JP2021035990A - 1段階の工程によるマイタンシノイド−抗体複合体の調製 - Google Patents
1段階の工程によるマイタンシノイド−抗体複合体の調製 Download PDFInfo
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Abstract
【解決手段】本発明は、細胞結合物質−細胞毒性物質複合体を調製する1段階の工程を提供し、この工程は、細胞結合物質を細胞毒性物質と接触させて、細胞結合物質と細胞毒性物質とを含む第一の混合物を形成し、細胞結合物質と細胞毒性物質とを含む第一の混合物を、pHが約4〜約9の溶液中でリンカーを与える二官能性架橋試薬と接触させて、細胞結合物質がリンカーを介して細胞毒性物質と化学的に結合している細胞結合物質−細胞毒性物質複合体と、遊離の細胞毒性物質と、反応副生成物とを含む第二の混合物を得ることを含む。次いで、任意選択で、第二の混合物を精製に供して、精製された細胞結合物質−細胞毒性物質複合体を得る。
【選択図】なし
Description
本出願は、2011年3月29日に出願された米国特許仮出願第61/468,997号の利益を主張するものであり、上記出願は参照により本明細書に組み込まれるものとする。
(電子提出された物件の参照による援用)
以下:
9,233バイトのASCII(テキスト)ファイル1件(名称「710088SequenceListing.TXT」、2013年4月3日作成)、
と特定される、コンピューターで可読なヌクレオチド/アミノ酸の配列表が、本明細書中、参照によりその全体が援用される。
物質を細胞結合物質と接触させて、細胞結合物質と細胞毒性物質とを含む混合物を形成した後に、混合物を二官能性架橋試薬と接触させることが不可欠である。
階a)の一定時間後(例えば、約1時間、約2時間、約3時間またはそれ以上後)に行う。別の実施形態では、段階c)を行う前に段階b)を複数回(例えば、1、2、3、4回またはそれ以上)繰り返してもよい。追加の段階b)は最初の段階b)の一定時間後(例えば、約1時間、約2時間、約3時間または後)に行ってもよい。
または約25℃)で行う。
抑えるものでもある。極性のある荷電チオール反応停止試薬(4−マレイミド酪酸または3−マレイミドプロピオン酸など)による反応停止の際には、過剰な未反応の細胞毒性物質が、精製段階で共有結合した複合体から容易に分離することが可能な極性のある荷電水溶性付加物に変換される。このほか非極性および中性のチオール反応停止試薬を使用することができる。
最初に選択的沈殿、吸着ろ過、吸着クロマトグラフィーまたは非吸着クロマトグラフィーにより複合体を精製し、次いでTFFにより精製する。当業者は、細胞結合物質−細胞毒性物質複合体の精製により、細胞毒性物質と化学的に結合した細胞結合物質を含む安定な複合体の単離が可能であることを理解するであろう。
、室温(例えば、約20℃〜約30℃または約20℃〜約25℃)または高温(例えば、約30℃〜約37℃)に維持することを含む。一実施形態では、保持段階は、溶液を約16℃〜約24℃の温度(例えば、約15℃、約16℃、約17℃、約18℃、約19℃、約20℃、約21℃、約22℃、約23℃、約24℃または約25℃)に維持することを含む。別の実施形態では、保持段階は、溶液を約2℃〜約8℃の温度(例えば、約0℃、約1℃、約2℃、約3℃、約4℃、約5℃、約6℃、約7℃、約8℃、約9℃または約10℃)に維持することを含む。別の実施形態では、保持段階は、溶液を約37℃の温度(例えば、約34℃、約35℃、約36℃、約37℃、約38℃、約39℃または約40℃)に維持することを含む。
以下、6%以下、5%以下、4%以下、3%以下、2%以下、1%以下または0%)である(総リンカーに対して)、(c)複合体種の10%未満(例えば、約9%以下、8%以下、7%以下、6%以下、5%以下、4%以下、3%以下、2%以下、1%以下または0%)が架橋されている、(d)複合体調製物中の遊離の細胞毒性物質レベルが約2%未満(例えば、約1.5%以下、1.4%以下、1.3%以下、1.2%以下、1.1%以下、1.0%以下、0.9%以下、0.8%以下、0.7%以下、0.6%以下、0.5%以下、0.4%以下、0.3%以下、0.2%以下、0.1%以下または0%)(総細胞毒性物質に対するmol/mol)であるおよび/または(e)保管時(例えば、約1週間後、約2週間後、約3週間後、約1か月後、約2か月後、約3か月後、約4か月後、約5か月後、約6か月後、約1年後、約2年後、約3年後、約4年後または約5年後)に遊離の細胞毒性物質レベルの実質的な増加がみられない。遊離の細胞毒性物質レベルの「実質的な増加」は、特定の保管期間(例えば、約1週間、約2週間、約3週間、約1か月、約2か月、約3か月、約4か月、約5か月、約6か月、約1年、約2年、約3年、約4年または約5年)の後に遊離の細胞毒性物質レベルの増加が約0.1%未満、約0.2%未満、約0.3%未満、約0.4%未満、約0.5%未満、約0.6%未満、約0.7%未満、約0.8%未満、約0.9%未満、約1.0%未満、約1.1%未満、約1.2%未満、約1.3%未満、約1.4%未満、約1.5%未満、約1.6%未満、約1.7%未満、約1.8%未満、約1.9%未満、約2.0%未満、約2.2%未満、約2.5%未満、約2.7%未満、約3.0%未満、約3.2%未満、約3.5%未満、約3.7%未満または約4.0%未満であることを意味する。
1984))など、栄養素輸送分子(例えば、トランスフェリン)、ビタミン(例えば、葉酸塩)ならびに細胞表面の標的分子と特異的に結合する他の任意の物質または分子が挙げられる。
GEP、PSMA、PSCA、TMEFF2およびSTEAP1など;LGR5、B7H4ならびに任意の上記ポリペプチドのフラグメントなどの分子が挙げられる。
としては、例えば、酵素結合免疫吸着測定法(ELISA)、ウエスタンブロット分析およびラジオイムノアッセイが挙げられる。ハイブリドーマの集団をスクリーニングして、それぞれが抗原に対する単一の抗体種を分泌する個々のクローンを単離する。各ハイブリドーマは単一のB細胞との融合に由来するクローンであるため、それが産生する抗体分子はすべて、その抗原結合部位およびアイソタイプを含めた構造が同一である。またモノクローナル抗体を、EBV−ハイブリドーマ技術(例えば、HaskardおよびArcher,J.Immunol.Methods,74(2):361−67(1984)ならびにRoderら,Methods Enzymol.,121:140−67(1986)を参照)、バクテリオファージベクター発現システム(例えば、Huseら,Science,246:1275−81(1989)を参照)またはFabおよびscFv(一本鎖可変領域)などの抗体フラグメントを含むファージディスプレイライブラリー(例えば、米国特許第5,885,793号および同第5,969,108号ならびに国際公開第92/01047号および同第99/06587号を参照)を含めた他の適切な技術を用いて作製してもよい。
ークとヒト抗体のフレームワークが類似していることから、この方法により、抗原性がヒト抗体と同一であるが、CDR配列が由来するマウスモノクローナル抗体と同じ抗原と結合するモノクローナル抗体が作製されることが当該技術分野において一般に認められている。ヒト化抗体を作製する方法は当該技術分野で公知であり、例えば、Janewayら(上記)、米国特許第5,225,539号、同第5,585,089号および同第5,693,761号、欧州特許第0239400B1号ならびに英国特許第2188638号に詳細に記載されている。また、米国特許第5,639,641号およびPedersenら,J.Mol.Biol.,235:959−973(1994)に記載されている抗体リサーフィシング(resurfacing)技術を用いてヒト化抗体を作製してもよい。本発明の組成物の複合体で使用する抗体は、最も好ましくはヒト化モノクローナル抗体であるが、上記のようなヒトモノクローナル抗体およびマウスモノクローナル抗体も本発明の範囲内にある。
(2004)を参照)などであってもよい。
願公開第2010/0111979号、同第2009/0240038号、同第2009/0175887号、同第2009/0156790号および同第2009/0155282号に記載されている。また米国特許第7,982,024号に記載されているようなインスリン様成長因子受容体と結合する抗IGF−IR抗体も複合体に使用することができる。またCD27L、Cripto、CD138、CD38、EphA2、インテグリン、CD37、葉酸塩、CD20、PSGR、NGEP、PSCA、TMEFF2、STEAP1、エンドグリンおよびHer3と結合する抗体も複合体に使用することができる。
1、RASNLEA(配列番号5)を含む軽鎖CDR2およびQQSREYPYT(配列番号6)を含む軽鎖CDR3とを含み、式中、Xaa1はK、Q、HおよびRから選択され、Xaa2はQ、H、NおよびRから選択され、Xaa3はG、E、T、S、AおよびVから選択される。好ましくは、重鎖CDR2配列はRIHPYDGDTFYNQKFQG(配列番号7)を含む。
QVQLVQSGAEVVKPGASVKISCKASGYTFTGYFMNWVKQSPGQSLEWIGRIHPYDGDTFYNQKFQGKATLTVDKSSNTAHMELLSLTSEDFAVYYCTRYDGSRAMDYWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(配列番号8)
を有する重鎖を含む。
QVQLVQSGAEVVKPGASVKISCKASGYTFTGYFMNWVKQSPGQSLEWIGRIHPYDGDTFYNQKFQGKATLTVDKSSNTAHMELLSLTSEDFAVYYCTRYDGSRAMDYWGQGTTVTVSS(配列番号9)
と少なくとも約90%、95%、99%または100%同一である重鎖可変ドメインと、DIVLTQSPLSLAVSLGQPAIISCKASQSVSFAGTSLMHWYHQKPGQQPRLLIYRASNLEAGVPDRFSGSGSKTDFTLNISPVEAEDAATYYCQQSREYPYTFGGGTKLEIKR(配列番号10);または
DIVLTQSPLSLAVSLGQPAIISCKASQSVSFAGTSLMHWYHQKPGQQPRLLIYRASNLEAGVPDRFSGSGSKTDFTLTISPVEAEDAATYYCQQSREYPYTFGGGTKLEIKR(配列番号11)と少なくとも約90%、95%、99%または100%同一である軽鎖可変ドメインとを含む、ヒト化抗体またはその抗原結合フラグメントである。
Today,5:155−158(1984)を参照)、ソマトスタチンおよびトランスフェリン(例えば、O’Keefeら,J.Biol.Chem.,260:932−
937(1985)を参照)が挙げられる。例えば、GM−CSFは骨髄性細胞と結合し、急性骨髄性白血病細胞を標的とする細胞結合物質として使用することができる。さらに、IL−2は活性化T細胞と結合し、移植片拒絶反応の予防、移植片対宿主病の治療および予防ならびに急性T細胞白血病の治療に使用することができる。上皮成長因子(EGF)は肺癌および頭頸部癌などの扁平上皮癌を標的とするのに使用することができる。ソマトスタチンは神経芽腫細胞その他の腫瘍細胞型を標的とするのに使用することができる。
個の炭素原子を有する環状アルキルもしくはアルケニル、フェニル、置換フェニルまたは複素環芳香族またはヘテロシクロアルキルラジカルであり、さらに、置換基の1つがHであってよく、アシル基が、カルボニル官能基と硫黄原子との間に少なくとも炭素原子3個の直鎖長を有するアシル化アミノ酸側鎖とを有する、マイタンシノイドである。
Y’は(CR7R8)l(CR9=CR10)p(C≡C)qAo(CR5R6)mDu(CR11=CR12)r(C≡C)sBt(CR3R4)nCR1R2SZを表し、式中、
R1およびR2は、それぞれ独立してCH3、C2H5、1〜10個の炭素原子を有する直鎖アルキルもしくはアルケニル、3〜10個の炭素原子を有する分岐もしくは環状のアルキルもしくはアルケニル、フェニル、置換フェニルまたは複素環芳香族またはヘテロシクロアルキルラジカルであり、R2はHであってもよく,
A、B、Dは、3〜10個の炭素原子を有するシクロアルキルもしくはシクロアルケニル、単純もしくは置換アリールまたは複素環芳香族またはヘテロシクロアルキルラジカルであり、
R3、R4、R5、R6、R7、R8、R9、R10、R11およびR12は、それぞれ独立してH、CH3、C2H5、1〜10個の炭素原子を有する直鎖アルキルもしくはアルケニル、3〜10個の炭素原子を有する分岐もしくは環状のアルキルもしくはアルケニル、フェニル、置換フェニルまたは複素環芳香族またはヘテロシクロアルキルラジカルであり、
l、m、n、o、p、q、r、sおよびtは、それぞれ独立してゼロまたは1〜5の整数であり、ただし、l、m、n、o、p、q、r、sおよびtのうちの少なくとも2つは同時にゼロになることがなく、
ZはH、SRまたはCORであり、式中、Rは1〜10個の炭素原子を有する直鎖アルキルもしくはアルケニル、3〜10個の炭素原子を有する分岐もしくは環状のアルキルもしくはアルケニルまたは単純もしくは置換アリールまたは複素環芳香族またはヘテロシクロアルキルラジカルである。
であり、R2がメチルであり、Zが−SCH3である、ならびに(d)R1およびR2がメチルであり、Zが−SCH3である、式(III)の化合物が挙げられる。
Yは(CR7R8)l(CR5R6)m(CR3R4)nCR1R2SZを表し、式中、
R1およびR2は、それぞれ独立してCH3、C2H5、1〜10個の炭素原子を有する直鎖アルキルもしくはアルケニル、3〜10個の炭素原子を有する分岐もしくは環状のアルキルもしくはアルケニル、フェニル、置換フェニルまたは複素環芳香族またはヘテロシクロアルキルラジカルであり、R2はHであってもよく、
R3、R4、R5、R6、R7およびR8は、それぞれ独立してH、CH3、C2H5、1〜10個の炭素原子を有する直鎖アルキルもしくはアルケニル、3〜10個の炭素原子を有する分岐もしくは環状のアルキルもしくはアルケニル、フェニル、置換フェニルまたは複素環芳香族またはヘテロシクロアルキルラジカルであり、
l、mおよびnは、それぞれ独立して1〜5の整数であり、さらにnはゼロであってもよく、
Zは、H、SRまたはCORであり、式中、Rは、1〜10個の炭素原子を有する直鎖もしくは分岐のアルキルもしくはアルケニル、3〜10個の炭素原子を有する環状アルキルもしくはアルケニルまたは単純もしくは置換アリールまたは複素環芳香族またはヘテロシクロアルキルラジカルであり、
Mayは、C−3、C−14ヒドロキシメチル、C−15ヒドロキシまたはC−20デスメチルに側鎖を有するマイタンシノイドを表す。
Yは(CR7R8)l(CR5R6)m(CR3R4)nCR1R2SZを表し、式中、
R1およびR2は、それぞれ独立してCH3、C2H5、1〜10個の炭素原子を有する直鎖アルキルもしくはアルケニル、3〜10個の炭素原子を有する分岐もしくは環状のアルキルもしくはアルケニル、フェニル、置換フェニルまたは複素環芳香族またはヘテロシクロアルキルラジカルであり、R2はHであってもよく、
R3、R4、R5、R6、R7およびR8は、それぞれ独立してH、CH3、C2H5、1〜10個の炭素原子を有する直鎖アルキルもしくはアルケニル、3〜10個の炭素原子を有する分岐もしくは環状のアルキルもしくはアルケニル、フェニル、置換フェニルまたは複素環芳香族またはヘテロシクロアルキルラジカルであり、
l、mおよびnは、それぞれ独立して1〜5の整数であり、さらにnはゼロであってもよく、
Zは、H、SRまたはCORであり、式中、Rは、1〜10個の炭素原子を有する直鎖アルキルもしくはアルケニル、3〜10個の炭素原子を有する分岐もしくは環状のアルキルもしくはアルケニルまたは単純もしくは置換アリールまたは複素環芳香族またはヘテロシクロアルキルラジカルである。
Y2は(CR7R8)l(CR5R6)m(CR3R4)nCR1R2SZ2を表し、式中、
R1およびR2は、それぞれ独立してCH3、C2H5、1〜10個の炭素原子を有する直鎖アルキルもしくはアルケニル、3〜10個の炭素原子を有する分岐もしくは環状のアルキルもしくはアルケニル、フェニル、置換フェニルまたは複素環芳香族またはヘテロシクロアルキルラジカルであり、R2はHであってもよく、
R3、R4、R5、R6、R7およびR8は、それぞれ独立してH、CH3、C2H5、1〜10個の炭素原子を有する直鎖環状アルキルもしくはアルケニル、3〜10個の炭素原子を有する分岐もしくは環状のアルキルもしくはアルケニル、フェニル、置換フェニルまたは複素環芳香族またはヘテロシクロアルキルラジカルであり、
l、mおよびnは、それぞれ独立して1〜5の整数であり、さらにnはゼロであってもよく、
Z2は、SRまたはCORであり、式中、Rは、1〜10個の炭素原子を有する直鎖アルキルもしくはアルケニル、3〜10個の炭素原子を有する分岐もしくは環状のアルキルもしくはアルケニル、または単純もしくは置換アリールまたは複素環芳香族またはヘテロシクロアルキルラジカルであり、
Mayは、マイタンシノイドの大環状構造である。
Y2’は(CR7R8)l(CR9=CR10)p(C≡C)qAo(CR5R6)mD
u(CR11=CR12)r(C≡C)sBt(CR3R4)nCR1R2SZ2を表し、式中、
R1およびR2は、それぞれ独立してCH3、C2H5、1〜10個の炭素原子を有する直鎖分岐もしくはアルキルもしくはアルケニル、3〜10個の炭素原子を有する環状アルキルもしくはアルケニル、フェニル、置換フェニルまたは複素環芳香族またはヘテロシクロアルキルラジカルであり、さらにR2はHであってもよく、
A、BおよびDは、それぞれ独立して3〜10個の炭素原子を有するシクロアルキルもしくはシクロアルケニル、単純もしくは置換アリールまたは複素環芳香族またはヘテロシクロアルキルラジカルであり、
R3、R4、R5、R6、R7、R8、R9、R10、R11およびR12は、それぞれ独立してH、CH3、C2H5、1〜10個の炭素原子を有する直鎖アルキルもしくはアルケニル、3〜10個の炭素原子を有する分岐もしくは環状のアルキルもしくはアルケニル、フェニル、置換フェニルまたは複素環芳香族またはヘテロシクロアルキルラジカルであり、
l、m、n、o、p、q、r、sおよびtは、それぞれ独立してゼロまたは1〜5の整数であり、ただし、l、m、n、o、p、q、r、sおよびtのうちの少なくとも2つは同時にゼロになることがなく、
Z2は、SRまたは−CORであり、式中、Rは、1〜10個の炭素原子を有する直鎖アルキルもしくはアルケニル、3〜10個の炭素原子を有する分岐もしくは環状のアルキルもしくはアルケニルまたは単純もしくは置換アリールまたは複素環芳香族またはヘテロシクロアルキルラジカルである。
物(例えば、米国特許第6,630,579号を参照)も細胞毒性物質として使用することができる。
IAB)、N−スクシンイミジル−ヨードアセタート(SIA)、N−スクシンイミジル−ブロモアセタート(SBA)およびN−スクシンイミジル−3−(ブロモアセトアミド)プロピオナート(SBAP)、ビス−マレイミドポリエチレングリコール(BMPEO)、BM(PEO)2、BM(PEO)3、N−(β−マレイミドプロピルオキシ)スクシンイミドエステル(BMPS)、5−マレイミド吉草酸NHS、HBVS、4−(4−N−マレイミドフェニル)−酪酸ヒドラジド・HCl(MPBH)、スクシンイミジル−(4−ビニルスルホニル)ベンゾアート(SVSB),ジチオビス−マレイミドエタン(DTME)、1,4−ビス−マレイミドブタン(BMB)、1,4−ビスマレイミジル−2,3−ジヒドロキシブタン(BMDB)、ビス−マレイミドヘキサン(BMH)、ビス−マレイミドエタン(BMOE)、スルホスクシンイミジル−4−(N−マレイミド−メチル)シクロヘキサン−1−カルボキシラート(スルホ−SMCC)、スルホスクシンイミジル(4−ヨード−アセチル)アミノベンゾアート(スルホ−SIAB)、m−マレイミドベンゾイル−N−ヒドロキシスルホスクシンイミドエステル(スルホ−MBS)、N−(γ−マレイミドブトリルオキシ)スルホスクシンイミドエステル(スルホ−GMBS)、N−(ε−マレイミドカプロイルオキシ)スルホスクシミド(sulfosuccimido)エステル(スルホ−EMCS)、N−(κ−マレイミドウンデカノイルオキシ)スルホスクシンイミドエステル(スルホ−KMUS)、スルホスクシンイミジル−4−(p−マレイミドフェニル)ブチラート(スルホ−SMPB)CX1−1、スルホ−MalおよびPEGn−Malが挙げられる。好ましくは、二官能性架橋試薬はSMCCである。
可能なリンカーは穏やかな条件下、すなわち、細胞毒性物質の活性が影響を受けない細胞内条件下で切断される。
一般式(IX):
HOOC−Xl−Yn−Zm−COOH
(IX)
のα,ω−ジカルボン酸が挙げられ、上式中、Xは、2〜20個の炭素原子を有する直鎖または分岐のアルキル、アルケニルまたはアルキニル基であり、Yは、3〜10個の炭素原子を有するシクロアルキルまたはシクロアルケニル基であり、Zは、6〜10個の炭素原子を有する置換もしくは非置換芳香族基またはヘテロ原子がN、OもしくはSから選択される置換もしくは非置換複素環基であり、l、mおよびnは、それぞれ0または1であり、ただし、l、mおよびnは同時にすべてがゼロになることはない。
これまでに記載されている工程(例えば、米国特許第5,208,020号)および本出願の対象である1段階の工程を用いて、ヒト化CD37−3抗体をヘテロ二官能性架橋試薬SMCCおよびマイタンシノイドDM1と反応させた。
H6.9)中、16℃で90分間実施した。1M酢酸塩で反応を停止させてpHを4.5に調整し、修飾抗体を、平衡化したSephadex G−25F樹脂のカラムを用いて精製し、2mM EDTAを含有する20mM酢酸ナトリウム(pH4.5)で溶出させた。精製後、修飾抗体(5mg/mL)をマイタンシノイドDM1(抗体量に対して6.8倍モル過剰;測定された抗体上のリンカー量に対して1.3倍過剰)と反応させて、コンジュゲート抗体を形成した。コンジュゲーション反応を、2mM EDTAと5%DMAとを含有する20mM酢酸ナトリウム緩衝液(pH5.0)中、20℃で約20時間実施した。次いで反応混合物を、平衡化したSephadex G−25F樹脂のカラムを用いて精製し、10mMコハク酸ナトリウム(pH5.0)で溶出させた。
これまでに記載されている2つの工程および本出願の対象である改善された工程を用いて、ヒト化葉酸受容体抗体huMov19(米国特許出願公開第2012/0009181号を参照)をヘテロ二官能性架橋試薬スルホ−SPDBおよびマイタンシノイドDM4と反応させた。
この実施例は、本明細書に記載の1段階の工程を用いて、各種のリンカーおよびマイタンシノイド細胞毒性物質から出発して複合体を製造し得ることを示すものである。
Claims (1)
- 細胞結合物質−細胞毒性物質複合体を調製する工程であって、
(a)細胞結合物質を細胞毒性物質と接触させて、前記細胞結合物質と前記細胞毒性物質とを含む第一の混合物を形成し、次いで、前記第一の混合物をpHが約4〜約9の溶液中でリンカーを含む二官能性架橋試薬と接触させて、(i)前記細胞結合物質が前記リンカーを介して前記細胞毒性物質と化学的に結合している前記細胞結合物質−細胞毒性物質複合体と、(ii)遊離の細胞毒性物質と、(iii)反応副生成物とを含む第二の混合物を得る段階
を含む工程。
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JPH03161490A (ja) * | 1989-10-25 | 1991-07-11 | Immunogen Inc | メイタンシノイドを含む細胞障害剤及び該細胞障害剤を有効成分とする医薬 |
JPH04266829A (ja) * | 1990-11-15 | 1992-09-22 | Brunswick Corp | 免疫結合体を形成するための抗体の化学修飾 |
JP2009506302A (ja) * | 2005-08-04 | 2009-02-12 | イェシバ・ユニバーシティ | Ablによるタウのリン酸化 |
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