JP4693839B2 - 動物由来の成分なしで培養可能である細胞株及びその作出方法、これを用いたウイルスの生産方法、及びワクチンの生産方法 - Google Patents
動物由来の成分なしで培養可能である細胞株及びその作出方法、これを用いたウイルスの生産方法、及びワクチンの生産方法 Download PDFInfo
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Description
・RPMI 1640 Medium(GIBCO、Catalogue No.21870)
・大豆ペプトン(Peptone from soybean、enzymatic digest、Fluka、Catalogue No.87972)15グラムを1,000ml滅菌蒸留水に溶解し、220nmフィルターで濾過後、RPMI1640培地100ml当たり5mlを添加(最終濃度 750μg/ml)
・L−グルタミンを300mg/Lになるように添加(最終濃度 300μg/ml)
・抗生物質として、ペニシリンGカリウムを100U/ml、硫酸ストレプトマイシンを100μg/ml、アンフォテリシンBを2.5μg/mlになるように添加(いずれも最終濃度)
MDCK細胞を、「Opti−Pro SFM」培地で2代及び「Opti−MEM I Reduced−Serum Medium」培地で33代継代培養した後、RPMI/SP培地で28代継代培養すると、RPMI/SP培地に対して順化が進み、細胞の増殖が安定した。過去数代に渡って、細胞シートの形成に要する時間と継代間隔が一定になり、5〜7日間隔で4倍に継代された。この新規な細胞株を「MDCK−SP株」と命名した。さらに、RPMI/SP培地で45代まで継代培養すると、MDCK細胞は、無血清培地であるRPMI/SP培地に完全に順化した。これにより、犬腎臓由来細胞であるMDCK細胞から誘導した細胞株であって、動物由来成分なしで培養可能である細胞株が樹立された。MDCK−SP株細胞(RPMI/SP培地で45代継代細胞、無血清培地では総計80代継代細胞)は、2004年12月16日に独立行政法人産業技術総合研究所 特許生物寄託センター(茨城県つくば市東1−1−1)に寄託された(受託番号FERM P−20329)。その後、2005年2月4日に受託番号FERM BP−10225として、国際寄託に移管された。
本実施例で用いた犬腎臓由来細胞であるMDCK細胞は、1958年9月に、Madin & Darbyによって健康正常な雌コッカースパニエルの腎臓から作出された細胞系である。これは、ATCC(American Type Culture Collection)に登録された細胞(ATCC No.CCL−34)に由来するものと考えられる。1970年代に東京大学農学部獣医畜産学科家畜微生物学教室で本願発明者が研究用に使っており、その後、同細胞は鹿児島大学農学部獣医学科家畜微生物学講座、共立製薬株式会社臨床微生物研究所へと受け継がれてきた。最後者の臨床微生物研究所では1995年4月より、Eagle’s MEM基礎培地(日水製薬株式会社製、イーグルMEM培地「ニッスイ(1)」)に、牛胎児血清を7.5%、Tryptose Phosphate Brothを10%、およびL−グルタミン(0.292g/L)を含み、細菌増殖抑止を目的にペニシリン(100U/ml)、ストレプトマイシン(100μg/ml)、アンフォテリシンB(0.25〜0.5μg/ml)を添加した培地(7.5% MEM)で継代培養してきた。これを親細胞とした。
MDCK−SP細胞を、市販のマイクロキャリアビーズを用いて浮遊培養した。
実施例3において、現在広く、世界中の飼い犬の予防接種に用いられているワクチンを構成している、犬ジステンパーウイルス、1型と2型の犬アデノウイルス、犬パラインフルエンザウイルス、犬パルボウイルス2型の5種類を用いた。これらのウイルス液のストックはこれまで牛胎児血清やTryptose Phosphate Brothを添加した、例えばEagle’s MEM培地などの細胞培養内で増殖させている。そのため、無血清培地による細胞培養内でウイルスを増殖させるためにはこれらの牛血清成分などの動物蛋白質を取り除く必要がある。そこで、本実施例において無血清シードウイルス液を作成した。表2には上記のウイルス種のうち、実際に用いたウイルス株名と、それらを用いて作出したシードウイルス液のウイルス力価を示した。
1)25cm2Tフラスコに親細胞であるMDCK細胞を7.5% MEM培地で、MDCK−SP細胞をRPMI/SP培地で培養開始し、シートを形成した培養3日後に細胞数を計測した。
実施例4同じ方法で実施したが、相違するのは、
1)用いたウイルス株が、犬アデノウイルス1型(CAV−1)はPR 109株、犬アデノウイルス2型(CAV−2)はManhattan株であること、
2)感染価測定のMicro−titration法に用いた細胞がMDCK細胞であること、
の2点である。
実施例4と同じ方法で実施したが、相違するのは、
1)用いたウイルス株がTsukuba株であること、
2)感染価測定のMicro−titration法に用いた細胞がMDCK細胞であること、
3)感染価測定のMicro−titration法で用いた、感染価終末点の確定には、各希釈穴の上清中に産生されている血球凝集素の有無で行った。即ち、各穴から50μlの上清を取り出し、別に用意した血球凝集反応用マイクロプレートに移し、総ての穴に等量のpH7.0のリン酸緩衝食塩水(PBS)と等量のアカゲザル血球浮遊液を加えた。アカゲザル血球浮遊液は同じPBSに0.75%の割合で赤血球を浮遊し調整した。よく攪拌後、室温に2時間静置し、凝集の有無にて感染価を算出した。
実施例4と同じ方法で実施したが、相違するのは、
1)用いたウイルス株は2b抗原型のMD97−037株であること、
2)m.o.i.が0.05になるようにストックウイルス液を希釈し、実施例3で説明したように、細胞が培地に浮遊された時点でウイルス接種を行ったこと、
3)感染価測定のMicro−titration法に用いた細胞がMDCK細胞であること、
4)実施例6と同じように、感染価終末点の確定には、各希釈穴の上清中に産生されている血球凝集素の有無で行ったこと、
5)その際に用いたPBSのpHは6.8で、4℃で反応させたこと、
以上の5点である。
RPMI/SP培地に、DMSO(Wako Pure Chemical Industries,Ltd.Catalogue No.043−07216)を10%に含む細胞凍結用培地を調整した。この培地に、RPMI/SP培地で44代継代したMDCK−SP細胞を106/ml以上になるように浮遊し、凍結保存用バイアルに1.8mlずつ分注した。正確な細胞数は6.5x106/バイアルであった。本バイアルを冷蔵しておいた簡易細胞凍結器「BICELL(商標)」(Nihon Freezer Co.,Ltd.)に入れ、−80℃フリーザーで一晩かけて凍結した。その後、液体窒素(液相)に移管した。
Claims (6)
- 犬腎臓由来細胞であるMDCK細胞から誘導した細胞株であって、動物由来の成分なしで培養可能である受託番号FERM BP−10225で寄託された細胞株。
- 請求項1の細胞株にウイルスを感染させる工程と、感染した細胞株を培養してウイルスを増殖させる工程とを含むウイルスの生産方法。
- 前記感染した細胞株を培養する際の培地は、RPMI 1640 培地及び大豆由来ペプトンを含有する培地であって、動物由来の成分を含まない培地である請求項2のウイルスの生産方法。
- 前記感染した細胞株を培養する際に浮遊培養法を用いる請求項2又は3のウイルスの生産方法。
- 前記ウイルスは、パラミクソウイルス科、オルトミクソウイルス科、ラブドウイルス科、フラビウイルス科、カリシウイルス科、アデノウイルス科、ヘルペスウイルス科及びパルボウイルス科からなる群から選ばれる請求項2〜4のいずれかのウイルスの生産方法。
- 前記ウイルスは、犬ジステンパーウイルス、麻疹ウイルス、犬パラインフルエンザウイルス、SV5ウイルス、インフルエンザウイルス、狂犬病ウイルス、日本脳炎ウイルス、犬カリシウイルス、1型および2型犬アデノウイルス、人アデノウイルス、犬ヘルペスウイルス及び1型と2型犬パルボウイルスからなる群から選ばれる請求項2〜4のいずれかのウイルスの生産方法。
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US7682619B2 (en) | 2006-04-06 | 2010-03-23 | Cornell Research Foundation, Inc. | Canine influenza virus |
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WO2004005493A1 (en) * | 2002-07-09 | 2004-01-15 | Baxter International, Inc. | Animal protein free media for cultivation of cells |
WO2004078955A1 (en) * | 2003-03-03 | 2004-09-16 | Glaxosmithkline Biologicals S.A. | Animal-free cell culture method |
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EP1862537A1 (en) | 2007-12-05 |
EP1862537A4 (en) | 2009-01-21 |
US20080138362A1 (en) | 2008-06-12 |
JPWO2006095431A1 (ja) | 2008-08-14 |
CA2601006C (en) | 2012-10-23 |
CA2601006A1 (en) | 2006-09-14 |
ES2424365T3 (es) | 2013-10-01 |
US7910366B2 (en) | 2011-03-22 |
EP1862537B1 (en) | 2013-05-08 |
WO2006095431A1 (ja) | 2006-09-14 |
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