopoietic stem cells and methods of use thereof

Family Cites Families (35)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4980286A (en) 1985-07-05 1990-12-25 Whitehead Institute For Biomedical Research In vivo introduction and expression of foreign genetic material in epithelial cells
IL79289A (en) 1985-07-05 1992-01-15 Whitehead Biomedical Inst Introduction and expression of foreign genetic material into keratinocytes using a recombinant retrovirus
US5219740A (en) 1987-02-13 1993-06-15 Fred Hutchinson Cancer Research Center Retroviral gene transfer into diploid fibroblasts for gene therapy
ATE117375T1 (de) 1987-09-11 1995-02-15 Whitehead Biomedical Inst Transduktionsveränderte fibroblasten und ihre anwendung.
JP2914692B2 (ja) 1987-12-11 1999-07-05 ホワイトヘツド・インスチチユート・フオー・バイオメデイカル・リサーチ 内皮細胞の遺伝子修飾
WO1989007136A2 (en) 1988-02-05 1989-08-10 Whitehead Institute For Biomedical Research Modified hepatocytes and uses therefor
US5013556A (en) 1989-10-20 1991-05-07 Liposome Technology, Inc. Liposomes with enhanced circulation time
ES2096750T3 (es) 1990-10-31 1997-03-16 Somatix Therapy Corp Vectores retroviricos utiles para la terapia genica.
SE9201984D0 (sv) 1992-06-29 1992-06-29 Pharmacia Biosensor Ab Improvement in optical assays
DK1621554T4 (da) 1992-08-21 2012-12-17 Univ Bruxelles Immunoglobuliner blottet for lette kæder
US5308341A (en) 1993-09-28 1994-05-03 Becton, Dickinson And Company Method of testing the dose accuracy of a medication delivery device
US6146361A (en) 1996-09-26 2000-11-14 Becton Dickinson And Company Medication delivery pen having a 31 gauge needle
US6302855B1 (en) 1998-05-20 2001-10-16 Novo Nordisk A/S Medical apparatus for use by a patient for medical self treatment of diabetes
US6192891B1 (en) 1999-04-26 2001-02-27 Becton Dickinson And Company Integrated system including medication delivery pen, blood monitoring device, and lancer
US6277099B1 (en) 1999-08-06 2001-08-21 Becton, Dickinson And Company Medication delivery pen
WO2003022330A2 (en) 2001-09-12 2003-03-20 Becton, Dickinson And Company Microneedle-based pen device for drug delivery and method for using same
FR2849436B1 (fr) 2002-12-27 2007-01-05 Patrick Frayssinet Particules et ceramiques de phosphates de calcium pour transfection in vivo et in vitro
EP2655624B1 (en) 2010-12-23 2017-11-29 Biogen MA Inc. Linker peptides and polypeptides comprising same
US9163090B2 (en) * 2012-05-07 2015-10-20 Cellerant Therapeutics, Inc. Antibodies specific for CLL-1
SG10201913782UA (en) * 2014-07-21 2020-03-30 Novartis Ag Treatment of cancer using a cll-1 chimeric antigen receptor
MA40579A (fr) * 2014-09-12 2016-03-17 Genentech Inc Anticorps anti-cll-1 et immunoconjugués
BR112017013981A2 (pt) 2015-01-26 2018-01-02 Cellectis receptores antigênicos quiméricos com uma única cadeia específicos anti-cll1 (sccars) para imunoterapia de câncer
AU2016337525B2 (en) 2015-10-16 2022-01-20 The Trustees Of Columbia University In The City Of New York Compositions and methods for inhibition of lineage specific antigens
CN108472365A (zh) 2015-10-30 2018-08-31 艾丽塔生物治疗剂公司 用于肿瘤转导的组合物和方法
US10508143B1 (en) 2015-10-30 2019-12-17 Aleta Biotherapeutics Inc. Compositions and methods for treatment of cancer
AU2018225164A1 (en) 2017-02-22 2019-09-19 Aleta Biotherapeutics Inc. Compositions and methods for treatment of cancer
US20200306375A1 (en) 2017-02-22 2020-10-01 Aleta Biotherapeutics Inc. Compositions and methods for tumor transduction
CA3110837A1 (en) 2018-08-28 2020-03-05 Vor Biopharma Inc. Genetically engineered hematopoietic stem cells and uses thereof
EP3850013A4 (en) * 2018-09-10 2022-10-05 Nanjing Legend Biotech Co., Ltd. SINGLE DOMAIN ANTIBODIES AGAINST CLL1 AND USES THEREOF
WO2020113063A1 (en) * 2018-11-30 2020-06-04 Aleta Biotherapeutics Inc. Single domain antibodies against cll-1
AU2020338011A1 (en) 2019-08-28 2022-03-10 Vor Biopharma Inc. Compositions and methods for CLL1 modification
JP7512394B2 (ja) * 2020-05-06 2024-07-08 ドラゴンフライ セラピューティクス, インコーポレイテッド Nkg2d、cd16及びclec12aに結合するタンパク質
WO2022047168A1 (en) 2020-08-28 2022-03-03 Vor Biopharma Inc. Compositions and methods for cll1 modification
US20240238344A1 (en) 2020-08-28 2024-07-18 Vor Biopharma Inc. Compositions and methods for cd123 modification
CN113045658B (zh) * 2020-12-11 2021-12-24 广州百暨基因科技有限公司 抗cll1抗体及其应用

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Publication number Publication date
AU2023254830A1 (en) 2024-10-17
US20250333515A1 (en) 2025-10-30
WO2023201238A1 (en) 2023-10-19
EP4507794A1 (en) 2025-02-19
JP2025513855A (ja) 2025-04-30
CA3248167A1 (en) 2023-10-19

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