JP5837820B2 - 形質細胞から抗体を産生する方法 - Google Patents
形質細胞から抗体を産生する方法 Download PDFInfo
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Description
形質細胞は、表面免疫グロブリンを発現しないため、アイソタイプまたは抗原特異性に従って選択されることは不可能である。形質細胞によって産生された抗体は、したがって、特徴付けられるために単離されなければならない。現在のところ、形質細胞からヒトモノクローナル抗体を作る当該技術分野で主に使用されている方法は2つある。これらのうちの一つは免疫のあるドナーの全骨髄から調製された抗体のディスプレイライブラリーをスクリーニングすることである(Williamson et al.,1993 Proc Natl Acad Sci USA 90、4141−4145)。しかしながら、この方法は骨髄試料の入手の可能性に制限されている。
本発明は、本発明のいずれかの方法によって産生される抗体もしくは抗体断片を含む。
本発明は、本発明のいずれかの方法によって産生された抗体もしくは抗体断片の治療における使用、例えば、アレルギー、感染状態もしくは疾病、癌、自己免疫状態もしくは疾病における治療で提供する。
本発明はまた、本発明のいずれかの方法によって産生された単離された抗体もしくは抗体断片を固定支持体の上に固定化する方法も含む。用語「固体支持体」は、固体もしくは半固体支持体の両方を含み、単離された抗体もしくは抗体断片を固定するために使用され得るいずれの支持体も包含する。固体支持体は、ジェル、メッシュ、ガラス球または電磁ビーズを含むビーズ、カラム、管、マイクロタイタープレートのウェル、プラスチックシートを含み得る。本発明のいずれかの方法によって産生された固定化された抗体もしくは抗体断片は、タンパク質精製において使用され得る。一実施形態において、固定化された抗体は免疫親和性クロマトグラフィーで使用され得る。関心のタンパク質を含む溶液は、本発明のいずれかの方法によって産生された固定化された抗体もしくは抗体断片を含む固定支持体に適用されることができ、またそれらは、関心のタンパク質への特異性を有すると周知である。抗体もしくは抗体断片は、例えば、ビーズ上で固定化されることができ、幾つかの実施形態において、カラム内に保持され得る。
用語「含む(comprising)」は、「含む(including)」および「から成る」を包含する。例えば、Xを「含む」組成物は、Xのみから成るか、またはさらに別のものを含むことがあり、例えばX+Yが挙げられる。
本発明人は、細胞を分泌する抗体を含む基準の方法(Pittenger et al.,1999 Science 284:143−147;Bieback et al,2004 Stem cells 22:625−634;Dominici et al,2006,Cytotherapy 8:315−317;Sotiropoulou et al 2006,Stem Cells 24:462−471)に従って通常の骨髄から確率されたヒト間葉系間質細胞の初代培養物を観察した。これらの細胞を、ELISPOTによって検出し、また形質細胞として同定した。間葉系間質細胞培養物中における形質細胞は、インビトロで3週間後も検出可能であった(データ示さず)。
産生された抗体が培養時間の関数として累算し得るように個々の形質細胞を生存させ続けることができる培養システムを発達させるために、本発明人は、基準の方法に従って調製された初代間葉系間質細胞の異なる発生源を試験した。簡潔に言えば、組織培養フラスコをあらかじめ1時間、FCSでコーティングした。骨髄細胞を、30%FCSおよび10−8Mデキサメタゾンを追加された完全IMDM培地において、一晩接着させた。非接着細胞を洗い流し、また接着細胞を完全DMEM−10%FCS中で培養した。7株のうち3株はヒト形質細胞の指示された生存を試験したが、数回の継代の後で増殖が止まった。その後の実施形態において、テロメラーゼ逆転写酵素遺伝子と共に形質転換によって不死化された間葉系間質細胞(MSC−TERT)を使用した。これらの細胞はMihara et alによって単離されたものである(Br J Haematol 2003,120,846−849)。
末梢血液または骨髄からの形質細胞は、抗PE微粒子および細胞分類に続いて、PE共役抗CD138抗体を用いて単離し、また間葉系間質細胞単層上に96ウェルプレート内で0.5細胞/ウェルで播種した。培養物を含むIgGは、標準の試料によって22〜23日間観察した。培地を16日目に変更した。モノクローナル培養物中でのIgG産生物の率は、培養の全期間にわたって72〜134pg/細胞/日の率であり定数だった。(図2a、生成した末梢血液(4培養);図2b、生成した骨髄(5培養))。
IgG、IgA、IgMおよびIgEを産生する末梢血液CD138陽性細胞を、健康なドナーから単離し、617同型培養物において、間葉系間質細胞単層を含む384ウェルプレート内で5細胞/ウェルで平板した。10日目の培養上清を、アイソタイプ特定ELISAを用いて、IgG、IgA、IgMおよびIgEの存在を試験した。4つのアイソタイプの合計量を、培養上清内で測定した(図3に示す)。IgG、IgA、IgMおよびIgE形質細胞の産生力の中央値は、10日間で860、770、1100および1800pgであって、すなわちそれぞれ86、77、110および180pg/細胞/日であった。
ヒト形質細胞を生成した末梢血液を、CD138発現に従って7人のドナーから単離し、1または25細胞/ウェルで播種した。培養の初期に細胞を分泌するIgG、IgA、IgM抗体の数は、アイソタイプ特定ELISPOTによって算出した。平板効率を、ポアソン分布分析に従って細胞を分泌するIgG、IgA、IgM抗体を基に算出し、IgGは50%〜74%、IgAは31%〜78%およびIgMは0%〜26%の間で変動した(図4に示す)。加えて、多クローン性培養物から回収された形質細胞は、Ig分泌の一定の率を維持する単細胞培養物中において再度プレーティングされ得る(図示せず)。
形質細胞を、アレルギー患者の末梢血液から単離し、10個の384ウェルマイクロプレート内で、hMSC−TERT単層上で1細胞/ウェルで平板した。5つの培養上清は、IgE生成物を陽性とした。IgE陽性培養物は、RT−PCRを受け、2対のVH/VL遺伝子を回収し、配列した(表1)。V遺伝子は、Wardemann et al.,(Science301,1374−1377,2003)に説明される方法に従って、軽鎖またはヒトIgG1もしくはIgEの重鎖の発現のため、発現ベクターにクローン化した。IgGまたはIgE抗体を293T細胞の一過性導入によって産生した。この実施例は希少な形質細胞を回収するため、および代表のIgEモノクローナル抗体を単離するための可能性を示す。
形質細胞を、破傷風トキソイド(TT)と共に追加免疫ワクチンの7日後のドナーの末梢血液から単離し、また384ウェルマイクロプレート内で、MSC−TERT単層上で、クローン状態で播種した。10日目の培養上清を、TT特定IgG抗体(OD405)およびTT特定抗体を産生するモノクローナル培養物を同定したのと同様に、合計IgG(ng/培養物)が存在するか分析した(図5に示す)。この実施例は追加免疫付与に続いて抗原特異的な形質細胞の多数を同定する可能性を示す。
季節性インフルエンザワクチンで7日前に免疫を与えられたドナーからのCD138陽性細胞を、10ng/mlIL−6の存在下、0.5細胞/ウェルで、16の384細胞/ウェルに播種した。6日および8日目の培養上清を、3回のパラレルELISAにおいて、抗原として組換え型H5またはH9バキュロウイルス由来組換え血球凝集素(HA)および無関連破傷風トキソイド(TT)を用いて試験した。スクリーンされた4,928の培養上清のうち、12個がH5HAに結合し、25個がH9HAに結合し、54個がH5およびH9に結合した。最も高い過剰摂取の合図があった後半の幾つかは、RT−PCRを受け、2対のVH/VL遺伝子は回収された。2つのモノクローナル抗体、FI6およびFI28はV、DおよびJ遺伝子断片(IGHV3−30*01、IGHD3−9*01、IGHJ4*02およびIGKV4−1*01)を共有したが、N領域、IGKJ使用量、体細胞変異のパターンにおいて一致しなかった。したがってそれらは、クローン的に関係していなかった。
CD138+HLA−DR+CD62L+形質細胞を、破傷風トキソイド(TT)ワクチンを受けたドナーの10年後の末梢血液から細胞分類によって単離した。合計1,700個の細胞を、384ウェルマイクロプレート内で、0.5細胞/ウェルで播種し、また細胞培養上清は破傷風トキソイド特定IgG抗体の存在を確認するため、ELISAによって7日目にスクリーンした。1つの破傷風トキソイド特定培養物を同定し、8日目には、VH/VL遺伝子はRT−PCRによって回収し、配列した(表5に示す)。遺伝子を発現ベクターにクローン化し、組換え抗体(TT14)を293T細胞の一時的トランスフェクションによって産生した。抗体は、ELISA法によって破傷風トキソイドまたは無関連の抗原(陰性制御)へ結合するために異なる濃度で試験した(図6に示す)。
Claims (8)
- 抗体または抗体断片を産生する方法であって、
a. IL−6または間葉系間質細胞の存在下において、限られた数の形質細胞を培養すること、およびそれから抗体を採取するステップと、ここで、培養される形質細胞の数が10個以下である、
b. 所望の特性を有する抗体を産生する培養物を同定するステップと、
c. 前記抗体をコードする核酸を単離するステップと、
d. 宿主細胞内で前記核酸を発現させるステップと、
を含む、方法。 - モノクローナル抗体または抗体断片を産生する方法であって、
a. IL−6または間葉系間質細胞の存在下において、単細胞培養で形質細胞を培養すること、およびそれから抗体を採取するステップと、
b. 所望の特性を有する抗体を産生する培養物を同定するステップと、
c. 前記抗体をコードする核酸を単離するステップと、
d. 宿主細胞内で前記核酸を発現させるステップと、
を含む、方法。 - 前記抗体がヒト抗体であり、前記形質細胞がヒト形質細胞である、請求項1または2に記載の方法。
- 前記形質細胞が、前記抗体が前記抗体の特徴付けに必要とされる数量で産生されるために十分な時間、形質細胞の生存を延長させるIL−6または間葉系間質細胞を含む培養培地中で培養される、請求項1〜3のいずれか一項に記載の方法。
- 前記形質細胞の前記生存が、短期間延長され、前記短期間が5日〜7日である、請求項4に記載の方法。
- 前記形質細胞の前記生存が、長期間延長され、前記長期間が少なくとも10日である、請求項4に記載の方法。
- 前記形質細胞の前記生存が少なくとも20日間または少なくとも30日間延長される、請求項4または6に記載の方法。
- さらに前記抗体または抗体断片の特徴付けを含む請求項1〜7のいずれか一項に記載の方法であって、ここで、前記抗体または抗体断片の特徴付けは、前記抗体または抗体断片の機能を判別するための機能検定、前記抗体もしくは抗体断片または前記抗体もしくは抗体断片によって認識されるエピトープの結合特異性を判別するための結合検定、および/または毒素もしくは病原体を中和する前記抗体もしくは抗体断片の能力を判別するための中和検定を行うことを含む、方法。
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EP2522678A1 (en) | 2006-05-15 | 2012-11-14 | Sea Lane Biotechnologies, LLC | Neutralizing antibodies to influenza viruses |
US8192927B2 (en) | 2006-09-07 | 2012-06-05 | Crucell Holland B.V. | Human bind molecules capable of neutralizing influenza virus h5n1 and uses thereof |
EP2094307A4 (en) | 2006-11-08 | 2015-08-26 | Macrogenics West Inc | TES7 AND THEREO BINDING ANTIBODIES |
CN102046654A (zh) | 2007-03-13 | 2011-05-04 | 胡马斯有限公司 | 针对甲型流感病毒h5n1株系的抗体 |
US8524656B2 (en) * | 2008-07-08 | 2013-09-03 | Jacques Galipeau | GM-CSF and truncated CCL2 conjugates and methods and uses thereof |
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WO2010046775A3 (en) | 2010-06-17 |
BRPI0914092A2 (pt) | 2015-10-27 |
EA024586B1 (ru) | 2016-10-31 |
ES2525346T3 (es) | 2014-12-22 |
DK2350128T3 (da) | 2014-12-01 |
IL212121A0 (en) | 2011-06-30 |
CL2011000797A1 (es) | 2012-03-16 |
CN102282170A (zh) | 2011-12-14 |
KR101606608B1 (ko) | 2016-03-25 |
NZ592036A (en) | 2012-12-21 |
EP2350128A2 (en) | 2011-08-03 |
US9347043B2 (en) | 2016-05-24 |
US20100145031A1 (en) | 2010-06-10 |
EP2848630A1 (en) | 2015-03-18 |
KR20110073506A (ko) | 2011-06-29 |
CA2740138A1 (en) | 2010-04-29 |
CN102282170B (zh) | 2015-04-08 |
AU2009306010B2 (en) | 2015-12-24 |
PL2350128T3 (pl) | 2015-03-31 |
WO2010046775A2 (en) | 2010-04-29 |
CA2740138C (en) | 2017-01-10 |
JP2012506251A (ja) | 2012-03-15 |
EP2350128B1 (en) | 2014-10-01 |
EA201100668A1 (ru) | 2012-06-29 |
AU2009306010A1 (en) | 2010-04-29 |
IL212121A (en) | 2016-03-31 |
BRPI0914092B1 (pt) | 2021-08-31 |
ZA201102387B (en) | 2012-09-26 |
MX2011003855A (es) | 2011-12-16 |
HK1164899A1 (en) | 2012-09-28 |
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