JP6479024B2 - 抗体親和性の最適化のための高スループットマウスモデル - Google Patents
抗体親和性の最適化のための高スループットマウスモデル Download PDFInfo
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- JP6479024B2 JP6479024B2 JP2016548101A JP2016548101A JP6479024B2 JP 6479024 B2 JP6479024 B2 JP 6479024B2 JP 2016548101 A JP2016548101 A JP 2016548101A JP 2016548101 A JP2016548101 A JP 2016548101A JP 6479024 B2 JP6479024 B2 JP 6479024B2
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- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
- A01K67/00—Rearing or breeding animals, not otherwise provided for; New or modified breeds of animals
- A01K67/027—New or modified breeds of vertebrates
- A01K67/0275—Genetically modified vertebrates, e.g. transgenic
- A01K67/0278—Knock-in vertebrates, e.g. humanised vertebrates
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- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
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- C07K16/08—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from viruses
- C07K16/10—RNA viruses
- C07K16/112—Retroviridae (F), e.g. leukemia viruses
- C07K16/114—Lentivirus (G), e.g. human immunodeficiency virus [HIV], feline immunodeficiency virus [FIV] or simian immunodeficiency virus [SIV]
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- C12N15/09—Recombinant DNA-technology
- C12N15/63—Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
- C12N15/79—Vectors or expression systems specially adapted for eukaryotic hosts
- C12N15/85—Vectors or expression systems specially adapted for eukaryotic hosts for animal cells
- C12N15/8509—Vectors or expression systems specially adapted for eukaryotic hosts for animal cells for producing genetically modified animals, e.g. transgenic
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- A—HUMAN NECESSITIES
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- A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
- A01K2207/00—Modified animals
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- A01K2207/15—Humanized animals
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- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
- A01K2217/00—Genetically modified animals
- A01K2217/05—Animals comprising random inserted nucleic acids (transgenic)
- A01K2217/052—Animals comprising random inserted nucleic acids (transgenic) inducing gain of function
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- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
- A01K2217/00—Genetically modified animals
- A01K2217/05—Animals comprising random inserted nucleic acids (transgenic)
- A01K2217/054—Animals comprising random inserted nucleic acids (transgenic) inducing loss of function
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- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
- A01K2217/00—Genetically modified animals
- A01K2217/07—Animals genetically altered by homologous recombination
- A01K2217/072—Animals genetically altered by homologous recombination maintaining or altering function, i.e. knock in
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- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
- A01K2217/00—Genetically modified animals
- A01K2217/15—Animals comprising multiple alterations of the genome, by transgenesis or homologous recombination, e.g. obtained by cross-breeding
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- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
- A01K2227/00—Animals characterised by species
- A01K2227/10—Mammal
- A01K2227/105—Murine
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- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
- A01K2267/00—Animals characterised by purpose
- A01K2267/01—Animal expressing industrially exogenous proteins
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- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
- A01K2267/00—Animals characterised by purpose
- A01K2267/03—Animal model, e.g. for test or diseases
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/10—Immunoglobulins specific features characterized by their source of isolation or production
- C07K2317/14—Specific host cells or culture conditions, e.g. components, pH or temperature
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
- C07K2317/21—Immunoglobulins specific features characterized by taxonomic origin from primates, e.g. man
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- C—CHEMISTRY; METALLURGY
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- 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
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- 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
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- 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
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- 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
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- 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
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- 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
- C12N15/63—Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
- C12N15/79—Vectors or expression systems specially adapted for eukaryotic hosts
- C12N15/85—Vectors or expression systems specially adapted for eukaryotic hosts for animal cells
- C12N15/8509—Vectors or expression systems specially adapted for eukaryotic hosts for animal cells for producing genetically modified animals, e.g. transgenic
- C12N2015/8518—Vectors or expression systems specially adapted for eukaryotic hosts for animal cells for producing genetically modified animals, e.g. transgenic expressing industrially exogenous proteins, e.g. for pharmaceutical use, human insulin, blood factors, immunoglobulins, pseudoparticles
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- 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
- C12N15/63—Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
- C12N15/79—Vectors or expression systems specially adapted for eukaryotic hosts
- C12N15/85—Vectors or expression systems specially adapted for eukaryotic hosts for animal cells
- C12N15/8509—Vectors or expression systems specially adapted for eukaryotic hosts for animal cells for producing genetically modified animals, e.g. transgenic
- C12N2015/8527—Vectors or expression systems specially adapted for eukaryotic hosts for animal cells for producing genetically modified animals, e.g. transgenic for producing animal models, e.g. for tests or diseases
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- 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
- C12N2800/00—Nucleic acids vectors
- C12N2800/30—Vector systems comprising sequences for excision in presence of a recombinase, e.g. loxP or FRT
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- Biochemistry (AREA)
- Molecular Biology (AREA)
- Biotechnology (AREA)
- Medicinal Chemistry (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Immunology (AREA)
- Virology (AREA)
- Animal Husbandry (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Biodiversity & Conservation Biology (AREA)
- Wood Science & Technology (AREA)
- General Engineering & Computer Science (AREA)
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- Bioinformatics & Cheminformatics (AREA)
- Cell Biology (AREA)
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- Plant Pathology (AREA)
- Micro-Organisms Or Cultivation Processes Thereof (AREA)
- Peptides Or Proteins (AREA)
- AIDS & HIV (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
- Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US201461931074P | 2014-01-24 | 2014-01-24 | |
| US61/931,074 | 2014-01-24 | ||
| PCT/US2015/012577 WO2015112790A2 (en) | 2014-01-24 | 2015-01-23 | High-throughput mouse model for optimizing antibody affinities |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| JP2017505127A JP2017505127A (ja) | 2017-02-16 |
| JP2017505127A5 JP2017505127A5 (https=) | 2018-03-01 |
| JP6479024B2 true JP6479024B2 (ja) | 2019-03-06 |
Family
ID=53682124
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2016548101A Active JP6479024B2 (ja) | 2014-01-24 | 2015-01-23 | 抗体親和性の最適化のための高スループットマウスモデル |
Country Status (4)
| Country | Link |
|---|---|
| US (2) | US10034463B2 (https=) |
| EP (1) | EP3096609B1 (https=) |
| JP (1) | JP6479024B2 (https=) |
| WO (1) | WO2015112790A2 (https=) |
Families Citing this family (46)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103025884B (zh) | 2010-07-26 | 2015-11-25 | 特里安尼公司 | 转基因动物和使用方法 |
| US10662256B2 (en) | 2010-07-26 | 2020-05-26 | Trianni, Inc. | Transgenic mammals and methods of use thereof |
| US10793829B2 (en) | 2010-07-26 | 2020-10-06 | Trianni, Inc. | Transgenic mammals and methods of use thereof |
| US10323236B2 (en) | 2011-07-22 | 2019-06-18 | President And Fellows Of Harvard College | Evaluation and improvement of nuclease cleavage specificity |
| DK3456831T3 (da) | 2013-04-16 | 2021-09-06 | Regeneron Pharma | Målrettet modifikation af rottegenom |
| US9163284B2 (en) | 2013-08-09 | 2015-10-20 | President And Fellows Of Harvard College | Methods for identifying a target site of a Cas9 nuclease |
| US9359599B2 (en) | 2013-08-22 | 2016-06-07 | President And Fellows Of Harvard College | Engineered transcription activator-like effector (TALE) domains and uses thereof |
| US9526784B2 (en) | 2013-09-06 | 2016-12-27 | President And Fellows Of Harvard College | Delivery system for functional nucleases |
| US9322037B2 (en) | 2013-09-06 | 2016-04-26 | President And Fellows Of Harvard College | Cas9-FokI fusion proteins and uses thereof |
| US9228207B2 (en) | 2013-09-06 | 2016-01-05 | President And Fellows Of Harvard College | Switchable gRNAs comprising aptamers |
| CN106459995B (zh) | 2013-11-07 | 2020-02-21 | 爱迪塔斯医药有限公司 | 使用统治型gRNA的CRISPR相关方法和组合物 |
| KR102170502B1 (ko) | 2013-12-11 | 2020-10-28 | 리제너론 파마슈티칼스 인코포레이티드 | 게놈의 표적화된 변형을 위한 방법 및 조성물 |
| US20150165054A1 (en) | 2013-12-12 | 2015-06-18 | President And Fellows Of Harvard College | Methods for correcting caspase-9 point mutations |
| US10034463B2 (en) * | 2014-01-24 | 2018-07-31 | Children's Medical Center Corporation | High-throughput mouse model for optimizing antibody affinities |
| US10077453B2 (en) | 2014-07-30 | 2018-09-18 | President And Fellows Of Harvard College | CAS9 proteins including ligand-dependent inteins |
| KR102531016B1 (ko) | 2014-11-21 | 2023-05-10 | 리제너론 파마슈티칼스 인코포레이티드 | 쌍 형성된 가이드 rna를 사용하는 표적화된 유전자 변형을 위한 방법 및 조성물 |
| IL310721B2 (en) | 2015-10-23 | 2025-11-01 | Harvard College | Nucleobase editors and uses thereof |
| US10813346B2 (en) | 2015-12-03 | 2020-10-27 | Trianni, Inc. | Enhanced immunoglobulin diversity |
| EP4414484A3 (en) | 2016-02-04 | 2025-01-15 | Trianni, Inc. | Enhanced production of immunoglobulins |
| JP2019513415A (ja) * | 2016-04-04 | 2019-05-30 | イーティーエッチ チューリッヒ | タンパク質産生及びライブラリー生成のための哺乳類細胞株 |
| CN110214183A (zh) | 2016-08-03 | 2019-09-06 | 哈佛大学的校长及成员们 | 腺苷核碱基编辑器及其用途 |
| WO2018031683A1 (en) | 2016-08-09 | 2018-02-15 | President And Fellows Of Harvard College | Programmable cas9-recombinase fusion proteins and uses thereof |
| US11542509B2 (en) | 2016-08-24 | 2023-01-03 | President And Fellows Of Harvard College | Incorporation of unnatural amino acids into proteins using base editing |
| KR102622411B1 (ko) | 2016-10-14 | 2024-01-10 | 프레지던트 앤드 펠로우즈 오브 하바드 칼리지 | 핵염기 에디터의 aav 전달 |
| WO2018119359A1 (en) | 2016-12-23 | 2018-06-28 | President And Fellows Of Harvard College | Editing of ccr5 receptor gene to protect against hiv infection |
| EP3592853A1 (en) | 2017-03-09 | 2020-01-15 | President and Fellows of Harvard College | Suppression of pain by gene editing |
| US12390514B2 (en) | 2017-03-09 | 2025-08-19 | President And Fellows Of Harvard College | Cancer vaccine |
| US11542496B2 (en) | 2017-03-10 | 2023-01-03 | President And Fellows Of Harvard College | Cytosine to guanine base editor |
| CA3094322A1 (en) * | 2017-03-20 | 2018-09-27 | Washington University | Cells and methods of uses and making the same |
| KR20240116572A (ko) | 2017-03-23 | 2024-07-29 | 프레지던트 앤드 펠로우즈 오브 하바드 칼리지 | 핵산 프로그램가능한 dna 결합 단백질을 포함하는 핵염기 편집제 |
| JP7257967B2 (ja) | 2017-05-01 | 2023-04-14 | ザ チルドレンズ メディカル センター コーポレーション | 抗pd1抗体試薬に関する方法および組成物 |
| US11560566B2 (en) | 2017-05-12 | 2023-01-24 | President And Fellows Of Harvard College | Aptazyme-embedded guide RNAs for use with CRISPR-Cas9 in genome editing and transcriptional activation |
| CN111801345A (zh) | 2017-07-28 | 2020-10-20 | 哈佛大学的校长及成员们 | 使用噬菌体辅助连续进化(pace)的进化碱基编辑器的方法和组合物 |
| EP3676376B1 (en) | 2017-08-30 | 2025-01-15 | President and Fellows of Harvard College | High efficiency base editors comprising gam |
| KR20250107288A (ko) | 2017-10-16 | 2025-07-11 | 더 브로드 인스티튜트, 인코퍼레이티드 | 아데노신 염기 편집제의 용도 |
| US12406749B2 (en) | 2017-12-15 | 2025-09-02 | The Broad Institute, Inc. | Systems and methods for predicting repair outcomes in genetic engineering |
| US12157760B2 (en) | 2018-05-23 | 2024-12-03 | The Broad Institute, Inc. | Base editors and uses thereof |
| WO2019241122A1 (en) * | 2018-06-13 | 2019-12-19 | The Children's Medical Center Corporation | Methods and compositions relating to high-throughput models for antibody discovery and/or optimization |
| US12522807B2 (en) | 2018-07-09 | 2026-01-13 | The Broad Institute, Inc. | RNA programmable epigenetic RNA modifiers and uses thereof |
| WO2020092453A1 (en) | 2018-10-29 | 2020-05-07 | The Broad Institute, Inc. | Nucleobase editors comprising geocas9 and uses thereof |
| US12351837B2 (en) | 2019-01-23 | 2025-07-08 | The Broad Institute, Inc. | Supernegatively charged proteins and uses thereof |
| WO2020191233A1 (en) | 2019-03-19 | 2020-09-24 | The Broad Institute, Inc. | Methods and compositions for editing nucleotide sequences |
| US12473543B2 (en) | 2019-04-17 | 2025-11-18 | The Broad Institute, Inc. | Adenine base editors with reduced off-target effects |
| US12435330B2 (en) | 2019-10-10 | 2025-10-07 | The Broad Institute, Inc. | Methods and compositions for prime editing RNA |
| IL297761A (en) | 2020-05-08 | 2022-12-01 | Broad Inst Inc | Methods and compositions for simultaneously editing two helices of a designated double-helix nucleotide sequence |
| WO2022256739A2 (en) * | 2021-06-04 | 2022-12-08 | Nonagen Therapeutics Corporation | Antibody specific for bcl-6 and methods of use |
Family Cites Families (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6130364A (en) | 1995-03-29 | 2000-10-10 | Abgenix, Inc. | Production of antibodies using Cre-mediated site-specific recombination |
| EP2669298A3 (en) | 2008-05-23 | 2014-02-26 | Ablexis, LLC | Single variable immunoglobulin domain comprising VL-DH-JL |
| JP5827127B2 (ja) | 2008-12-18 | 2015-12-02 | エラスムス・ユニヴァーシティ・メディカル・センター・ロッテルダム | ヒト化抗体を発現する非ヒトトランスジェニック動物及びその使用 |
| HUE047278T2 (hu) * | 2011-08-05 | 2020-04-28 | Regeneron Pharma | Humanizált univerzális könnyûláncú egerek |
| BR112014006394A2 (pt) * | 2011-09-19 | 2017-03-28 | Kymab Ltd | manipulação de diversidade genética de imunoglobulina e terapêuticos multi-anticorpos |
| SG11201401181YA (en) * | 2011-10-17 | 2014-04-28 | Regeneron Pharma | Restricted immunoglobulin heavy chain mice |
| ME03551B (me) | 2012-06-12 | 2020-07-20 | Regeneron Pharma | Humanizovane nehumane živoтinje sa ograničenim lokusima imunoglobulinskog тeškog lanca |
| US10034463B2 (en) * | 2014-01-24 | 2018-07-31 | Children's Medical Center Corporation | High-throughput mouse model for optimizing antibody affinities |
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2015
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- 2015-01-23 WO PCT/US2015/012577 patent/WO2015112790A2/en not_active Ceased
- 2015-01-23 EP EP15739843.9A patent/EP3096609B1/en active Active
- 2015-01-23 JP JP2016548101A patent/JP6479024B2/ja active Active
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| CA2936976A1 (en) | 2015-07-30 |
| WO2015112790A8 (en) | 2015-10-15 |
| EP3096609A2 (en) | 2016-11-30 |
| US20180295822A1 (en) | 2018-10-18 |
| EP3096609B1 (en) | 2021-09-22 |
| US11974553B2 (en) | 2024-05-07 |
| WO2015112790A2 (en) | 2015-07-30 |
| EP3096609A4 (en) | 2017-06-21 |
| US10034463B2 (en) | 2018-07-31 |
| WO2015112790A3 (en) | 2015-12-10 |
| JP2017505127A (ja) | 2017-02-16 |
| US20160374320A1 (en) | 2016-12-29 |
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