JPWO2005056603A1 - 細胞死誘導剤 - Google Patents
細胞死誘導剤 Download PDFInfo
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- JPWO2005056603A1 JPWO2005056603A1 JP2005516197A JP2005516197A JPWO2005056603A1 JP WO2005056603 A1 JPWO2005056603 A1 JP WO2005056603A1 JP 2005516197 A JP2005516197 A JP 2005516197A JP 2005516197 A JP2005516197 A JP 2005516197A JP WO2005056603 A1 JPWO2005056603 A1 JP WO2005056603A1
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Abstract
Description
Fayen et al.,Int.Immunol 10:1347−1358(1998) Genestier et al.,Blood 90:3629−3639(1997) Genestier et al.,Blood 90:726−735(1997) Genestier et al.,J.Biol.Chem.273:5060−5066(1998) Woodle et al.,J.Immunol.158:2156−2164(1997) Matsuoka et al.,J.Exp.Med.181:2007−2015(1995) Goto,et al.Blood 84:1922(1994)
〔1〕2つの重鎖可変領域及び2つの軽鎖可変領域を含み、ヒト白血球抗原(HLA)への結合活性を有する一本鎖ポリペプチドであることを特徴とする抗体。
〔2〕2つの重鎖可変領域及び2つの軽鎖可変領域が、一本鎖ポリペプチドのN末端側を基点として重鎖可変領域、軽鎖可変領域、重鎖可変領域、軽鎖可変領域の順に並んでいることを特徴とする、〔1〕に記載の抗体。
〔3〕2つの重鎖可変領域及び2つの軽鎖可変領域がリンカーで結合されていることを特徴とする、〔1〕または〔2〕に記載の抗体。
〔4〕リンカーが15アミノ酸であることを特徴とする、〔3〕に記載の抗体。
〔5〕HLAがHLA class Iである、〔1〕〜〔4〕のいずれかに記載の抗体。
〔6〕HLA class IがHLA−Aである、〔5〕に記載の抗体。
〔7〕sc(Fv)2である〔1〕〜〔6〕のいずれかに記載の抗体。
〔8〕配列番号:3、4、5に記載のアミノ酸配列からなるCDR1、2、3を有する重鎖可変領域を含むsc(Fv)2。
〔9〕配列番号:6、7、8に記載のアミノ酸配列からなるCDR1、2、3を有する軽鎖可変領域を含むsc(Fv)2。
〔10〕配列番号:3、4、5に記載のアミノ酸配列からなるCDR1、2、3を有する重鎖可変領域および配列番号:6、7、8に記載のアミノ酸配列からなるCDR1、2、3を有する軽鎖可変領域を含むsc(Fv)2。
〔11〕配列番号:10に記載のアミノ酸配列を有する重鎖可変領域を含むsc(Fv)2。
〔12〕配列番号:12に記載のアミノ酸配列を有する軽鎖可変領域を含むsc(Fv)2。
〔13〕配列番号:10に記載のアミノ酸配列を有する重鎖可変領域および配列番号:12に記載のアミノ酸配列を有する軽鎖可変領域を含むsc(Fv)2。
〔14〕配列番号:14に記載のアミノ酸配列を有するsc(Fv)2。
〔15〕配列番号:2に記載のアミノ酸配列を有するsc(Fv)2。
〔16〕〔8〕〜〔15〕のいずれかに記載のアミノ酸配列において1又は複数のアミノ酸が置換、欠失、付加および/または挿入され、かつ〔8〕〜〔15〕のいずれかに記載の抗体と同等の活性を有するsc(Fv)2。
〔17〕〔1〕〜〔16〕のいずれかに記載の抗体をコードするポリヌクレオチド。
〔18〕〔17〕に記載のポリヌクレオチドとストリンジェントな条件下でハイブリダイズし、かつ〔1〕〜〔16〕のいずれかに記載の抗体と同等の活性を有する抗体をコードするポリヌクレオチド。
〔19〕〔17〕または〔18〕に記載のポリヌクレオチドを含むベクター。
〔20〕〔17〕または〔18〕に記載のポリヌクレオチドまたは〔19〕に記載のベクターを保持する宿主細胞。
〔21〕以下の工程を含む〔1〕〜〔16〕のいずれかに記載の抗体を作製する方法。
(a)HLAを認識する抗体を調製する工程
(b)(a)で調製した抗体の配列を基に、〔1〕〜〔16〕のいずれかに記載の抗体をコードするポリヌクレオチドを作製する工程
(c)(b)のポリヌクレオチドを含むベクターを作製する工程
(d)(c)のベクターを宿主細胞に導入する工程
(e)(d)の宿主細胞を培養する工程
〔22〕〔1〕〜〔16〕のいずれかに記載の抗体を有効成分として含有する、細胞死誘導剤。
〔23〕B細胞又はT細胞に対する細胞死誘導であることを特徴とする、〔22〕に記載の細胞死誘導剤。
〔24〕B細胞又はT細胞が、活性化B細胞又は活性化T細胞である、〔23〕に記載の細胞死誘導剤。
〔25〕〔1〕〜〔16〕のいずれかに記載の抗体を有効成分として含有する、細胞増殖抑制剤。
〔26〕〔1〕〜〔16〕のいずれかに記載の抗体を有効成分として含有する、抗腫瘍剤。
〔27〕腫瘍が血液腫瘍である〔26〕に記載の抗腫瘍剤。
〔28〕〔1〕〜〔16〕のいずれかに記載の抗体を有効成分として含有する、自己免疫疾患治療剤。
[VH]リンカー[VL]リンカー[VH]リンカー[VL]
[VL]リンカー[VH]リンカー[VH]リンカー[VL]
[VH]リンカー[VL]リンカー[VL]リンカー[VH]
[VH]リンカー[VH]リンカー[VL]リンカー[VL]
[VL]リンカー[VL]リンカー[VH]リンカー[VH]
[VL]リンカー[VH]リンカー[VL]リンカー[VH]
本発明においては、好ましくは、[VH]リンカー[VL]リンカー[VH]リンカー[VL]の配置を有するsc(Fv)2である。
Ser
Gly・Ser
Gly・Gly・Ser
Ser・Gly・Gly
Gly・Gly・Gly・Ser
Ser・Gly・Gly・Gly
Gly・Gly・Gly・Gly・Ser
Ser・Gly・Gly・Gly・Gly
Gly・Gly・Gly・Gly・Gly・Ser
Ser・Gly・Gly・Gly・Gly・Gly
Gly・Gly・Gly・Gly・Gly・Gly・Ser
Ser・Gly・Gly・Gly・Gly・Gly・Gly
(Gly・Gly・Gly・Gly・Ser)n
(Ser・Gly・Gly・Gly・Gly)n
[nは1以上の整数である]等を挙げることができる。
(a)配列番号:3、4、5に記載のアミノ酸配列からなるCDR1、2、3を有する重鎖可変領域を含むsc(Fv)2。
(b)配列番号:6、7、8に記載のアミノ酸配列からなるCDR1、2、3を有する軽鎖可変領域を含むsc(Fv)2。
(c)配列番号:3、4、5に記載のアミノ酸配列からなるCDR1、2、3を有する重鎖可変領域および配列番号:6、7、8に記載のアミノ酸配列からなるCDR1、2、3を有する軽鎖可変領域を含むsc(Fv)2。
(d)配列番号:10に記載のアミノ酸配列を有する重鎖可変領域を含むsc(Fv)2。
(e)配列番号:12に記載のアミノ酸配列を有する軽鎖可変領域を含むsc(Fv)2。
(f)配列番号:10に記載のアミノ酸配列を有する重鎖可変領域および配列番号:12に記載のアミノ酸配列を有する軽鎖可変領域を含むsc(Fv)2。
(g)配列番号:14に記載のアミノ酸配列を有するsc(Fv)2。
(h)配列番号:2に記載のアミノ酸配列を有するsc(Fv)2。
(i)(a)〜(h)のいずれかに記載のアミノ酸配列において1又は複数のアミノ酸が置換、欠失、付加および/または挿入され、かつ本発明の抗体と同等の活性を有するsc(Fv)2。
さらに本発明は、本発明の抗体を用いることにより、細胞の細胞死を誘導する方法に関する。具体的には、本発明の抗体を細胞に接触させることにより、該細胞に細胞死を誘導する方法に関する。
なお本明細書において引用された全ての先行技術文献は、参照として本明細書に組み入れられる。
〔実施例1〕2D7sc(Fv)2型DIABODY発現ベクターの作製
WO2004/033499に記載した通り、HLAクラスIに対する抗体2D7モノクローナル抗体を、重鎖および軽鎖可変領域を5merのリンカーで接続した低分子抗体(2D7diabody)(図1A)に改変することにより、ミエローマ細胞に対する細胞死誘導活性が劇的に上昇したことを既に示した。そこで、この2D7diabodyを、構造的により安定であると考えられるsc(Fv)2型(図1B)に改変し、細胞死誘導活性を従来型diabody(HL5)と比較検討した。
PvuIで切断し直鎖化したpCXND3−2D7sc(Fv)2 20μgをCHO細胞(DG44株)に以下のようにelectroporation法により導入した。
T−125フラスコでサブコンフルエントの2D7sc(Fv)2高産生CHO細胞株を1X105/mlになるようにローラーボトル(CHO−S−SFM II培地250ml/ボトル)に移した。37℃で培養し、6日後に培養液を回収した。遠心によって死細胞を除去した後、0.45μmフィルターを通してこれを精製に用いた。
まず、buffer A(20mM Na−phosphate pH6.8)で平衡化したHydroxyapatiteカラム(micro prep ceramic Hydroxyapatite type I,Bio−Rad)に回収した培養上清をapplyした。buffer Aでカラムを洗浄した後、buffer C(250mM Na−phosphate pH6.8)で2D7sc(Fv)2を溶出した。2D7sc(Fv)2を含むフラクションを等量のbuffer Aで希釈した後、これをAnti−Flag M2アガロースアフィニティカラム(Bio−Rad)にapplyした。このカラムをbuffer C(50mM Tris−HCl pH7.4,150mM NaCl,0.01%Tween20)で洗浄した後、buffer D(100mM Glycine H3.5,0.01%Tween20)で2D7sc(Fv)2を溶出した。回収したサンプルは直ちに終濃度25mMになるようにTris−HCl pH8.0で中和した。その後、このフラクションを、セントリプレップYM−10(AMICON)で濃縮し、Superdex200HR(26/60)カラム(アマシャムファルマシア)によるゲルろ過クロマトグラム精製に使用した。
0.01%Tween20を含むPBSでゲルろ過クロマトグラム精製を行い、サンプル溶出時のチャートを図3に示した。2D7sc(Fv)2高産生CHO細胞株より産生された低分子化抗体は、そのほとんどが分子量約52Kdの位置に溶出ピークを有し(図3(1)参照)、同じく52Kdで溶出される2D7diabodyのピークと完全に一致した(図3(2)参照)。このことから本発明で構築した2D7sc(Fv)2は、当初の目的どおり図1Bに示す構造(1本鎖抗体が分子内で折れ曲がることで形成されるsc(Fv)2構造)を形成していると考えられた。
ゲルろ過クロマトグラム精製により分離された52Kdのピークのみを回収し、これを2D7sc(Fv)2蛋白標品とした。回収したサンプルの一部をSDS電気泳動および銀染色を行うことで、目的の蛋白が100%の純度で精製されていることを確認した。回収した精製標品はセントリプレップYM−10(AMICON)で濃縮し、2D7sc(Fv)2精製標品として以下の実験に使用した。
ヒト骨髄腫細胞株ARH77細胞を、10%FCSを含むRPMI1640培地(インビトロジェン)で1X105cells/wellになるように24well plateに細胞を撒いた。これに、精製した2D7sc(Fv)2を終濃度100ng/ml、及び、250ng/mlになるように添加した。また比較検体として、精製した2D7diabody(HL5)を別のwellに同一条件で添加した。37℃で3時間培養後、各細胞を回収し、PI溶液(5μg/ml PI,2%FCS/PBS)に細胞を懸濁した。遮光して室温で15分インキュベートした後、flow cytometoryを用いてPIで染色された死細胞の割合を測定した(EPICS ELITE,COULTER)。
ヒトEBV−transformed B細胞株IM9細胞(ATCC)を3X103cells/wellで、またヒトバーキットリンパ腫由来細胞株HS−Sultan細胞を1X104cells/wellになるように10%FCSを含むRPMI1640培地で希釈し、96well plateに撒いた。これに、精製した2D7sc(Fv)2、および、2D7diabody(HL5)を終濃度0、0.0032、0.016、0.08、0.4、2μg/mlになるように添加し、37℃で培養した。3日間培養後、細胞数測定WST−8キット(同仁化学)を用いて生細胞数を測定した。
生細胞数の割合(%)=(抗体存在下で培養した生細胞数)/(抗体非添加で培養した生細胞数)で算出し、これに100を乗じ縦軸に示した(図5)。
その結果、2D7sc(Fv)2は濃度依存的にIM9細胞、および、HS−Sultan細胞の増殖を阻害し、2D7diabodyと同等の細胞増殖抑制活性を持つことがわかった。
丸底ポリエチレンチューブの底の部分を約1cmの深さに切り取り、この底の部分に250mmol/L NaCl及びTween20 0.05vol%含有20mmol/Lリン酸緩衝液(pH7.0)、Na125I溶液及び2D7sc(Fv)2または2D7diabody(HL5)溶液を添加した。0.15mol/L NaCl溶液を染み込ませ乾燥させたろ紙(5×5mm)をカバーガラス上にのせ、ろ紙に32mg/mL Chloramine T溶液を染み込ませ、ろ紙が内側になるようにカバーガラスを反応チューブの上にかぶせた。
反応液にTween20 0.05vol%含有PBS(−)を添加後、反応液をTween20 0.05vol%含有PBS(−)で平衡化したPD−10column(アマシャムファルマシア)にのせ、Tween20 0.05vol%含有PBS(−)にて溶出させ未反応の125Iを除去した。さらに、Superdex200 10/300GLカラム(アマシャムファルマシア)によりゲルろ過精製し、放射性ヨード標識2D7sc(Fv)2および放射性ヨード標識2D7diabody(HL5)を調製した。
雄性マウス(C.B−17/Icr Scid Jcl、日本クレア)に放射性標識2D7sc(Fv)2および放射性標識2D7diabody(HL5)を1mg/5 MBq/kgで単回尾静脈内投与した。投与15、30分、1、2、4、8、24時間後にエーテル麻酔下マウスを開腹し、心臓よりヘパリン処理した25G注射針付テルモシリンジを用いて採血した。採取した血液は直ちに4℃、12,000rpmで5分間遠心し、血漿を分離した。
血漿試料の放射能をγ−カウンターにて測定した。また、投与液の放射能を同時に測定し、投与液中の放射性標識被験物質の比放射能を算出し、それを基に血漿中総放射能濃度を算出した。放射能測定後、血漿試料に精製水およびTCA25w/v%溶液を加え、攪拌後、4℃で3000rpm、10分間遠心分離した。上清をアスピレーターで吸引後、沈殿物の放射能を測定した。総放射能に対する沈殿物の放射能の割合を血漿中総放射能濃度に乗じて血漿中TCA沈殿画分放射能濃度を算出した。
Claims (28)
- 2つの重鎖可変領域及び2つの軽鎖可変領域を含み、ヒト白血球抗原(HLA)への結合活性を有する一本鎖ポリペプチドであることを特徴とする抗体。
- 2つの重鎖可変領域及び2つの軽鎖可変領域が、一本鎖ポリペプチドのN末端側を基点として重鎖可変領域、軽鎖可変領域、重鎖可変領域、軽鎖可変領域の順に並んでいることを特徴とする、請求項1に記載の抗体。
- 2つの重鎖可変領域及び2つの軽鎖可変領域がリンカーで結合されていることを特徴とする、請求項1または2に記載の抗体。
- リンカーが15アミノ酸であることを特徴とする、請求項3に記載の抗体。
- HLAがHLA class Iである、請求項1〜4のいずれかに記載の抗体。
- HLA class IがHLA−Aである、請求項5に記載の抗体。
- sc(Fv)2である請求項1〜6のいずれかに記載の抗体。
- 配列番号:3、4、5に記載のアミノ酸配列からなるCDR1、2、3を有する重鎖可変領域を含むsc(Fv)2。
- 配列番号:6、7、8に記載のアミノ酸配列からなるCDR1、2、3を有する軽鎖可変領域を含むsc(Fv)2。
- 配列番号:3、4、5に記載のアミノ酸配列からなるCDR1、2、3を有する重鎖可変領域および配列番号:6、7、8に記載のアミノ酸配列からなるCDR1、2、3を有する軽鎖可変領域を含むsc(Fv)2。
- 配列番号:10に記載のアミノ酸配列を有する重鎖可変領域を含むsc(Fv)2。
- 配列番号:12に記載のアミノ酸配列を有する軽鎖可変領域を含むsc(Fv)2。
- 配列番号:10に記載のアミノ酸配列を有する重鎖可変領域および配列番号:12に記載のアミノ酸配列を有する軽鎖可変領域を含むsc(Fv)2。
- 配列番号:14に記載のアミノ酸配列を有するsc(Fv)2。
- 配列番号:2に記載のアミノ酸配列を有するsc(Fv)2。
- 請求項8〜15のいずれかに記載のアミノ酸配列において1又は複数のアミノ酸が置換、欠失、付加および/または挿入され、かつ請求項8〜15のいずれかに記載の抗体と同等の活性を有するsc(Fv)2。
- 請求項1〜16のいずれかに記載の抗体をコードするポリヌクレオチド。
- 請求項17に記載のポリヌクレオチドとストリンジェントな条件下でハイブリダイズし、かつ請求項1〜16のいずれかに記載の抗体と同等の活性を有する抗体をコードするポリヌクレオチド。
- 請求項17または18に記載のポリヌクレオチドを含むベクター。
- 請求項17または18に記載のポリヌクレオチドまたは請求項19に記載のベクターを保持する宿主細胞。
- 以下の工程を含む請求項1〜16のいずれかに記載の抗体を作製する方法。
(a)HLAを認識する抗体を調製する工程
(b)(a)で調製した抗体の配列を基に、請求項1〜16のいずれかに記載の抗体をコードするポリヌクレオチドを作製する工程
(c)(b)のポリヌクレオチドを含むベクターを作製する工程
(d)(c)のベクターを宿主細胞に導入する工程
(e)(d)の宿主細胞を培養する工程 - 請求項1〜16のいずれかに記載の抗体を有効成分として含有する、細胞死誘導剤。
- B細胞又はT細胞に対する細胞死誘導であることを特徴とする、請求項22に記載の細胞死誘導剤。
- B細胞又はT細胞が、活性化B細胞又は活性化T細胞である、請求項23に記載の細胞死誘導剤。
- 請求項1〜16のいずれかに記載の抗体を有効成分として含有する、細胞増殖抑制剤。
- 請求項1〜16のいずれかに記載の抗体を有効成分として含有する、抗腫瘍剤。
- 腫瘍が血液腫瘍である請求項26に記載の抗腫瘍剤。
- 請求項1〜16のいずれかに記載の抗体を有効成分として含有する、自己免疫疾患治療剤。
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JP2005516197A JP4767016B2 (ja) | 2003-12-12 | 2004-12-10 | 細胞死誘導剤 |
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US (1) | US20070280951A1 (ja) |
EP (1) | EP1712565A4 (ja) |
JP (1) | JP4767016B2 (ja) |
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AU (1) | AU2004297109A1 (ja) |
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EP1712565A4 (en) | 2009-03-11 |
KR20060130606A (ko) | 2006-12-19 |
WO2005056603A1 (ja) | 2005-06-23 |
EP1712565A1 (en) | 2006-10-18 |
US20070280951A1 (en) | 2007-12-06 |
JP4767016B2 (ja) | 2011-09-07 |
AU2004297109A1 (en) | 2005-06-23 |
CA2548929A1 (en) | 2005-06-23 |
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