JP7458185B2 - 改善されたヒト自然免疫細胞の発生を有するヒト化マウスモデル - Google Patents
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- 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
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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
- A01K67/0271—Chimeric vertebrates, e.g. comprising exogenous cells
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- A61K49/0004—Screening or testing of compounds for diagnosis of disorders, assessment of conditions, e.g. renal clearance, gastric emptying, testing for diabetes, allergy, rheuma, pancreas functions
- A61K49/0008—Screening agents using (non-human) animal models or transgenic animal models or chimeric hosts, e.g. Alzheimer disease animal model, transgenic model for heart failure
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- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/52—Cytokines; Lymphokines; Interferons
- C07K14/53—Colony-stimulating factor [CSF]
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/52—Cytokines; Lymphokines; Interferons
- C07K14/53—Colony-stimulating factor [CSF]
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- C—CHEMISTRY; METALLURGY
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- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
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- A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
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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
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- A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
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- A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
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- A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
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- A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
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Description
本発明は、国立衛生研究所により授与された助成金CA034196、ODO18259、DK104218、およびAI132963の下における政府の援助によってなされた。政府は本発明において一定の権利を有する。
本出願は、2016年11月30日に出願された米国特許仮出願62/428,131および2017年9月29日に出願された同62/565,783の優先権を主張しており、その両方の全体の内容は、参照により本明細書に組み込まれている
遺伝子組換え免疫不全マウスにヒト腫瘍細胞を投与すること、ここで、ヒト腫瘍細胞は、遺伝子組換え免疫不全マウス中で固形または非固形の腫瘍を形成する;
遺伝子組換え免疫不全マウスに検体を投与すること;および
固形または非固形の腫瘍の検体に対する反応をアッセイすること、ここで腫瘍および/または腫瘍細胞に対する検体の阻害効果は、検体を、抗腫瘍活性を有するものとして同定する、を包含する。
遺伝子組換え免疫不全マウスにヒト腫瘍細胞を投与すること、ここでヒト腫瘍細胞は、遺伝子組換え免疫不全マウス中で固形または非固形の腫瘍を形成する;
遺伝子組換え免疫不全マウスに検体を投与すること;および
固形又は非固形の腫瘍の検体に対する反応をアッセイすること、ここで腫瘍および/または腫瘍細胞に対する検体の阻害効果は、検体を、抗腫瘍活性を有するものと同定する、を包含する。
遺伝子組換え免疫不全マウスにヒト腫瘍細胞を投与すること、ここでヒト腫瘍細胞は、遺伝子組換え免疫不全マウス中で固形または非固形の腫瘍を形成する;
遺伝子組換え免疫不全マウスに検体を投与すること;および
固形または非固形の腫瘍の検体に対する反応をアッセイすること、ここで腫瘍および/または腫瘍細胞に対する検体の阻害効果は、検体を、抗腫瘍活性を有するものと同定する、を包含する。
遺伝子組換え免疫不全マウスにヒト腫瘍細胞を投与すること、ここでヒト腫瘍細胞は、遺伝子組換え免疫不全マウス中で固形または非固形の腫瘍を形成する;
遺伝子組換え免疫不全マウスに検体を投与すること;および
固形または非固形の腫瘍の検体に対する反応をアッセイすること、ここで腫瘍および/または腫瘍細胞に対する検体の阻害効果は、検体を、抗腫瘍活性を有するものと同定する、を包含する。
遺伝子組換え免疫不全マウスにヒト腫瘍細胞を投与すること、ここでヒト腫瘍細胞は、遺伝子組換え免疫不全マウス中で固形または非固形の腫瘍を形成する;
遺伝子組換え免疫不全マウスに検体を投与すること;および
固形または非固形の腫瘍の検体に対する反応をアッセイすること、ここで腫瘍および/または腫瘍細胞に対する検体の阻害効果は、検体を、抗腫瘍活性を有するものと同定する、を包含する。
遺伝子組換え免疫不全マウスにヒト腫瘍細胞を投与すること、ここでヒト腫瘍細胞は、遺伝子組換え免疫不全マウス中で固形または非固形の腫瘍を形成する;
遺伝子組換え免疫不全マウスに検体を投与すること;および
固形または非固形の腫瘍の検体に対する反応をアッセイすること、ここで腫瘍および/または腫瘍細胞に対する検体の阻害効果は、検体を、抗腫瘍活性を有するものと同定する、を包含する。
遺伝子組換え免疫不全マウスにヒト腫瘍細胞を投与すること、ここでヒト腫瘍細胞は、遺伝子組換え免疫不全マウス中で固形または非固形の腫瘍を形成する;
遺伝子組換え免疫不全マウスに検体を投与すること;および
固形または非固形の腫瘍の検体に対する反応をアッセイすること、ここで腫瘍および/または腫瘍細胞に対する検体の阻害効果は、検体を、抗腫瘍活性を有するものと同定する、を包含する。
遺伝子組換え免疫不全マウスにヒト腫瘍細胞を投与すること、ここでヒト腫瘍細胞は、遺伝子組換え免疫不全マウス中で固形または非固形の腫瘍を形成する;
遺伝子組換え免疫不全マウスに検体を投与すること;および
固形または非固形の腫瘍の検体に対する反応をアッセイすること、ここで腫瘍および/または腫瘍細胞に対する検体の阻害効果は、検体を、抗腫瘍活性を有するものと同定する、を包含する。
本明細書において使用される科学的および技術的用語は、当業者により一般に理解される意味を有するものと意図される。かかる用語は、例示的に以下を含む様々な標準的な参考文献における文脈中に定義され、使用されているものが見出される:J. Sambrook and D.W. Russell, Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory Press; 3rd Ed., 2001;F.M. Ausubel, Ed., Short Protocols in Molecular Biology, Current Protocols; 5th Ed., 2002;B. Alberts et al., Molecular Biology of the Cell, 4th Ed., Garland, 2002;D.L. Nelson and M.M. Cox, Lehninger Principles of Biochemistry, 4th Ed., W.H. Freeman & Company, 2004;Herdewijn, P. (Ed.), Oligonucleotide Synthesis: Methods and Applications, Methods in Molecular Biology, Humana Press, 2004;A. Nagy, M. Gertsenstein, K. Vintersten, R. Behringer, Manipulating the Mouse Embryo: A Laboratory Manual, 3rd edition, Cold Spring Harbor Laboratory Press; December 15, 2002, ISBN-10: 0879695919;and Kursad Turksen (Ed.), Embryonic stem cells: methods and protocols in Methods Mol Biol. 2002;185, Humana Press;Current Protocols in Stem Cell Biology, ISBN: 9780470151808。
例1.ヒト造血幹細胞異種移植片を有するNSG-Quadマウスの分析
Claims (22)
- 遺伝子組換え免疫不全マウスであって、以下:
(a)ヒト幹細胞因子(hSCF)をコードするヌクレオチド配列;
(b)ヒト顆粒球マクロファージコロニー刺激因子(hGM-CSF)をコードするヌクレオチド配列;
(c)ヒトインターロイキン-3(hIL-3)をコードするヌクレオチド配列;および
(d)ヒトコロニー刺激因子1(hCSF1)をコードするヌクレオチド配列
を含み、
ここでヌクレオチド配列のそれぞれがプロモーターに作動可能に連結されており、
ここで遺伝子組換え免疫不全マウスがhSCF、hGM-CSF、hIL-3、およびhCSF1を発現しており、
ここでマウスが、NOD(non-obese diabetic)マウスであり、
ここでマウスが、機能的マウスT細胞および機能的マウスB細胞を欠いており、ならびに
ここでマウスが、機能的内在性IL-2rg(インターロイキン-2受容体γサブユニット)遺伝子を欠き、かつ機能的IL-2RGタンパク質を発現しない、前記遺伝子組換え免疫不全マウス。 - マウスが、
遺伝子組換えのNOD.Cg-PrkdcscidIl2rgtm1Wjl/SzJ(NSG)マウス;
遺伝子組換えのNOD.Cg-Rag1tm1MomIl2rgtm1Wjl/SzJ(NRG)マウス;または
遺伝子組換えのNOD.Cg-PrkdcscidIl2rgtm1Sug/JicTac(NOG)マウス
であって、
前記NSG、NRG、またはNOGマウスが、hSCF、hGM-CSF、hIL-3、およびhCSF1をコードするヌクレオチド配列を含む、請求項1に記載の遺伝子組換え免疫不全マウス。 - hSCF、hGM-CSF、hIL-3、またはhCSF1をコードするヌクレオチド配列のいずれか1つ以上が、構成的プロモーターに作動可能に連結されている、請求項1または2に記載の遺伝子組換え免疫不全マウス。
- ヒト造血幹細胞をさらに含む、請求項1~3のいずれか一項に記載の遺伝子組換え免疫不全マウス。
- マウスが、ヒト造血幹細胞から分化された細胞を含み、前記分化された細胞が、ヒト骨髄前駆細胞、ヒトリンパ球前駆細胞、ヒトCD33+骨髄細胞、ヒトマスト細胞、ヒト単球、ヒトマクロファージ、ヒト骨髄樹状細胞、ヒトB細胞、ヒトプラズマ細胞、ヒトT細胞、ヒトヘルパーT細胞、ヒト細胞傷害性T細胞、ヒトTreg細胞、およびヒトナチュラルキラー細胞からなる群より選択される、請求項1~4のいずれか一項に記載の遺伝子組換え免疫不全マウス。
- マウスが、CD45+、CD20+、CD20+CD45+、CD3+、CD3+CD45+、CD33+、CD33+CD45+、CD14+、CD14+CD45+、CD56+、およびCD56+CD45+白血球からなる群より選択されるヒト白血球を含む、請求項1~5のいずれか一項に記載の遺伝子組換え免疫不全マウス。
- 前記マウスが、免疫学的攻撃の不在下において、以下:
マウスのヒトCD45+白血球の少なくとも約20%が、CD3+CD45+白血球である;
マウスのヒトCD45+白血球の少なくとも約10%が、CD33+CD45+白血球である;
マウスのヒトCD45+白血球の少なくとも約5%が、CD14+CD45+白血球である;または
マウスのヒトCD45+白血球の少なくとも約0.5%が、CD56+CD45+白血球である
ことを含む、請求項6に記載の遺伝子組換え免疫不全マウス。 - マウスが、ヒトインターロイキン-8、ヒトインターロイキン-1β、ヒト腫瘍壊死因子、ヒトインターロイキン-12p70、およびヒトインターロイキン-6からなる群より選択されるヒトサイトカインを発現する、請求項4~7のいずれか一項に記載の遺伝子組換え免疫不全マウス。
- ヒト腫瘍細胞を含むヒト異種移植片をさらに含む、請求項4~8のいずれか一項に記載の遺伝子組換え免疫不全マウス。
- 遺伝子組換え免疫不全ヒト化マウスモデルを作成する方法であって、以下:
請求項1~3のいずれか一項に従った、遺伝子組換え免疫不全マウスを提供するステップ;および
遺伝子組換え免疫不全マウスにヒト造血幹細胞を投与するステップ
を含む、前記方法。 - ヒト造血幹細胞を投与する前に、遺伝子組換え免疫不全マウスにマウス造血幹細胞を減少させるよう調整するステップをさらに含む、請求項10に記載の方法。
- 調整するステップが、
遺伝子組換え免疫不全マウスに放射線を照射すること、および/または
遺伝子組換え免疫不全マウスに放射線様作用薬を投与すること
を含む、請求項11に記載の方法。 - 遺伝子組換え免疫不全マウスにヒト腫瘍細胞を含むヒト異種移植片を投与するステップをさらに含む、請求項10~12のいずれか一項に記載の方法。
- ヒト造血幹細胞およびヒト腫瘍細胞が、少なくとも2、少なくとも3、少なくとも4、少なくとも5、少なくとも6、少なくとも7、少なくとも8、少なくとも9、少なくとも10、少なくとも11、少なくとも12、少なくとも13、少なくとも14、少なくとも15、少なくとも16、少なくとも17、少なくとも18、少なくとも19、または少なくとも20の一致するHLAアリルを含む、請求項13に記載の方法。
- 検体の抗腫瘍活性を同定する方法であって、以下:
請求項4~8のいずれか一項に従った遺伝子組換え免疫不全マウスを提供するステップ;
遺伝子組換え免疫不全マウスにヒト腫瘍細胞を投与するステップであって、ここでヒト腫瘍細胞が遺伝子組換え免疫不全マウスにおいて固形または非固形の腫瘍を形成するステップ;
遺伝子組換え免疫不全マウスに検体を投与するステップ;および
検体への固形または非固形の腫瘍の反応をアッセイするステップであって、ここで腫瘍および/または腫瘍細胞に対する検体の阻害効果が抗腫瘍活性を有するものとしての検体を同定するステップ
を含む、前記方法。 - 標準物質との反応と比較して、異種移植の腫瘍細胞に対する検体の効果を決定することであって、異種移植の腫瘍細胞に対する検体の阻害効果が検体を、抗腫瘍活性を有するものと同定することをさらに含む、請求項15に記載の方法。
- 検体が免疫療法薬である、請求項15または16に記載の方法。
- 検体が免疫チェックポイント阻害剤である、請求項15~17のいずれか一項に記載の方法。
- 免疫チェックポイント阻害剤が、PD-1阻害剤、PD-L1阻害剤、またはCTLA-4阻害剤である、請求項18に記載の方法。
- 免疫チェックポイント阻害剤が、アテゾリズマブ、アベルマブ、デュルバルマブ、イピリムマブ、ニボルマブ、またはペンブロリズマブであるか、または
免疫チェックポイント阻害剤が、前述のいずれか1つの抗原結合性フラグメントを含む、請求項18または19に記載の方法。 - 検体が抗体である、請求項15~20のいずれか一項に記載の方法。
- 検体が抗がん剤である、請求項15~21のいずれか一項に記載の方法。
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