JP6619454B2 - キャプシド - Google Patents
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- JP6619454B2 JP6619454B2 JP2017558723A JP2017558723A JP6619454B2 JP 6619454 B2 JP6619454 B2 JP 6619454B2 JP 2017558723 A JP2017558723 A JP 2017558723A JP 2017558723 A JP2017558723 A JP 2017558723A JP 6619454 B2 JP6619454 B2 JP 6619454B2
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Classifications
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- 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
- A61K48/0008—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 'non-active' part of the composition delivered, e.g. wherein such 'non-active' part is not delivered simultaneously with the 'active' part of the composition
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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
- C07K14/005—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from viruses
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- 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
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- 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
- C12N15/86—Viral vectors
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- C12N2750/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA ssDNA viruses
- C12N2750/00011—Details
- C12N2750/14011—Parvoviridae
- C12N2750/14111—Dependovirus, e.g. adenoassociated viruses
- C12N2750/14122—New viral proteins or individual genes, new structural or functional aspects of known viral proteins or genes
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- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
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- C12N2750/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA ssDNA viruses
- C12N2750/00011—Details
- C12N2750/14011—Parvoviridae
- C12N2750/14111—Dependovirus, e.g. adenoassociated viruses
- C12N2750/14141—Use of virus, viral particle or viral elements as a vector
- C12N2750/14143—Use of virus, viral particle or viral elements as a vector viral genome or elements thereof as genetic vector
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Description
本発明は、アデノ随伴ウイルス(AAV)キャプシド変異体に関する。
近年、様々なウイルスに基づく、多数の組換え遺伝子導入ベクターが開発されている。様々な組織の様々なタイプの分裂及び非分裂細胞を形質導入し得る能力や、安定で長期間の導入遺伝子の発現を確立し得る能力から、アデノ随伴ウイルス(AAV)に基づく遺伝子導入ベクター、すなわちAAVベクターが好ましい。例えばアデノウイルスやレトロウイルスなどの他のウイルスに基づくベクターは、特定の望ましい特徴を有し得るものの、それらは望ましくない副作用にも結び付いている。かかる副作用は、AAVに基づく遺伝子導入ベクターでは検出されていない(Manno et al.,Nature Medicine,12(3):342(2006))。
本発明は、これより、図面を参照してのみ例として詳細に説明される:
本発明の第一の態様において、配列番号3に対して少なくとも98%の同一性、又は配列番号4に対して少なくとも94%の同一性を有するアミノ酸配列を有するAAVキャプシドタンパク質が提供される。
新規のハイブリッドキャプシドは、4つの異なるAAVキャプシド((1)AAV8、(2)AAV5、(3)AAV3B及び(4)AAV−LK03)由来の様々なドメインを実験的に交換することにより作製した(図1参照)。後者は、現在利用可能な天然に生じるAAVキャプシドよりも効率よくヒト肝細胞を形質導入できることが報告されている。注目すべきは、LK03がAAV3Bと95%を超えるアミノ酸配列相同性を有することである。本発明のキャプシドタンパク質は、血清型1−rh10由来の野生型AAVキャプシド由来のモチーフを選択することにより開発された合成キャプシドである。LK03のVP2及びVP3領域を、AAV8及びAAV5由来の対応する領域で置換し、変異体A(配列番号1)(MutA)及び変異体B(配列番号2)(Mut B)をそれぞれ作製した。変異体C(配列番号3)(Mut C)においては、AAV3BキャプシドのVP2及びVP3ドメインの上流に、AAV8のVP1領域を含む146アミノ酸の領域をクローニングした。同様に、変異体D(配列番号4)(MutD)においては、AAV5−VP1領域を、AAV3BのV2及びV3領域の上流にクローニングした。変異体E(配列番号5)(MutE)においては、AAV8のドメインv−I、v−II及びv−IXを、AAV3B由来の同系(cognate)により置換した。変異体F(配列番号6)(MutF)においては、AAV3Bの肝細胞成長因子受容体結合部位を含有する262のアミノ酸領域をAAV8キャプシドの対応する領域へクローニングした。
組換えAAVベクターの製造。EGFP受容体遺伝子がCMVプロモーターの制御下にあるベクタープラスミド、アデノウイルスヘルパープラスミド、及び、それぞれのAAV cap遺伝子が内在性プロモーターの制御下にあるAAV2 Rep遺伝子の下流に存在するパッケージングプラスミドからなるプラスミドの組合せで、接着性HEK293T細胞をコトランスフェクションすることにより、AAVベクターを作製した。AVBカラムクロマトグラフィーを用いて、ベクターを精製した。全てのベクターの力価測定はqPCRアッセイ及びアルカリゲル解析により行った。
集中的な研究において、Huh7(肝臓がん細胞株)及びHepG2細胞株(肝臓がん細胞株)におけるAAV8、AAV5、AAV−rh10、AAV−LK03及びAAV Mut Cのインビトロでの形質導入効率を比較した。全てのベクターは、サイトメガロウイルス(CMV)プロモーターの制御下にある緑色蛍光タンパク質(GFP)レポーター遺伝子を含有した。
任意抽出の重度血友病患者由来の血漿試料をスクリーニングし、ELISA免疫吸着法を用いて、AAV Mut Cに対する既存抗体の保有を評価した。63%の患者は、AAV Mut Cに対する検出可能な抗体を呈さなかった。AAV8及びAAV−LK03に関して、対応するレベルは51%であった。従って、これはAAV Mut Cに対する抗体を有する重度の血友病患者が比較的少ないことを示唆している。
Claims (10)
- 以下のアミノ酸配列を含むAAVキャプシドタンパク質:
(i)配列番号3の配列、又は、
(ii)配列番号3の配列に対して少なくとも99%の同一性を有し、且つ、AAV3B及びAAV8キャプシドの領域を含むハイブリッドキャプシドである、配列。 - 前記アミノ酸配列が、配列番号3の配列に対して少なくとも99.5%の同一性を有する、請求項1記載のAAVキャプシドタンパク質。
- 前記アミノ酸配列が、配列番号3の配列である、請求項1又は2記載のAAVキャプシドタンパク質。
- 請求項1〜3のいずれか1項記載のキャプシドタンパク質を含む、AAVキャプシド。
- 請求項1〜3のいずれか1項記載のキャプシドタンパク質を含む、ウイルス粒子。
- 請求項1〜3のいずれか1項記載のキャプシドタンパク質をコードする核酸分子。
- 請求項1〜3のいずれか1項記載のキャプシドタンパク質、又は請求項6記載の核酸分子を含む、宿主細胞。
- 請求項1〜3のいずれか1項記載のキャプシドタンパク質、又は請求項6記載の核酸分子を含む細胞を含む、非ヒトトランスジェニック動物。
- 請求項1〜3のいずれか1項記載のキャプシドタンパク質、又は請求項6記載の核酸分子、及び1以上の医薬上許容される賦形剤を含む、医薬組成物。
- 請求項1〜3のいずれか1項記載のキャプシドタンパク質、又は請求項6記載の核酸分子を含む、医薬用剤。
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CN107864653B (zh) | 2022-06-21 |
CA2985945C (en) | 2022-09-06 |
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HRP20190442T1 (hr) | 2019-05-03 |
JP2020096587A (ja) | 2020-06-25 |
US20200079821A1 (en) | 2020-03-12 |
CN107864653A (zh) | 2018-03-30 |
PT3250239T (pt) | 2019-02-19 |
US20180111965A1 (en) | 2018-04-26 |
AU2016261454B2 (en) | 2019-07-11 |
KR20180019543A (ko) | 2018-02-26 |
HUE042693T2 (hu) | 2019-07-29 |
PL3250239T3 (pl) | 2019-05-31 |
EP3511021A1 (en) | 2019-07-17 |
WO2016181123A1 (en) | 2016-11-17 |
TW201704253A (zh) | 2017-02-01 |
JP2018520997A (ja) | 2018-08-02 |
EP3250239A1 (en) | 2017-12-06 |
CA2985945A1 (en) | 2016-11-17 |
LT3250239T (lt) | 2019-03-25 |
AU2016261454A1 (en) | 2017-11-23 |
US10414803B2 (en) | 2019-09-17 |
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