WO2019236998A1 - Compositions and methods for the modulation of adaptive immunity - Google Patents

Compositions and methods for the modulation of adaptive immunity Download PDF

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Publication number
WO2019236998A1
WO2019236998A1 PCT/US2019/036050 US2019036050W WO2019236998A1 WO 2019236998 A1 WO2019236998 A1 WO 2019236998A1 US 2019036050 W US2019036050 W US 2019036050W WO 2019236998 A1 WO2019236998 A1 WO 2019236998A1
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Prior art keywords
sequence
rna
seq
disclosure
grna
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Ceased
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PCT/US2019/036050
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English (en)
French (fr)
Inventor
David A. Nelles
Ranjan BATRA
Gene Yeo
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Locana Inc
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Locana Inc
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Priority to CA3102783A priority Critical patent/CA3102783A1/en
Priority to AU2019281006A priority patent/AU2019281006A1/en
Priority to EP19814000.6A priority patent/EP3801641A4/en
Priority to JP2021518054A priority patent/JP2021526860A/ja
Priority to SG11202012015YA priority patent/SG11202012015YA/en
Priority to CN201980051039.7A priority patent/CN113286619A/zh
Priority to KR1020217000507A priority patent/KR20210060429A/ko
Publication of WO2019236998A1 publication Critical patent/WO2019236998A1/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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
    • C12N15/11—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
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
    • A61K48/005—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy characterised by an aspect of the 'active' part of the composition delivered, i.e. the nucleic acid delivered
    • 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
    • C12N15/10—Processes for the isolation, preparation or purification of DNA or RNA
    • C12N15/102—Mutagenizing nucleic acids
    • 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
    • C12N15/1136—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 against growth factors, growth regulators, cytokines, lymphokines or hormones
    • 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
    • C12N15/1138—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 against receptors or cell surface proteins
    • 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
    • C12N15/87—Introduction of foreign genetic material using processes not otherwise provided for, e.g. co-transformation
    • C12N15/90—Stable introduction of foreign DNA into chromosome
    • 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
    • C12N2310/20—Type of nucleic acid involving clustered regularly interspaced short palindromic repeats [CRISPR]

Definitions

  • the disclosure provides a composition comprising: (a) a first sequence comprising a guide RNA (gRNA) that specifically binds a first target sequence within a first RNA molecule, wherein the first target sequence comprises a sequence encoding a component of an adaptive immune response and (b) a second sequence comprising a second guide RNA (gRNA) that specifically binds a second target sequence within a second RNA molecule and (c) a sequence encoding a fusion protein, the sequence comprising a sequence encoding a first RNA-binding polypeptide and a sequence encoding a second RNA-binding polypeptide, wherein neither the first RNA-binding polypeptide nor the second RNA-binding polypeptide comprises a significant DNA-nuclease activity, wherein the first RNA-binding polypeptide and the second RNA-binding polypeptide are not identical, and wherein the second RNA-binding polypeptide comprises an RNA-nuclease activity.
  • the first RNA binding protein comprises a Cas9 polypeptide or an RNA- binding portion thereof.
  • the CRISPR-Cas protein is a Type V CRISPR- Cas protein.
  • the first RNA binding protein comprises a Cpfl polypeptide or an RNA-binding portion thereof.
  • the CRISPR-Cas protein is a Type VI CRISPR-Cas protein.
  • the first RNA binding protein comprises a Casl3 polypeptide or an RNA-binding portion thereof.
  • the CRISPR-Cas protein comprises a native RNA nuclease activity.
  • compositions of the disclosure comprising a first sequence comprising a first guide RNA (gRNA) that specifically binds a first target sequence within a first RNA molecule
  • first target sequence comprises a sequence encoding a component of an adaptive immune response and a second sequence comprising a second guide RNA (gRNA) that specifically binds a second target sequence within a second RNA molecule
  • the sequence encoding the first RNA binding protein further comprises a first sequence encoding a first NLS and a second sequence encoding a second NLS.
  • the sequence encoding the first NLS or the second NLS is positioned 3’ to the sequence encoding the first RNA binding protein.
  • compositions of the disclosure comprising a first sequence comprising a first guide RNA (gRNA) that specifically binds a first target sequence within a first RNA molecule
  • first target sequence comprises a sequence encoding a component of an adaptive immune response and a second sequence comprising a second guide RNA (gRNA) that specifically binds a second target sequence within a second RNA molecule
  • the second RNA binding protein comprises or consists of a human beta-lactamase-like protein 2 (hLACTB2) polypeptide.
  • the hLACTB2 comprises or consists of SEQ ID NO: 37.
  • compositions of the disclosure comprising a first sequence comprising a first guide RNA (gRNA) that specifically binds a first target sequence within a first RNA molecule, wherein the first target sequence comprises a sequence encoding a component of an adaptive immune response and a second sequence comprising a second guide RNA (gRNA) that specifically binds a second target sequence within a second RNA molecule
  • the second RNA binding protein comprises or consists of a Reactive Intermediate Imine Deaminase A (RIDA) polypeptide.
  • RIDA Reactive Intermediate Imine Deaminase A
  • the RIDA polypeptide comprises or consists of SEQ ID NO: 44.
  • compositions of the disclosure comprising a first sequence comprising a first guide RNA (gRNA) that specifically binds a first target sequence within a first RNA molecule, wherein the first target sequence comprises a sequence encoding a component of an adaptive immune response and a second sequence comprising a second guide RNA (gRNA) that specifically binds a second target sequence within a second RNA molecule
  • the second RNA binding protein comprises or consists of a Ribonuclease A Al (RAA1) polypeptide.
  • RAA1 polypeptide comprises or consists of SEQ ID NO: 139.
  • the TALEN polypeptide comprises or consists of:
  • the composition further comprises (a) a sequence comprising a gRNA that specifically binds within an RNA molecule and (b) a sequence encoding a nuclease.
  • the sequence encoding a nuclease comprises a sequence isolated or derived from a CRISPR/Cas protein.
  • a protein component of an adaptive immune response is, without limitation, Beta-2-microglobulin (b2M), Human Leukocyte Antigen A (HLA-A), Human Leukocyte Antigen B (HLA-B), Human Leukocyte Antigen C (HLA-C), Cluster of Differentiation 28 (CD28), Cluster of Differentiation 80 (CD80), Cluster of Differentiation 86 (CD86), Inducible T-cell Costimulator (ICOS), ICOS Ligand (ICOSLG), OX40L, Interleukin 12 (IL12), or CC Chemokine Receptor 7 (CCR7).
  • b2M Beta-2-microglobulin
  • HLA-A Human Leukocyte Antigen A
  • HLA-B Human Leukocyte Antigen B
  • HLA-C Human Leukocyte Antigen C
  • CD28 Cluster of Differentiation 28
  • CD80 Cluster of Differentiation 80
  • CD86 Cluster of Differentiation 86
  • ICR7 ICOS Ligand
  • the modified cell is invisible to a host immune system.
  • the gRNA sequence comprises a promoter capable of expressing the gRNA in a eukaryotic cell.
  • the promoter sequence is isolated or derived from an alanine tRNA promoter, an arginine tRNA promoter, an asparagine tRNA promoter, an aspartic acid tRNA promoter, a cysteine tRNA promoter, a glutamine tRNA promoter, a glutamic acid tRNA promoter, a glycine tRNA promoter, a histidine tRNA promoter, an isoleucine tRNA promoter, a leucine tRNA promoter, a lysine tRNA promoter, a methionine tRNA promoter, a phenylalanine tRNA promoter, a proline tRNA promoter, a serine tRNA promoter, a threonine tRNA promoter, a tryptophan tRNA promoter, a tyrosine tRNA promoter, or a valine tRNA promoter.
  • the promoter sequence is isolated or derived from an
  • a guide RNA or a portion thereof comprises or consists of between 10 and 100 nucleotides, inclusive of the endpoints.
  • a spacer sequence of the disclosure comprises or consists of between 10 and 30 nucleotides, inclusive of the endpoints.
  • a scaffold sequence of the disclosure comprises or consists of 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30 nucleotides.
  • the spacer sequence of the disclosure comprises or consists of 20 nucleotides.
  • the spacer sequence of the disclosure comprises or consists of 21 nucleotides.
  • the Cas9 protein can be S. pyogenes Cas9 and may comprise or consist of the amino acid sequence:
  • the Cas9 protein can be S. thermophiles CRISPR1 Cas9 and may comprise or consist of the amino acid sequence:
  • the Cas9 protein can be Listeria innocua Cas9 and may comprise or consist of the amino acid sequence:
  • Exemplary CasRX/Casl3d proteins may comprise or consist of the sequence: CasRX/Casl3d Gut_metagenome_contig20020004l 1 :

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  • Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Biomedical Technology (AREA)
  • Chemical & Material Sciences (AREA)
  • Biotechnology (AREA)
  • Molecular Biology (AREA)
  • Organic Chemistry (AREA)
  • General Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Zoology (AREA)
  • Wood Science & Technology (AREA)
  • General Health & Medical Sciences (AREA)
  • Biophysics (AREA)
  • Microbiology (AREA)
  • Biochemistry (AREA)
  • Plant Pathology (AREA)
  • Physics & Mathematics (AREA)
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  • Mycology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Crystallography & Structural Chemistry (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Micro-Organisms Or Cultivation Processes Thereof (AREA)
PCT/US2019/036050 2018-06-08 2019-06-07 Compositions and methods for the modulation of adaptive immunity Ceased WO2019236998A1 (en)

Priority Applications (7)

Application Number Priority Date Filing Date Title
CA3102783A CA3102783A1 (en) 2018-06-08 2019-06-07 Compositions and methods for the modulation of adaptive immunity
AU2019281006A AU2019281006A1 (en) 2018-06-08 2019-06-07 Compositions and methods for the modulation of adaptive immunity
EP19814000.6A EP3801641A4 (en) 2018-06-08 2019-06-07 COMPOSITIONS AND METHODS OF MODULATION OF ADAPTIVE IMMUNITY
JP2021518054A JP2021526860A (ja) 2018-06-08 2019-06-07 適応免疫をモジュレートするための組成物および方法
SG11202012015YA SG11202012015YA (en) 2018-06-08 2019-06-07 Compositions and methods for the modulation of adaptive immunity
CN201980051039.7A CN113286619A (zh) 2018-06-08 2019-06-07 用于调节适应性免疫的组合物和方法
KR1020217000507A KR20210060429A (ko) 2018-06-08 2019-06-07 적응 면역의 조절을 위한 조성물 및 방법

Applications Claiming Priority (2)

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US201862682276P 2018-06-08 2018-06-08
US62/682,276 2018-06-08

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WO2019236998A1 true WO2019236998A1 (en) 2019-12-12

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US (2) US20190382759A1 (https=)
EP (1) EP3801641A4 (https=)
JP (1) JP2021526860A (https=)
KR (1) KR20210060429A (https=)
CN (1) CN113286619A (https=)
AU (1) AU2019281006A1 (https=)
CA (1) CA3102783A1 (https=)
SG (1) SG11202012015YA (https=)
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Cited By (3)

* Cited by examiner, † Cited by third party
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WO2020150287A1 (en) * 2019-01-14 2020-07-23 University Of Rochester Targeted nuclear rna cleavage and polyadenylation with crispr-cas
US11111493B2 (en) 2018-03-15 2021-09-07 KSQ Therapeutics, Inc. Gene-regulating compositions and methods for improved immunotherapy
CN116042571A (zh) * 2021-05-26 2023-05-02 武汉大学 一种Cas12a变体及其在基因编辑中的应用

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US9499805B2 (en) 2010-06-18 2016-11-22 The University Of North Carolina At Chapel Hill Methods and compositions for synthetic RNA endonucleases
JP2021526858A (ja) 2018-06-08 2021-10-11 ロックアネイビオ， インコーポレイテッド Ｒｎａ標的化融合タンパク質組成物および使用方法
WO2021011504A1 (en) * 2019-07-12 2021-01-21 Duke University Nanoparticle systems for targeted delivery of crispr/cas13 and methods of using same
US11661459B2 (en) 2020-12-03 2023-05-30 Century Therapeutics, Inc. Artificial cell death polypeptide for chimeric antigen receptor and uses thereof
AU2021392032A1 (en) 2020-12-03 2023-06-22 Century Therapeutics, Inc. Genetically engineered cells and uses thereof
WO2023150131A1 (en) * 2022-02-01 2023-08-10 The Regents Of The University Of California Method of regulating alternative polyadenylation in rna
CN114848808B (zh) * 2022-03-24 2023-04-25 四川大学 基于阳离子脂多肽及细胞因子的免疫增强剂及制法、应用
CN114720699A (zh) * 2022-04-22 2022-07-08 浙江大学 一种结直肠癌早期预警血清指标及其检测方法和应用
CN116949011A (zh) * 2022-04-26 2023-10-27 中国科学院动物研究所 经分离的Cas13蛋白、基于它的基因编辑系统及其用途
CN115068632A (zh) * 2022-06-22 2022-09-20 华中科技大学同济医学院附属同济医院 Ago2在制备治疗心衰的药物方面的用途及其蛋白、基因、转化体、药物与制备方法
WO2024264035A2 (en) * 2023-06-22 2024-12-26 The General Hospital Corporation Compositions and methods of generating endogenous tdr molecules

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11111493B2 (en) 2018-03-15 2021-09-07 KSQ Therapeutics, Inc. Gene-regulating compositions and methods for improved immunotherapy
US11421228B2 (en) 2018-03-15 2022-08-23 KSQ Therapeutics, Inc. Gene-regulating compositions and methods for improved immunotherapy
US11608500B2 (en) 2018-03-15 2023-03-21 KSQ Therapeutics, Inc. Gene-regulating compositions and methods for improved immunotherapy
WO2020150287A1 (en) * 2019-01-14 2020-07-23 University Of Rochester Targeted nuclear rna cleavage and polyadenylation with crispr-cas
US12371698B2 (en) 2019-01-14 2025-07-29 University Of Rochester Targeted nuclear RNA cleavage and polyadenylation with CRISPR-Cas
CN116042571A (zh) * 2021-05-26 2023-05-02 武汉大学 一种Cas12a变体及其在基因编辑中的应用

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US20240344060A1 (en) 2024-10-17
EP3801641A1 (en) 2021-04-14
SG11202012015YA (en) 2021-01-28
CN113286619A (zh) 2021-08-20
US20190382759A1 (en) 2019-12-19
CA3102783A1 (en) 2019-12-12
JP2021526860A (ja) 2021-10-11
KR20210060429A (ko) 2021-05-26
EP3801641A4 (en) 2022-09-28
AU2019281006A1 (en) 2021-01-28

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