JP2010526821A - システイン改変抗muc16抗体および抗体−薬物結合体 - Google Patents
システイン改変抗muc16抗体および抗体−薬物結合体 Download PDFInfo
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- JP2010526821A JP2010526821A JP2010507620A JP2010507620A JP2010526821A JP 2010526821 A JP2010526821 A JP 2010526821A JP 2010507620 A JP2010507620 A JP 2010507620A JP 2010507620 A JP2010507620 A JP 2010507620A JP 2010526821 A JP2010526821 A JP 2010526821A
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Classifications
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- C07K2317/71—Decreased effector function due to an Fc-modification
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Abstract
Ab−(L−D)p I
を有する、システイン改変抗MUC16抗体−薬物結合体が形成され、ここで、pは、1〜4である。システイン改変抗体薬物化合物および組成物に対する診断的および治療的な用途が開示される。
Description
37CFR§1.53(b)の下で出願された、この本出願は、米国特許法§119(e)の下、2007年5月8日に出願された米国仮出願第60/916,657号(これは、その全体が参考として本明細書に援用される)の利益を主張する。
発明の分野
本発明は、概して、反応性のシステイン残基を用いて操作された抗体に関し、より詳細には、治療的または診断的な用途で用いる抗体に関する。そのシステイン改変抗体は、化学療法薬、トキシン、ビオチンなどの親和性リガンドおよびフルオロフォアなどの検出標識と結合体化され得る。本発明はまた、哺乳動物細胞または関連する病理学的状態の、インビトロ、インサイチュおよびインビボでの診断または処置のために、抗体および抗体−薬物結合体複合物を使用する方法にも関する。
癌、免疫学的障害および血管新生障害を有する患者を標的化処置するための抗体治療が、確立されている。正常な非癌性細胞と比べて、癌細胞の表面上に特異的に発現する膜貫通型ポリペプチドまたは別の腫瘍関連ポリペプチドが、抗体を用いた癌の診断および治療のための細胞性標的として同定されている。そのような腫瘍関連細胞表面抗原ポリペプチド、すなわち、腫瘍関連抗原(TAA)が同定されることにより、抗体ベースの治療を介して破壊するための癌細胞の特異的な標的化が可能になる。
1つの局面において、本発明は、1つ以上の遊離システインアミノ酸および配列番号9〜40から選択される配列を含むシステイン改変抗MUC16抗体を包含する。システイン改変抗MUC16抗体は、MUC16ポリペプチドに結合する。O772P(CA125、MUC16)ポリペプチドなどの腫瘍関連抗原(TAA)は、当該分野で周知の、例えば、WO2007/001851における方法および情報を用いて、システイン改変抗体を作製する際に使用するために調製され得る。システイン改変抗MUC16抗体は、親抗MUC16抗体の1つ以上のアミノ酸残基をシステインで置換する工程を包含するプロセスによって調製され得る。
Ab−(L−D)p I
を有し、ここで、pは、1、2、3または4である。アウリスタチン薬物部分は、MMAEおよびMMAFを含む。
Ab−(L−D)p I
を有し、ここで、pは、1、2、3または4であり、平均薬物負荷は、1〜2である。
ここで、本発明のある特定の実施形態について詳細に言及し、その実施形態の例は、添付の構造および式に図示される。本発明は、列挙される実施形態とともに説明されるが、本発明がそれらの実施形態に限定されると意図されないことが理解されるだろう。それどころか、本発明は、すべての代替物、改変物および等価物を包含すると意図され、それらは、請求項に定義されるような本発明の範囲内に含められ得る。
別段定義されない限り、本明細書中で使用される専門用語および科学用語は、本発明が属する分野の当業者が通常理解している意味と同じ意味を有し、それは:Singletonら(1994)Dictionary of Microbiology and Molecular Biology,2nd Ed.,J.Wiley & Sons,New York,NY;およびJaneway,C.,Travers,P.,Walport,M.,Shlomchik(2001)Immunobiology,5th Ed.,Garland Publishing,New Yorkと一致するものである。
本発明の複合物は、システイン改変抗MUC16抗体を包含し、ここで、野生型抗MUC16抗体または親抗MUC16抗体の任意の形態の1つ以上のアミノ酸が、システインアミノ酸が置換されている。その操作されたシステインアミノ酸は、遊離システイン酸であり、鎖内または鎖間のジスルフィド単位の一部ではない。任意の形態の抗MUC16抗体が、そのように操作され得る、すなわち、変異され得る。例えば、親Fab抗体フラグメントは、本明細書中で「チオFab」と称される、システイン改変Fabを形成するように操作され得る。同様に、親モノクローナル抗体は、「チオMab」を形成するように操作され得る。1つの部位の変異によって、チオFabにおいて1つの操作されたシステイン残基がもたらされるが、チオMabでは、IgG抗体の二量体という性質に起因して、1つの部位の変異によって2つの操作されたシステイン残基がもたらされることに注意されるべきである。本発明のシステイン改変抗MUC16抗体には、モノクローナル抗体、ヒト化またはキメラモノクローナル抗体、抗体の抗原結合フラグメント、融合ポリペプチドおよび細胞関連MUC16ポリペプチドに優先的に結合するアナログが包含される。
本明細書中に記載される抗MUC16抗体における改変および変形は、例えば、保存的変異および非保存的変異に対して当該分野で公知の手法およびガイドラインのいずれか、例えば、US5364934におけるものを用いて作製され得る。変形は、天然配列の抗MUC16抗体と比べて、アミノ酸配列を変化させた抗体またはポリペプチドをコードする1つ以上のコドンの置換、欠失または挿入であり得る。必要に応じて、変形は、抗MUC16抗体のドメインの1つ以上における他の任意のアミノ酸による、少なくとも1つのアミノ酸の置換による。変形は、当該分野で公知の方法(例えば、オリゴヌクレオチド媒介性(部位特異的)突然変異誘発、アラニンスキャニングおよびPCR突然変異誘発)を用いて行われ得る。部位特異的突然変異誘発(Carterら(1986)Nucl.Acids Res.,13:4331;Zollerら(1987)Nucl.Acids Res.,10:6487)、カセット突然変異誘発(Wellsら(1985)Gene,34:315)、制限部位選択突然変異誘発(restriction selection mutagenesis)(Wellsら(1986)Philos.Trans.R.Soc.London SerA,317:415)または他の公知の手法が、抗MUC16抗体バリアントDNAを作製するために、クローニングされたDNAにおいて行われ得る。アミノ酸の変更は、抗MUC16抗体の翻訳後プロセスを変化させ得る(例えば、グリコシル化部位の数もしくは位置を変更し得るか、または膜アンカー特性を変化させ得る)。他の改変としては、グルタミニル残基およびアスパラギニル残基の、それぞれ対応するグルタミル残基およびアスパルチル残基へのアミド分解、プロリンおよびリシンのヒドロキシル化、セリル残基またはトレオニル残基のヒドロキシル基のリン酸化、リシン側鎖、アルギニン側鎖およびヒスチジン側鎖のα−アミノ基のメチル化(T.E.Creighton,Proteins:Structure and Molecular Properties,(1983)W.H.Freeman & Co.,San Francisco,pp.79−86)、N末端のアミンのアセチル化、ならびに任意のC末端のカルボキシル基のアミド化が挙げられる。抗MUC16抗体は、適切なヌクレオチドの変更をコードDNAに導入すること、および/または化学合成によって調製され得る。
本発明のシステイン改変抗MUC16抗体および親抗MUC16抗体のアミノ酸配列バリアントをコードするDNAは、種々の方法によって調製され、その方法としては、そのポリペプチドをコードする、予め調製されていたDNAの、天然の供給源からの単離(天然に存在するアミノ酸配列バリアントの場合)、部位特異的(またはオリゴヌクレオチド媒介性)突然変異誘発による調製(Carter(1985)ら、Nucleic Acids Res.13:4431−4443;Hoら(1989)Gene(Amst.)77:51−59;Kunkelら(1987)Proc.Natl.Acad.Sci.USA 82:488;Liuら(1998)J.Biol.Chem.273:20252−20260)、PCR突然変異誘発(Higuchi,(1990)PCR Protocols,pp.177−183,Academic Press;Itoら(1991)Gene 102:67−70;Bernhardら(1994)Bioconjugate Chem.5:126−132;およびValletteら(1989)Nuc.Acids Res.17:723−733)およびカセット突然変異誘発(Wellsら(1985)Gene 34:315−323)が挙げられるが、これらに限定されない。突然変異誘発プロトコル、キットおよび試薬は、市販されており、例えば、QuikChange(登録商標)Multi Site−Direct Mutagenesis Kit(Stratagene,La Jolla,CA)である。単一突然変異もまた、二本鎖プラスミドDNAをPCRベースの突然変異誘発(Sambrook and Russel,(2001)Molecular Cloning:A Laboratory Manual,3rd edition;Zollerら(1983)Methods Enzymol.100:468−500;Zoller,M.J.and Smith,M.(1982)Nucl.Acids Res.10:6487−6500)による鋳型として用いるオリゴヌクレオチド特異的突然変異誘発によってもたらされる。組換え抗体のバリアントは、制限フラグメント操作、または合成オリゴヌクレオチドを用いるオーバーラップ伸長PCRによっても構築され得る。変異原性プライマーは、システインコドン置換をコードする。標準的な突然変異誘発の手法は、そのようなシステインが操作された変異体抗体をコードするDNAを生成するために使用され得る(Sambrookら、Molecular Cloning,A Laboratory Manual,Cold Spring Harbor Laboratory Press,Cold Spring Harbor,N.Y.,1989;およびAusubelら、Current Protocols in Molecular Biology,Greene Publishing and Wiley−Interscience,New York,N.Y.,1993)。
本発明の設計、選択および調製の方法によって、求電子性官能基と反応性である、システイン改変抗MUC16抗体がもたらされる。これらの方法は、指摘され、設計された選択的部位において、薬物分子との抗体結合体複合物(例えば、抗体−薬物結合体(ADC)複合物)をさらにもたらす。抗体表面上の反応性システイン残基は、チオール反応基(例えば、マレイミドまたはハロアセチル)を介して薬物部分と特異的に結合体化することを可能にする。マレイミド基に対するCys残基のチオール官能基の求核的な反応性は、タンパク質中の他の任意のアミノ酸官能基(例えば、リシン残基のアミノ基またはN末端のアミノ基)と比べて約1000倍高い。ヨードアセチルおよびマレイミド試薬におけるチオール特異的官能基は、アミン基と反応性であり得るが、より高いpH(>9.0)およびより長い反応時間が必要である(Garman,1997,Non−Radioactive Labelling:A Practical Approach,Academic Press,London)。タンパク質中の遊離チオールの量は、標準的なEllmanアッセイによって推定され得る。免疫グロブリンMは、ジスルフィド結合五量体の例であり、免疫グロブリンGは、サブユニットを共に結合する内部ジスルフィド架橋を有するタンパク質の例である。このようなタンパク質では、試薬(例えば、ジチオトレイトール(DTT)またはセレノール)によるジスルフィド結合の還元(Singhら(2002)Anal.Biochem.304:147−156)が、反応性の遊離チオールを生成するために必要である。このアプローチは、抗体の三次構造および抗原結合特異性の喪失をもたらし得る。
(a)親抗MUC16抗体の1つ以上のアミノ酸残基をシステインで置換する工程;および
(b)システイン改変抗MUC16抗体をチオール反応性試薬と反応させることによって、そのシステイン改変抗体のチオール反応性を測定する工程
を包含するプロセスによって調製される。
(a)システイン改変抗MUC16抗体を作製するために、1つ以上のシステインアミノ酸を親抗MUC16抗体に導入する工程;および
(b)システイン改変抗体の、チオール反応性試薬に対するチオール反応性を測定する工程;
を包含し、
ここで、システイン改変抗体は、親抗体よりもチオール反応性試薬に対して反応性である。
(i)システイン改変抗体をコードする核酸配列を突然変異誘発する工程;
(ii)そのシステイン改変抗体を発現させる工程;および
(iii)そのシステイン改変抗体を単離し、精製する工程
を包含し得る。
(i)システイン改変抗体を、チオール反応性の親和性試薬と反応させることにより、システイン改変親和性標識抗体を作製する工程;および
(ii)そのシステイン改変親和性標識抗体の、捕捉媒体に対する結合を測定する工程
も包含し得る。
(a)システイン改変抗体を作製するために、親抗体に1つ以上のシステインアミノ酸を導入する工程;
(b)システイン改変抗体を、チオール反応性の親和性試薬と反応させることにより、システイン改変親和性標識抗体を作製する工程;および
(c)そのシステイン改変親和性標識抗体の、捕捉媒体に対する結合を測定する工程;および
(d)システイン改変抗体の、チオール反応性試薬に対するチオール反応性を測定する工程
を包含する。
(i)システイン改変抗体をコードする核酸配列を突然変異誘発する工程;
(ii)そのシステイン改変抗体を発現させる工程;および
(iii)システイン改変抗体を単離し、精製する工程
を包含し得る。
(i)システイン改変抗体を、チオール反応性の親和性試薬と反応させることにより、システイン改変親和性標識抗体を作製する工程;および
(ii)そのシステイン改変親和性標識抗体の、捕捉媒体に対する結合を測定する工程
も包含し得る。
本明細書中に記載されるシステイン操作方法によって、完全長、ヒト化およびキメラの親モノクローナル抗MUC16 3A5抗体内の重鎖117(抗MUC16 3A5抗体に対する連続的ナンバリング)部位にシステインを導入することにより、重鎖配列:配列番号1および軽鎖配列:配列番号2、図1を有するA117Cチオhu抗MUC16 3A5ヒト化バリアント、ならびに重鎖配列:配列番号3および軽鎖配列:配列番号4、図2を有するA117Cチオch抗MUC16 3A5キメラバリアントを得た。これらのシステイン改変モノクローナル抗体は、1mMシステインを含む培地中での一過性の発酵によって、CHO(チャイニーズハムスター卵巣)細胞において発現された。
システイン改変抗MUC16抗体は、チオール反応性試薬と、部位特異的および効率的に結合され得る。チオール反応性試薬は、多官能性(multifunctional)リンカー試薬、捕捉標識試薬、すなわち、親和性標識試薬(例えば、ビオチン−リンカー試薬)、検出標識(例えば、フルオロフォア試薬)、固相固定化試薬(例えば、SEPHAROSETM、ポリスチレンまたはガラス)または薬物−リンカー中間体であり得る。チオール反応性試薬の1つの例は、N−エチルマレイミド(NEM)である。例示的な実施形態において、チオFabとビオチン−リンカー試薬との反応は、ビオチン化チオFabをもたらし、それによって、操作されたシステイン残基の存在および反応性が検出され、測定され得る。チオFabと多官能性リンカー試薬との反応によって、薬物部分試薬または他の標識とさらに反応し得る、多官能化されたリンカーを有するチオFabが提供される。チオFabと薬物−リンカー中間体との反応は、チオFab薬物結合体を提供する。
システイン改変抗MUC16抗体、ならびにその抗体−薬物結合体および標識結合体は、治療用薬剤および/または診断用薬剤としての用途を見出し得る。本発明は、MUC16関連障害に関連する1つ以上の症状を予防するか、管理するか、処置するか、または回復させる方法をさらに提供する。特に、本発明は、細胞増殖性障害(例えば、癌、例えば、卵巣癌、子宮頸癌、子宮癌、膵臓腺癌を含む膵癌、肺癌および乳癌)に関連する1つ以上の症状を予防するか、管理するか、処置するか、または回復させる方法を提供する。本発明は、MUC16関連障害またはそのような障害を発症する素因を診断するための方法、ならびに細胞に会合したMUC16ポリペプチドに優先的に結合する抗体および抗体の抗原結合フラグメントを同定するための方法をなおもさらに提供する。
システイン改変抗MUC16抗体は、規定された部位においてほぼ一様の化学量論(薬物/抗体比、p値)で薬物部分の結合をもたらすことによって、抗体−薬物結合体不均一性の問題点を解決する。さらに、その結合体化条件は、すべての天然の免疫グロブリンジスルフィド結合を保持する。
Ab−(L−D)p I
を有し、ここで、pは、1、2、3または4であり;システイン改変抗体は、親抗MUC16抗体の1つ以上のアミノ酸残基を1つ以上の遊離システインアミノ酸で置換する工程を包含するプロセスによって調製される。単一のシステイン変異が、抗MUC16親抗体中に操作されることにより、システイン改変抗MUC16抗体が形成されるとき、重鎖および軽鎖の対称的な性質に起因して、2つの遊離システインアミノ酸が生じる。
式Iの抗体−薬物結合体(ADC)のアウリスタチン薬物部分としては、ドラスタチン、アウリスタチン(US5635483;US5780588;US5767237;US6124431)、ならびにそれらのアナログおよび誘導体が挙げられる。ドラスタチンおよびアウリスタチンは、微小管動態、GTP加水分解ならびに核分裂および細胞分裂を妨げること(Woykeら(2001)Antimicrob.Agents and Chemother.45(12):3580−3584)、ならびに抗癌活性(US5663149)および抗真菌活性(Pettitら(1998)Antimicrob.Agents Chemother.42:2961−2965)を有することが示されている。様々な形態のドラスタチンまたはアウリスタチン薬物部分が、ペプチド性の薬物部分のN(アミノ)末端またはC(カルボキシル)末端を介して、抗体に共有結合され得る(WO02/088172;Doroninaら(2003)Nature Biotechnology 21(7):778−784;Franciscoら(2003)Blood 102(4):1458−1465)。
「リンカー」、「リンカー単位」または「リンク(link)」とは、抗体を薬物部分に共有結合する、共有結合を含む化学部分または原子の鎖のことを意味する。様々な実施形態において、リンカーは、Lとして明記される。「リンカー」(L)は、1つ以上の薬物部分(D)と抗体単位(Ab)とを連結して、式Iの抗体−薬物結合体(ADC)を形成するために使用され得る二官能性または多官能性の部分である。抗体−薬物結合体(ADC)は、薬物および抗体への結合のための反応性官能性を有するリンカーを用いて都合よく調製され得る。システイン改変抗体(Ab)のシステインチオールは、リンカー試薬、薬物部分または薬物−リンカー中間体の求電子性官能基と結合を形成し得る。
−A−は、抗体(Ab)のシステインチオールに共有結合されたストレッチャー単位であり;
aは、0または1であり;
各−W−は、独立して、アミノ酸単位であり;
wは、独立して、0〜12の範囲の整数であり;
−Y−は、薬物部分に共有結合されたスペーサー単位であり;そして
yは、0、1または2である。
ストレッチャー単位(−A−)は、存在するとき、抗体単位をアミノ酸単位(−W−)に連結することができる。この点に関して、抗体(Ab)は、ストレッチャー単位の求電子性官能基と結合を形成し得る遊離システインチオール基を有する。式I結合体における例示的なストレッチャー単位は、式IIおよびIIIによって表され、ここで、Ab−、−W−、−Y−、−D、wおよびyは、上で定義したとおりであり、R17は、(CH2)r、C3−C8カルボシクリル、O−(CH2)r、アリーレン、(CH2)r−アリーレン、−アリーレン−(CH2)r−、(CH2)r−(C3−C8カルボシクリル)、(C3−C8カルボシクリル)−(CH2)r、C3−C8ヘテロシクリル、(CH2)r−(C3−C8ヘテロシクリル)、−(C3−C8ヘテロシクリル)−(CH2)r−、−(CH2)rC(O)NRb(CH2)r−、−(CH2CH2O)r−、−(CH2CH2O)r−CH2−、−(CH2)rC(O)NRb(CH2CH2O)r−、−(CH2)rC(O)NRb(CH2CH2O)r−CH2−、−(CH2CH2O)rC(O)NRb(CH2CH2O)r−、−(CH2CH2O)rC(O)NRb(CH2CH2O)r−CH2−および−(CH2CH2O)rC(O)NRb(CH2)r−から選択される二価のラジカルであり;ここで、Rbは、H、C1−C6アルキル、フェニルまたはベンジルであり;rは、独立して、1〜10の範囲の整数である。
リンカーは、アミノ酸残基を含み得る。アミノ酸単位(−Ww−)は、存在するとき、抗体(Ab)を、本発明のシステイン改変抗体−薬物結合体(ADC)の薬物部分(D)に連結する。
スペーサー単位(−Yy−)が存在し(y=1または2)、アミノ酸単位も存在するとき(w=1〜12)、そのスペーサー単位は、アミノ酸単位(−Ww−)を薬物部分(D)に連結する。あるいは、アミノ酸単位が存在しないとき、スペーサー単位は、ストレッチャー単位を薬物部分に連結する。アミノ酸単位とストレッチャー単位の両方が存在しないとき(w,y=0)、スペーサー単位は、薬物部分を抗体単位にも連結する。スペーサー単位は、2つの一般的なタイプ:自壊的(self−immolative)および非自壊的である。非自壊的スペーサー単位は、スペーサー単位の一部または全部が、抗体−薬物結合体または薬物部分−リンカーからのアミノ酸単位の切断後、特に酵素的切断後に、薬物部分に結合したままであるものである。グリシン−グリシンスペーサー単位またはグリシンスペーサー単位を含むADCが、腫瘍細胞関連プロテアーゼ、癌細胞関連プロテアーゼまたはリンパ球関連プロテアーゼを介して酵素的切断を起こすとき、グリシン−グリシン−薬物部分またはグリシン薬物部分は、Ab−Aa−Ww−から切断される。1つの実施形態では、無関係な加水分解反応が、標的細胞内で生じ、グリシン−薬物部分の結合が切断され、薬物が遊離される。
別の実施形態では、リンカーLは、分枝状の多官能性リンカー部分を介して抗体に2つ以上の薬物部分を共有結合させるための樹枝状タイプのリンカーであり得る(Sunら(2002)Bioorganic & Medicinal Chemistry Letters 12:2213−2215;Sunら(2003)Bioorganic & Medicinal Chemistry 11:1761−1768)。樹枝状リンカーは、ADCの効力に関連する、薬物と抗体とのモル比、すなわち、負荷を高め得る。したがって、システイン改変抗体が、ただ1つの反応性システインチオール基を有する場合、多数の薬物部分が、樹枝状リンカーを介して結合され得る。分枝状で樹枝状のリンカーの例示的な実施形態としては、2,6−ビス(ヒドロキシメチル)−p−クレゾールおよび2,4,6−トリス(ヒドロキシメチル)−フェノールデンドリマー単位(WO2004/01993;Szalaiら(2003)J.Amer.Chem.Soc.125:15688−15689;Shamisら(2004)J.Amer.Chem.Soc.126:1726−1731;Amirら(2003)Angew.Chem.Int.Ed.42:4494−4499)が挙げられる。
Yは:
ここで、Rは、独立して、HまたはC1−C6アルキルであり;nは、1〜12である。
抗体とアウリスタチンとの結合体は、種々の二官能性リンカー試薬(例えば、N−スクシンイミジル−3−(2−ピリジルジチオ)プロピオネート(SPDP)、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−カルボキシレート(SMCC)、イミノチオラン(IT)、イミドエステルの二官能性誘導体(例えば、アジプイミド酸ジメチルHCl)、活性エステル(例えば、ジスクシンイミジルスベレート)、アルデヒド類(例えば、グルタルアルデヒド)、ビス−アジド化合物(例えば、ビス(p−アジドベンゾイル)ヘキサンジアミン)、ビス−ジアゾニウム誘導体(例えば、ビス−(p−ジアゾニウムベンゾイル)−エチレンジアミン)、ジイソシアネート(例えば、トルエン2,6−ジイソシアネート)およびビス−活性フッ素化合物(例えば、1,5−ジフルオロ−2,4−ジニトロベンゼン))を用いて作製され得る。
式IのADCは、当業者に公知の有機化学の反応、条件および試薬を用いて、いくつかの経路によって調製され得、その経路としては:(1)システイン改変抗体のシステイン基をリンカー試薬と反応させることにより、共有結合を介して抗体−リンカー中間体Ab−Lを形成させた後、活性化された薬物部分Dと反応させる経路;および(2)薬物部分の求核基をリンカー試薬と反応させることにより、共有結合を介して薬物−リンカー中間体D−Lを形成させた後、システイン改変抗体のシステイン基と反応させる経路が挙げられる。結合体化の方法(1)および(2)は、システインが操作された種々の抗体、薬物部分およびリンカーとともに用いられることにより、式Iの抗体−薬物結合体が調製され得る。
本発明のなおも別の実施形態は、MUC16/CA125/O772Pポリペプチドを含むと疑われるサンプル中のMUC16/CA125/O772Pポリペプチドの存在を判定する方法に関し、ここで、その方法は、MUC16/CA125/O772Pポリペプチドに結合する、システイン改変抗MUC16抗体またはその抗体薬物結合体に上記サンプルを曝露する工程、およびそのサンプル中のMUC16/CA125/O772Pポリペプチドに対するシステイン改変抗MUC16抗体またはその抗体薬物結合体の結合を測定する工程(ここで、そのような結合の存在は、サンプル中のMUC16/CA125/O772Pポリペプチドの存在を示す)を包含する。必要に応じて、上記サンプルは、MUC16/CA125/O772Pポリペプチドを発現していると疑われる細胞(癌細胞であり得る)を含み得る。本方法において使用されるシステイン改変抗MUC16抗体またはその抗体薬物結合体は、必要に応じて、検出可能に標識され得るか、固体支持体などに結合され得る。
本発明の1つの実施形態は、MUC16ポリペプチドを発現する細胞の成長を阻害するための方法に関し、ここで、その方法は、その細胞を、MUC16ポリペプチドに対するシステイン改変抗MUC16抗体またはその抗体薬物結合体と接触させる工程を包含し、MUC16を発現している細胞の成長の阻害を引き起こす。その細胞は、癌細胞であり得、システイン改変抗体またはその抗体薬物結合体のMUC16ポリペプチドに対する結合は、MUC16ポリペプチドを発現している細胞の死を引き起こすか、またはその細胞の増殖を阻害する。
Sprague−Dawleyラットへの単回の静脈内ボーラス投薬後の抗体および薬物結合体の血清濃度を測定することによって、抗MUC16抗体−薬物結合体のインビボでの性質を解析した。少なくとも1つの細胞傷害性薬物を有する抗体−薬物結合体の濃度を、捕捉用にMUC16細胞外ドメイン(ECD)タンパク質、ならびに検出用に抗MMAEおよび西洋ワサビペルオキシダーゼ(HRP)結合体化抗マウスFc抗体を使用するELISAを用いて測定された。捕捉用にMUC16ECDおよび検出用に抗ヒト−FcHRPを使用するELISAを用いて、血清中の全Ch3A5およびチオCh3A5の濃度を測定した。このアッセイから、結合体化MMAE有りおよび無しの両方における、すべての抗MUC16抗体が測定された。このアッセイは、1:10という最低希釈での0.78ng/mLという定量化の下限を有する。このアッセイは、1:10という最低希釈での0.78ng/mLという定量化の下限を有する。IVボーラス投与、一次除去およびマクロ(macro)速度定数を用いる2成分モデル(Model 8,WinNonlin Pro v.5.0.1,Pharsight Corporation,Mountain View,CA)を使用して、各動物からの血清濃度−時間データを解析した。全体の適合度は、予測される推定値、その予測に対する標準誤差、および1次および2次パラメータに対する変動係数のパーセンテージ、ならびに観察された濃度−時間データと予測された濃度−時間データとの間の残差プロットの調査に基づいた。個別の主要なPKパラメータは、それぞれアルファ相およびベータ相に関連する時間ゼロにおける切片(AおよびB)ならびにマイクロ速度定数(アルファおよびベータ)を包含した。以下のモデリング選択肢を用いた:WinNonlinを用いて最初の推定値を決定した;予測される濃度の二乗値の逆数(1/y2)によって濃度を重み付けした;Nelder−Mead最小化アルゴリズムを用いた。
システイン改変抗MUC16抗体−薬物結合体の安全性を急性毒性ラットモデルにおいて評価した。雌Sprague−DawleyラットをADCで処置し、続いて様々な器官に対する影響を検査し、解析することによって、ADCの毒性を調べた。ADCの毒性は、巨視的観察(体重)、臨床病理学パラメータ(血清化学および血液学)および組織病理学に基づいて、観察され、特徴づけられ、そして測定され得る。等価な用量レベルにおいて、システイン改変抗MUC16抗体−薬物結合体は、対応する標準的な抗体−薬物結合体よりも急性でない毒性と関連することが見出された。
げっ歯類において癌細胞の同種移植片または異種移植片を移植し、その腫瘍をADCで処置することによって、システイン改変抗MUC16抗体−薬物結合体の有効性をインビボにおいて測定した。細胞株、癌細胞上に存在するレセプターに対するADCの抗体結合特異性、投薬レジメンおよび他の因子に応じて、可変的な結果が予測される。中レベルのMUC16を発現するトランスジェニック外植片マウスモデルを用いて、ADCのインビボでの有効性を測定した。被験体をADCで1回処置し、3〜6週間にわたってモニターすることにより、腫瘍が倍加するまでの時間、対数細胞殺滅および腫瘍縮小を測定した。用量反応の追跡調査および多用量の実験を行った。
本発明の別の実施形態は、MUC16/CA125/O772Pポリペプチドを発現する細胞を含む癌性腫瘍を有する哺乳動物を治療的に処置する方法に関し、ここで、その方法は、その哺乳動物に、MUC16/CA125/O772Pポリペプチドに結合する、治療有効量のシステイン改変抗体またはその抗体薬物結合体を投与することによって、その腫瘍の有効な治療的処置をもたらす工程を包含する。
本発明の抗体−薬物結合体(ADC)は、処置される状態に対して適切な任意の経路によって投与され得る。ADCは、代表的には、非経口的に、すなわち注入で、皮下、腹腔内、筋肉内、静脈内、皮内、髄腔内および硬膜外に、投与される。
本発明の治療的な抗体−薬物結合体(ADC)の薬学的処方物は、代表的には、薬学的に許容可能な非経口ビヒクルとともに、そして単位投薬量の滅菌された注射可能な形態での、非経口投与、すなわち、ボーラス、静脈内、腫瘍内注射のために調製される。所望の純度を有する抗体−薬物結合体(ADC)は、必要に応じて、凍結乾燥された処方物または水溶液の形態で、薬学的に許容可能な希釈剤、キャリア、賦形剤または安定剤と混合される(Remington’s Pharmaceutical Sciences(1980)16th edition,Osol,A.Ed.)。
本発明の抗体−薬物結合体(ADC)は、抗癌特性を有する第2化合物との、薬学的な併用処方物または併用療法としての投薬レジメンにおいて組み合わされ得る。その薬学的な併用処方物または投薬レジメンの第2化合物は、好ましくは、組み合わせのADCに対して補完的な活性を有するものであり、それらが互いに悪影響を及ぼさないものである。
本明細書中に記載されるADC複合物のインビボ代謝産物もまた、そのような生成物が、従来技術と比較して新規であり、自明でない程度まで、本発明の範囲内に入る。そのような生成物は、例えば、投与された化合物の酸化、還元、加水分解、アミド化、エステル化、酵素的切断などから生じ得る。したがって、本発明は、本発明の化合物を、その代謝産物を得るのに十分な時間にわたって哺乳動物と接触させる工程を包含するプロセスによって生成される新規かつ自明でない化合物を包含する。
本発明の別の実施形態において、上に記載した障害の処置に有用な材料を備えた製品すなわち「キット」が提供される。本製品は、容器、およびその容器上または容器に関連する、ラベルまたは添付文書を備える。その添付文書とは、治療的な生成物の市販のパッケージに慣例上含まれていて、適応症、使用法、投薬量、投与、禁忌症および/またはそのような治療的な生成物の使用に関する警告についての情報を含んでいる指示書のことを指し得る。適当な容器としては、例えば、ビン、バイアル、注射器、ブリスター包装などが挙げられる。その容器は、種々の材料(例えば、ガラスまたはプラスチック)から形成され得る。
ヒト化およびキメラ3A5抗Muc16 3A5抗体(図3および4)をWO2007/001851に従って調製した(その配列および抗体が参考として援用される)。
チオhu抗MUC16HC A117C 3A5:MW=144834.84;pI=8.28;pI(酸化型C)=8.79;長さ=1320;Ext.Coef.(280)=1.61。重鎖446aa;MW:48952.23,pI:8.55,pI(酸化型c):9.12,Ext.Coeff.(280):1.70;計算の前に切り落とされる潜在的なシグナル配列(MGWSCIILFLVATATGVHS).長さ=19;dna開始位置:987,dna停止位置:2324,図1,配列番号1。軽鎖214aa;MW:23483.20,pI:6.71,pI(酸化型c):6.72,Ext.Coeff(280):1.43;計算の前に切り落とされる潜在的なシグナル配列(MGWSCIILFLVATATGVHS).長さ=19;dna開始位置:7103,dna停止位置:7744,図1,配列番号2
チオch抗MUC16HC A117C:MW=145118.9;pI=7.99;pI(酸化型C)=8.44;長さ=1320;Ext.Coef.(280)=1.59.重鎖446aa;MW:49236.50,pI:8.29,pI(酸化型c):8.85,Ext.Coeff(280):1.66;計算の前に切り落とされる潜在的なシグナル配列(MGWSCIILFLVATATGAYA).長さ=19;dna開始位置:987,dna停止位置:2324,図2,配列番号3。軽鎖214aa;MW:23340.96,pI:6.71,pI(酸化型c):6.72,Ext.Coeff(280):1.44;計算の前に切り落とされる潜在的なシグナル配列(MGWSCIILFLVATATGVHS).長さ=19;dna開始位置:7103,dna停止位置:7744。図2,配列番号4
実施例2 還元および再酸化による結合体化のための、システイン改変抗MUC16抗体の調製
CHO細胞において発現させる、システイン改変完全長抗MUC16モノクローナル抗体(チオMab)は、システイン付加物(シスチン)を有するか、または細胞培養条件に起因して、操作されたシステイン上でグルタチオン付加される。操作されたシステインの反応性のチオール基を遊離させるために、チオMabをpH約8.0の500mMホウ酸ナトリウムおよび500mM塩化ナトリウムに溶解し、約50〜100倍過剰量の1mM TCEP(トリス(2−カルボキシエチル)ホスフィン塩酸塩;Getzら(1999)Anal.Biochem.Vol 273:73−80;Soltec Ventures,Beverly,MA)で、37℃において約1〜2時間還元する。あるいは、還元剤としてDTTを用いることができる。非還元SDS−PAGEまたは変性逆相HPLC PLRPカラムクロマトグラフィのいずれかによって、鎖間のジスルフィド結合の形成をモニターした。還元されたチオMab(図6a)を希釈し、10mM酢酸ナトリウム,pH5中のHiTrap Sカラム上に充填し、0.3M塩化ナトリウムを含むPBSで溶出する。溶出した還元型チオMabを、2mMデヒドロアスコルビン酸(dhAA)でpH7において3時間、または2mM硫酸銅(CuSO4)水溶液で室温において一晩、処理する。外気による酸化もまた有効であり得る。Sephadex G25樹脂からの溶出によって緩衝液を交換し、1mM DTPAを含むPBSで溶出する。DTNB(Aldrich,Milwaukee,WI)と反応させることによる、溶液の280nmにおける吸光度からの還元型抗体の濃度およびチオール濃度の測定ならびに412nmにおける吸光度の測定によって、チオール/Ab値を確認する。
実施例2の還元および再酸化手順の後、システイン改変抗MUC16抗体をPBS(リン酸緩衝食塩水)緩衝液に溶解し、氷上で冷却する。1抗体あたり操作されたシステインが約1.5モル濃度の、マレイミドなどのチオール反応性の官能基を有するアウリスタチン薬物リンカー中間体(例えば、MC−MMAE(マレイミドカプロイル−モノメチルアウリスタチンE)、MC−MMAF、MC−val−cit−PAB−MMAEまたはMC−val−cit−PAB−MMAF)をDMSOに溶解し、アセトニトリルおよび水で希釈し、そしてPBS中の、冷却され、還元され、再酸化された抗体に加える。約1時間後、過剰量のマレイミドを加えることによって、反応をクエンチし、そして任意の未反応抗体チオール基をキャッピングする。その反応混合物を遠心限外濾過によって濃縮し、システイン改変抗MUC16抗体薬物結合体を精製し、PBS中のG25樹脂に通して溶出することによって脱塩し、滅菌条件下において0.2μmフィルターで濾過し、そして保存のために凍結する。
A117Cチオhu3A5とMC−MMAFとの結合体化によるチオhu3A5−MC−MMAF;
A117Cチオhu3A5とMC−val−cit−PAB−MMAEとの結合体化によるチオhu3A5−MC−val−cit−PAB−MMAE;
A117Cチオch3A5とMC−MMAFとの結合体化によるチオch3A5−MC−MMAF;および
A117Cチオch3A5とMC−val−cit−PAB−MMAEとの結合体化によるチオch3A5−MC−val−cit−PAB−MMAE。
抗体−薬物結合体のインビトロにおける効力を細胞増殖アッセイによって測定した(図10および11)。CellTiter−Glo(登録商標)Luminescent Cell Viability Assayは、Coleopteraルシフェラーゼの組換え発現に基づく市販の(Promega Corp.,Madison,WI)均一なアッセイ方法である(US5583024;US5674713;US5700670)。この細胞増殖アッセイは、代謝的に活性な細胞の指標である、存在するATPの定量に基づいて培養物中の生存細胞数を決定する(Crouchら(1993)J.Immunol.Meth.160:81−88;US6602677)。CellTiter−Glo(登録商標)アッセイを、自動ハイスループットスクリーニング(HTS)に適用できるように96ウェル様式において行った(Creeら(1995)AntiCancer Drugs 6:398−404)。均一なアッセイ手順は、血清が補充された培地中で培養された細胞に単一の試薬(CellTiter−Glo(登録商標)試薬)を直接加える工程を包む。
1.約1000個(PC3)または3000個(OVCAR−3)の細胞を含む細胞培養物の50μlのアリコート:培地中の(1)MUC16ポリペプチドを発現する細胞株OVCAR−3;(2)細胞表面上にMUC16ポリペプチドを安定的に発現するように操作されたPC3由来細胞株(PC3/MUC16);および(3)MUC16ポリペプチドを発現しないPC3細胞株(PC3/neo)を、96ウェルの不透明な壁のプレートの各ウェルに沈着させた。
2.ADC(50ml)を3つ組の実験ウェルに、9000、3000、1000、333、111、37、12.4、4.1または1.4ng/mLという最終濃度になるように加え、「ADCなし」コントロールウェルには、培地のみを与え、3日間(PC3)または5日間(OVCAR−3)インキュベートした。
3.そのプレートを約30分間、室温に平衡化した。
4.CellTiter−Glo試薬(100ml)を加えた。
5.その内容物を回転シェーカー(orbital shaker)上で2分間混合することにより、細胞溶解を誘導した。
6.そのプレートを室温で10分間インキュベートすることにより、ルミネセンスシグナルを安定化させた。
7.ルミネセンスを記録し、RLU=相対ルミネセンス単位としてのグラフで報告した。ADCを含まない培地とともにインキュベートされた細胞からのデータを0.46ng/mlにおいてプロットした。
培地:PC3/neoおよびPC3/MUC16は、DMEM+Ham’s F012/10%FBS/グルタミン/250μg/mL G−418中で生育し、OVCAR−3は、RPMI/20%FBS/グルタミン中で生育する。
抗MUC16抗体−薬物結合体のインビボにおける性質を、Sprague−Dawleyラットへの単回の静脈内ボーラス投薬後に、抗体および薬物結合体の血清濃度を測定することによって、解析した。少なくとも1つの細胞傷害性薬物を有する抗体−薬物結合体の濃度を、捕捉用にMUC16細胞外ドメイン(ECD)タンパク質および検出用に抗MMAEおよび西洋ワサビペルオキシダーゼ(HRP)結合体化抗マウスFc抗体を用いるELISAで測定した。血清中の全Ch3A5濃度および全チオCh3A5濃度を、捕捉用にMUC16 ECDおよび検出用に抗ヒト−Fc HRPを用いるELISAで測定した。このアッセイは、結合体化MMAE有りおよび無しの両方で任意の抗MUC16抗体を測定した。このアッセイは、1:10の最低希釈で0.78ng/mLという定量化の下限を有する。このアッセイは、1:10の最低希釈で0.78ng/mLという定量化の下限を有する。各動物からの血清濃度−時間データを、IVボーラス注入、一次除去およびマクロ速度定数による2区画モデルを用いて解析した(Model 8,WinNonlin Pro v.5.0.1,Pharsight Corporation,Mountain View,CA)。
青年期雌ラット(100〜125g)における12日間の急性毒性研究を:1日目の、標準的なch3A5−VC−MMAE(24.19mg/kg=1934μg/m2)、チオch3A5−VC−MMAE(49.99mg/kg=1934μg/m2)およびコントロールビヒクルの単回注射によって行った。試験物の注射は、静脈内ボーラスとしてであった。体重を毎日測定した。5および12日目に、臨床化学、血清酵素および血液学の解析を行った。毒性シグナルには、体重減少の臨床所見が含められた。
雌C.B−17SCIDベージュマウス(Charles River Laboratories)を用いて有効性研究を行った。すべての研究をGuide for the Care and Use of Laboratory Animals(Institute of Laboratory Animal Resources,“Guide for the Care and Use of Laboratory Animals”,(NIH Publication #85−23).Washington(DC):National Academy Press;1996.)に従って行った。報告されているとおりに(Chenら(2007)Cancer Res 67:4924−4932)OVCAR−3乳房脂肪パッド移植有効性モデルを使用し、単回静脈内投薬後に腫瘍体積を評価した。
OVCAR−3細胞(1サンプルあたり30,000細胞)を、ヒト化標準またはチオ抗MUC16MAbとともに、総体積1mL中において75分間氷上でインキュベートした。抗体を、PBS+1%FBS+2mM EDTA中、25、50、100、200および400ng/mLで適用した。このインキュベートの後、細胞を洗浄し、次いで、フィコエリトリン(phycoerythrein)標識ヤギ抗ヒトFc二次抗体とともにインキュベートした(氷上で1時間)。次いで、細胞を洗浄し、フローサイトメトリーで解析した。3×104個のOVCAR−3細胞が、抗MUC16抗体3A5に対して約1×1010個の結合部位を発現する。試験された最低の抗体濃度(25ngまたは約1×1011個の抗体)でさえも、結合部位に対して過剰なモル濃度の抗体を提供する。ゆえに、結合が減少する濃度(フローサイトメトリーによって検出される)は、MUC16に対するこの抗体の親和性を反映する。抗MUC16バリアントの結合親和性を、従来の手順を用いて表面プラズモン共鳴および酵素結合免疫吸着測定法(ELISA)によって測定した。
Claims (57)
- MUC16ポリペプチドに結合し、1つ以上の遊離システインアミノ酸および配列番号9〜40から選択される配列を含む、システイン改変抗MUC16抗体。
- 親抗MUC16抗体の1つ以上のアミノ酸残基をシステインで置換する工程を包含するプロセスによって調製される、請求項1に記載のシステイン改変抗MUC16抗体。
- 前記1つ以上の遊離システインアミノ酸残基が、軽鎖に位置する、請求項1に記載のシステイン改変抗MUC16抗体。
- 以下:
- 以下:
- 前記1つ以上の遊離システインアミノ酸残基が、重鎖に位置する、請求項1に記載のシステイン改変抗MUC16抗体。
- 以下:
- 以下:
- 以下:
- 以下:
- 以下:
- 以下:
- 前記親抗MUC16抗体が、モノクローナル抗体、二重特異性抗体、キメラ抗体、ヒト抗体およびヒト化抗体から選択される、請求項1に記載のシステイン改変抗MUC16抗体。
- Fabフラグメントである、請求項1に記載のシステイン改変抗MUC16抗体。
- 細菌において産生される、請求項1に記載のシステイン改変抗MUC16抗体。
- CHO細胞において産生される、請求項1に記載のシステイン改変抗MUC16抗体。
- MUC16タンパク質を含むと疑われるサンプル中の該タンパク質の存在を判定する方法であって、該方法は、以下の工程:
該サンプルを、1つ以上の遊離システインアミノ酸および配列番号9〜40から選択される配列を有するシステイン改変抗MUC16抗体に曝露する工程、および;
該サンプル中の該抗体の該MUC16タンパク質への結合を測定する工程であって、ここで、該抗体の該タンパク質への結合は、該サンプル中の該タンパク質の存在を示す、工程
を包含する、方法。 - 前記細胞が、卵巣癌細胞、乳癌細胞、肺癌細胞または膵癌細胞である、請求項17に記載の方法。
- 前記抗体が、蛍光色素、放射性同位体、ビオチンまたは金属錯化リガンドから選択される標識に共有結合されている、請求項17に記載の方法。
- 前記抗体が、アウリスタチン薬物部分に共有結合されており、それによって、抗体−薬物結合体が形成されている、請求項1に記載のシステイン改変抗MUC16抗体。
- MUC16ポリペプチドに結合し、1つ以上の遊離システインアミノ酸および配列番号9〜40から選択される配列を含むシステイン改変抗MUC16抗体、ならびに薬学的に許容可能な希釈剤、キャリアまたは賦形剤を含む、薬学的処方物。
- MUC16ポリペプチドに結合し、1つ以上の遊離システインアミノ酸、配列番号9〜40から選択される配列を含むシステイン改変抗MUC16抗体(Ab)およびアウリスタチン薬物部分(D)を含む、抗体−薬物結合体であって、該システイン改変抗MUC16抗体は、1つ以上の遊離システインアミノ酸を介してリンカー部分(L)によってDに結合され;この複合物は、式I:
Ab−(L−D)p I
を有し、ここで、pは、1、2、3または4である、
抗体−薬物結合体。 - pが2である、請求項22に記載の抗体−薬物結合体複合物。
- Lが、式:
Aは、前記システイン改変抗体(Ab)のシステインチオールに共有結合されたストレッチャー単位であり;
aは、0または1であり;
各Wは、独立してアミノ酸単位であり;
wは、0〜12の範囲の整数であり;
Yは、前記薬物部分に共有結合されたスペーサー単位であり;そして
yは、0、1または2である、
請求項22に記載の抗体−薬物結合体複合物。 - 式:
請求項24に記載の抗体−薬物結合体複合物。 - Wwが、バリン−シトルリンである、請求項24に記載の抗体−薬物結合体複合物。
- R17が、(CH2)5または(CH2)2である、請求項24に記載の抗体−薬物結合体複合物。
- 式:
- R17が、(CH2)5または(CH2)2である、請求項28に記載の抗体−薬物結合体複合物。
- 式:
- Lが、MC−val−cit−PABまたはMCである、請求項22に記載の抗体薬物結合体。
- Lが、リンカー試薬のSMCC、BM(PEO)2またはBM(PEO)3によって形成されたリンカーである、請求項22に記載の抗体−薬物結合体複合物。
- Dが、構造:
- Dが、構造:
- 前記システイン改変抗MUC16抗体が、モノクローナル抗体、二重特異性抗体、キメラ抗体、ヒト抗体およびヒト化抗体から選択される、請求項22に記載の抗体−薬物結合体複合物。
- 前記システイン改変抗MUC16抗体が、Fabフラグメントである、請求項22に記載の抗体−薬物結合体複合物。
- 構造:
- Abが、配列番号1を含む、請求項37に記載の抗体薬物結合体。
- Abが、配列番号2を含む、請求項37に記載の抗体薬物結合体。
- Abが、配列番号3を含む、請求項37に記載の抗体薬物結合体。
- Abが、配列番号4を含む、請求項37に記載の抗体薬物結合体。
- Abが、配列番号1および配列番号2を含む、請求項37に記載の抗体薬物結合体。
- Abが、配列番号3および配列番号4を含む、請求項42に記載の抗体薬物結合体。
- MUC16ポリペプチドに結合し、1つ以上の遊離システインアミノ酸、配列番号9〜40から選択される配列を含むシステイン改変抗MUC16抗体(Ab)およびアウリスタチン薬物部分(D)を含む、抗体−薬物結合体複合物の混合物であって、ここで、該システイン改変抗MUC16抗体は、1つ以上の遊離システインアミノ酸を介してリンカー部分(L)によってDに結合され;該複合物は、式I:
Ab−(L−D)p I
を有し、ここで、pは、1、2、3または4であり、平均薬物負荷は、1〜2である、抗体−薬物結合体複合物の混合物。 - MUC16ポリペプチドに結合し、1つ以上の遊離システインアミノ酸および配列番号9〜40から選択される配列を含むシステイン改変抗MUC16抗体を含む抗体−薬物結合体、および薬学的に許容可能な希釈剤、キャリアまたは賦形剤を含む、薬学的処方物であって、ここで該システイン改変抗MUC16抗体は、アウリスタチン薬物部分に共有結合されている、薬学的処方物。
- レトロゾール、オキサリプラチン、ドセタキセル、5−FU、ラパチニブ、カペシタビン、ロイコボリン、エルロチニブ、パーツズマブ、ベバシズマブおよびゲムシタビンから選択される治療有効量の化学療法剤をさらに含む、請求項45に記載の薬学的処方物。
- MUC16ポリペプチドに結合し、1つ以上の遊離システインアミノ酸および配列番号9〜40から選択される配列を有するシステイン改変抗MUC16抗体を含む抗体−薬物結合体、および薬学的に許容可能な希釈剤、キャリアまたは賦形剤を含む薬学的処方物を患者に投与する工程を包含する、癌を処置する方法であって、ここで、該システイン改変抗MUC16抗体は、アウリスタチン薬物部分に共有結合されている、方法。
- 前記癌が、卵巣癌、前立腺癌、尿路の癌、膵癌、肺癌、乳癌および結腸癌からなる群から選択される、請求項47に記載の方法。
- 前記患者が、前記抗体−薬物結合体複合物とともに化学療法剤を投与され、ここで、該化学療法剤は、レトロゾール、シスプラチン、カルボプラチン、タキソール、パクリタキセル、オキサリプラチン、ドセタキセル、5−FU、ロイコボリン、エルロチニブ、パーツズマブ、ベバシズマブ、ラパチニブおよびゲムシタビンから選択される、請求項47に記載の方法。
- MUC16ポリペプチドに結合し、1つ以上の遊離システインアミノ酸および配列番号9〜40から選択される配列を有するシステイン改変抗MUC16抗体、および薬学的に許容可能な希釈剤、キャリアまたは賦形剤を含む抗体−薬物結合体を含む薬学的処方物であって、ここで、該システイン改変抗MUC16抗体は、アウリスタチン薬物部分に共有結合されている、薬学的処方物;
容器;および
該複合物が、MUC16ポリペプチドの過剰発現を特徴とする癌を処置するために使用され得ることを示している添付文書またはラベル
を備えた、製品。 - 前記癌が、卵巣癌、前立腺癌、尿路の癌、膵癌、肺癌、乳癌または結腸癌である、請求項50に記載の製品。
- MUC16ポリペプチドに結合し、1つ以上の遊離システインアミノ酸および配列番号9〜40から選択される配列を有するシステイン改変抗MUC16抗体(Ab)およびアウリスタチン薬物部分(D)を含む抗体薬物結合体複合物を作製するための方法であって、ここで、該システイン改変抗体は、該1つ以上の操作されたシステインアミノ酸を介してリンカー部分(L)によってDに結合され;該複合物は、式I:
Ab−(L−D)p I
を有し、ここで、pは、1、2、3または4であり;該方法は、以下の工程:
(a)該システイン改変抗体の操作されたシステイン基をリンカー試薬と反応させて、抗体−リンカー中間体Ab−Lを形成する工程;および
(b)Ab−Lを、活性化された薬物部分Dと反応させ;それによって、該抗体−薬物結合体複合物を形成する工程;
または、以下の工程:
(c)薬物部分の求核基をリンカー試薬と反応させて、薬物−リンカー中間体D−Lを形成する工程;および
(d)D−Lを、該システイン改変抗体の操作されたシステイン基と反応させ;それによって、該抗体−薬物結合体複合物を形成する工程
を包含する、方法。 - チャイニーズハムスター卵巣(CHO)細胞において、前記システイン改変抗体を発現させる工程をさらに包含する、請求項52に記載の方法。
- 前記発現されたシステイン改変抗体を還元剤で処理する工程をさらに包含する、請求項53に記載の方法。
- 前記還元剤が、TCEPおよびDTTから選択される、請求項54に記載の方法。
- 前記発現されたシステイン改変抗体を、前記還元剤で処理した後、酸化剤で処理する工程をさらに包含する、請求項55に記載の方法。
- 前記酸化剤が、硫酸銅、デヒドロアスコルビン酸および大気から選択される、請求項56に記載の方法。
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PCT/US2008/062903 WO2008141044A2 (en) | 2007-05-08 | 2008-05-07 | Cysteine engineered anti-muc16 antibodies and antibody drug conjugates |
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Cited By (12)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
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JP2015513541A (ja) * | 2012-02-24 | 2015-05-14 | アルテオジェン インコーポレイテッドAlteogen Inc. | システイン残基を含むモチーフが結合した修飾抗体、前記修飾抗体を含む修飾抗体−薬物複合体及びその製造方法 |
JP2016523961A (ja) * | 2013-07-09 | 2016-08-12 | ボード オブ リージェンツ オブ ザ ユニヴァーシティー オブ ネブラスカBoard Of Regents Of The University Of Nebraska | 癌を治療するための糖タンパク質の標的化方法 |
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JP2019524706A (ja) * | 2016-07-08 | 2019-09-05 | ジェネンテック, インコーポレイテッド | Muc16陽性癌治療の応答性を評価するためのヒト精巣上体タンパク質4(he4)の使用 |
JP2020128378A (ja) * | 2014-12-09 | 2020-08-27 | アッヴィ・インコーポレイテッド | Bcl−xL阻害性化合物およびこれを含む抗体薬物コンジュゲート |
JP2020143062A (ja) * | 2014-12-09 | 2020-09-10 | アッヴィ・インコーポレイテッド | 低細胞透過性を有するBcl−xL阻害性化合物およびこれを含む抗体薬物コンジュゲート |
JP2020529986A (ja) * | 2017-08-04 | 2020-10-15 | アムジエン・インコーポレーテツド | Cys−mabのコンジュゲーション方法 |
JP7504025B2 (ja) | 2017-08-04 | 2024-06-21 | アムジエン・インコーポレーテツド | Cys-mabのコンジュゲーション方法 |
Families Citing this family (207)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20100111856A1 (en) * | 2004-09-23 | 2010-05-06 | Herman Gill | Zirconium-radiolabeled, cysteine engineered antibody conjugates |
USRE47223E1 (en) * | 2005-06-20 | 2019-02-05 | Genentech, Inc. | Compositions and methods for the diagnosis and treatment of tumor |
AU2008251608B2 (en) | 2007-05-08 | 2014-03-27 | Genentech, Inc. | Cysteine engineered anti-MUC16 antibodies and antibody drug conjugates |
US8865875B2 (en) | 2007-08-22 | 2014-10-21 | Medarex, L.L.C. | Site-specific attachment of drugs or other agents to engineered antibodies with C-terminal extensions |
BRPI0818780A2 (pt) * | 2007-10-19 | 2015-04-22 | Genentech Inc | Anticorpo anti-tenb2 planejados por cisteína e conjugados de medicamento com anticorpos |
AU2009270988A1 (en) | 2008-07-15 | 2010-01-21 | Genentech, Inc. | Anthracycline derivative conjugates, process for their preparation and their use as antitumor compounds |
US8623828B2 (en) | 2008-12-05 | 2014-01-07 | The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services | Blocking mesothelin peptide fragments |
WO2010096394A2 (en) | 2009-02-17 | 2010-08-26 | Redwood Biosciences, Inc. | Aldehyde-tagged protein-based drug carriers and methods of use |
EP2400992B1 (en) | 2009-02-27 | 2015-07-22 | Genentech, Inc. | Methods and compositions for protein labelling |
BR112012000953A8 (pt) | 2009-07-15 | 2017-12-26 | Aimm Therapeutics Bv | anticorpos de ligação a bactérias gram-positivas, sequência de ácido nucleico,seus usos e seu método de produção, células isolada ou produtora de anticorpo isolado ou recombinante, composições, e método de isolamento de bactérias |
WO2011118739A1 (ja) * | 2010-03-26 | 2011-09-29 | 協和発酵キリン株式会社 | 新規修飾部位導入抗体および抗体フラグメント |
WO2011119979A2 (en) | 2010-03-26 | 2011-09-29 | Memorial Sloan-Kettering Cancer Center | Antibodies to muc16 and methods of use thereof |
BR112012026213B1 (pt) | 2010-04-15 | 2021-12-28 | Medimmune Limited | Compostos de pirrolobenzodiazepinas, conjugado das mesmas, composição farmacêutica compreendendo o conjugado e uso do mesmo para o tratamento de uma doença proliferativa |
MX336540B (es) | 2010-06-08 | 2016-01-22 | Genentech Inc | Conjugados y anticuerpos manipulados geneticamente con cisteina. |
CA2816426A1 (en) | 2010-11-17 | 2012-06-07 | Genentech, Inc. | Alaninyl maytansinol antibody conjugates |
MA34881B1 (fr) * | 2010-12-20 | 2014-02-01 | Genentech Inc | Anticorps et immunoconjugués anti-mésothéline |
CA2824143C (en) | 2011-01-14 | 2018-12-18 | Redwood Bioscience, Inc. | Aldehyde-tagged immunoglobulin polypeptides and method of use thereof |
MX346635B (es) | 2011-02-15 | 2017-03-27 | Immunogen Inc | Derivados citotoxicos de la benzodiazepina. |
CN110038135B (zh) | 2011-03-17 | 2021-03-05 | 伯明翰大学 | 重新定向的免疫治疗 |
UY34317A (es) | 2011-09-12 | 2013-02-28 | Genzyme Corp | Anticuerpo antireceptor de célula T (alfa)/ß |
CN103987407B (zh) | 2011-10-14 | 2016-08-24 | 麦迪穆有限责任公司 | 吡咯并苯并二氮杂卓及其偶联物 |
SG11201401518TA (en) | 2011-10-28 | 2014-05-29 | Teva Pharmaceuticals Australia Pty Ltd | Polypeptide constructs and uses thereof |
EP3539982A3 (en) | 2011-12-23 | 2020-01-15 | Pfizer Inc | Engineered antibody constant regions for site-specific conjugation and methods and uses therefor |
AU2013209512B2 (en) | 2012-01-20 | 2017-08-03 | I2 Pharmaceuticals, Inc. | Surrobody cojugates |
WO2013177481A1 (en) | 2012-05-25 | 2013-11-28 | Immunogen, Inc. | Benzodiazepines and conjugates thereof |
US9790268B2 (en) | 2012-09-12 | 2017-10-17 | Genzyme Corporation | Fc containing polypeptides with altered glycosylation and reduced effector function |
EP2906297B1 (en) | 2012-10-12 | 2017-12-06 | ADC Therapeutics SA | Pyrrolobenzodiazepine-antibody conjugates |
SI2906298T1 (sl) | 2012-10-12 | 2018-12-31 | Adc Therapeutics Sa | Konjugati pirolobenzodiazepin-protitelo |
WO2014057113A1 (en) | 2012-10-12 | 2014-04-17 | Adc Therapeutics Sarl | Pyrrolobenzodiazepine - anti-psma antibody conjugates |
TR201902494T4 (tr) | 2012-10-12 | 2019-03-21 | Medimmune Ltd | Pirrolobenzodiazepinler ve onların konjugatları. |
CA2941485C (en) | 2012-10-12 | 2018-06-12 | Philip Wilson Howard | Pyrrolobenzodiazepines and conjugates thereof |
CA2885305C (en) | 2012-10-12 | 2019-11-12 | Spirogen Sarl | Synthesis and intermediates of pyrrolobenzodiazepine derivatives for conjugation |
WO2014057114A1 (en) | 2012-10-12 | 2014-04-17 | Adc Therapeutics Sàrl | Pyrrolobenzodiazepine-anti-psma antibody conjugates |
BR112015008238A2 (pt) | 2012-10-12 | 2017-11-28 | Adc Therapeutics Sarl | conjugados de pirrolbenzodiazepina-anticorpo anti-cd22 |
JP6392764B2 (ja) | 2012-10-12 | 2018-09-19 | エイディーシー・セラピューティクス・エス・アーAdc Therapeutics Sa | ピロロベンゾジアゼピン−抗体結合体 |
US9353150B2 (en) | 2012-12-04 | 2016-05-31 | Massachusetts Institute Of Technology | Substituted pyrazino[1′,2′:1 ,5]pyrrolo[2,3-b]-indole-1,4-diones for cancer treatment |
US9393327B2 (en) | 2012-12-19 | 2016-07-19 | Genentech, Inc. | Methods and compositions for radiohalogen protein labeling |
CN105189507A (zh) | 2012-12-21 | 2015-12-23 | 斯皮罗根有限公司 | 吡咯并苯并二氮杂卓及其结合物 |
JP6527466B2 (ja) | 2012-12-21 | 2019-06-05 | メドイミューン・リミテッドMedImmune Limited | 増殖性疾患および自己免疫疾患の治療に使用するための非対称ピロロベンゾジアゼピンニ量体 |
CN103933575B (zh) | 2013-01-23 | 2017-09-29 | 上海新理念生物医药科技有限公司 | 一种三齿型连接子及其应用 |
KR102447350B1 (ko) * | 2013-02-08 | 2022-09-23 | 노파르티스 아게 | 면역접합체의 제조를 위한 항체의 변형에 사용되는 특정 부위 |
LT2958944T (lt) | 2013-02-22 | 2019-07-10 | Abbvie Stemcentrx Llc | Antikūno prieš dll3 ir pbd konjugatai bei jų panaudojimas |
EP2961434A2 (en) | 2013-02-28 | 2016-01-06 | ImmunoGen, Inc. | Conjugates comprising cell-binding agents and cytotoxic agents |
US9901647B2 (en) | 2013-02-28 | 2018-02-27 | Immunogen, Inc. | Conjugates comprising cell-binding agents and cytotoxic agents |
TWI636063B (zh) | 2013-03-08 | 2018-09-21 | 美國禮來大藥廠 | 結合il-23之抗體 |
CA2902530C (en) | 2013-03-11 | 2023-05-09 | Genzyme Corporation | Site-specific antibody-drug conjugation through glycoengineering |
EP2968585B1 (en) | 2013-03-13 | 2018-07-18 | Medimmune Limited | Pyrrolobenzodiazepines and conjugates thereof |
JP6340019B2 (ja) | 2013-03-13 | 2018-06-06 | メドイミューン・リミテッドMedImmune Limited | ピロロベンゾジアゼピン及びそのコンジュゲート |
SG11201507214SA (en) | 2013-03-13 | 2015-10-29 | Medimmune Ltd | Pyrrolobenzodiazepines and conjugates thereof |
MX2015011348A (es) | 2013-03-15 | 2016-01-15 | Regeneron Pharma | Moleculas biologicamente activas, conjugados de las mismas, y usos terapeuticos. |
PL3677591T3 (pl) | 2013-04-29 | 2023-06-26 | Teva Pharmaceuticals Australia Pty Ltd | Przeciwciała anty-cd38 i fuzje z interferonem alfa-2b o osłabionej aktywności |
US11117975B2 (en) | 2013-04-29 | 2021-09-14 | Teva Pharmaceuticals Australia Pty Ltd | Anti-CD38 antibodies and fusions to attenuated interferon alpha-2B |
MX369758B (es) | 2013-05-31 | 2019-11-20 | Genentech Inc | Anticuerpos anti-acido teicoico de pared y conjugados. |
EP3381939A1 (en) | 2013-05-31 | 2018-10-03 | Genentech, Inc. | Anti-wall teichoic antibodies and conjugates |
US9803002B2 (en) | 2013-05-31 | 2017-10-31 | Genentench, Inc. | Anti-wall teichoic antibodies and conjugates |
JP6208864B2 (ja) | 2013-06-24 | 2017-10-04 | エービーエルバイオ | 安定性が改善された抗体−薬物結合体およびこれの用途 |
JP6389880B2 (ja) | 2013-07-03 | 2018-09-12 | ソウル大学校産学協力団Seoul National University R&Db Foundation | システインで変形された鶏の抗体およびこれを用いた部位特異的接合 |
MX2016001862A (es) | 2013-08-12 | 2016-08-03 | Genentech Inc | Compuestos de conjugado anticuerpo-farmaco dimerico de 1-(clorometil)-2,3-dihidro-1h-benzo[e]indol, y metodos de uso y tratamiento. |
EA038192B1 (ru) | 2013-08-26 | 2021-07-21 | Регенерон Фармасьютикалз, Инк. | Фармацевтические композиции, содержащие диастереомеры макролида, способы их синтезирования и терапевтическое применение |
SG11201601424PA (en) | 2013-08-28 | 2016-03-30 | Stemcentrx Inc | Site-specific antibody conjugation methods and compositions |
GB201317981D0 (en) | 2013-10-11 | 2013-11-27 | Spirogen Sarl | Pyrrolobenzodiazepines and conjugates thereof |
US10010624B2 (en) | 2013-10-11 | 2018-07-03 | Medimmune Limited | Pyrrolobenzodiazepine-antibody conjugates |
GB201317982D0 (en) | 2013-10-11 | 2013-11-27 | Spirogen Sarl | Pyrrolobenzodiazepines and conjugates thereof |
WO2015052534A1 (en) | 2013-10-11 | 2015-04-16 | Spirogen Sàrl | Pyrrolobenzodiazepine-antibody conjugates |
EP3054986B1 (en) | 2013-10-11 | 2019-03-20 | Medimmune Limited | Pyrrolobenzodiazepine-antibody conjugates |
SG11201603397QA (en) | 2013-11-06 | 2016-05-30 | Stemcentrx Inc | Novel anti-claudin antibodies and methods of use |
RS62157B1 (sr) * | 2013-11-19 | 2021-08-31 | Remegen Co Ltd | Anti-her2 antitelo i njegov konjugat |
MX2016007369A (es) | 2013-12-12 | 2016-09-08 | Stemcentrx Inc | Nuevos anticuerpos anti-dpep3 y metodos de uso. |
WO2015095223A2 (en) | 2013-12-16 | 2015-06-25 | Genentech, Inc. | Peptidomimetic compounds and antibody-drug conjugates thereof |
EP3082875B1 (en) | 2013-12-16 | 2020-11-25 | Genentech, Inc. | Peptidomimetic compounds and antibody-drug conjugates thereof |
JP6980384B2 (ja) | 2013-12-16 | 2021-12-15 | ジェネンテック, インコーポレイテッド | 1−(クロロメチル)−2,3−ジヒドロ−1h−ベンゾ[e]インドール二量体抗体−薬物コンジュゲート化合物、並びに使用及び処置の方法 |
SG11201606898TA (en) | 2014-02-21 | 2016-09-29 | Stemcentrx Inc | Anti-dll3 antibodies and drug conjugates for use in melanoma |
CN104788566A (zh) * | 2014-03-11 | 2015-07-22 | 南京任诺药业有限公司 | 用于构建放射性同位素偶联标记的ADC药物的改造抗体IgG1-CH-V280C |
CN104672330A (zh) * | 2014-03-11 | 2015-06-03 | 南京任诺药业有限公司 | 用于构建放射性同位素偶联标记的ADC药物的改造抗体IgG1-CH-N267C |
PT3129067T (pt) | 2014-03-19 | 2023-03-22 | Genzyme Corp | Glicomanipulação em sítios específicos de frações de direcionamento |
GB201406767D0 (en) | 2014-04-15 | 2014-05-28 | Cancer Rec Tech Ltd | Humanized anti-Tn-MUC1 antibodies anf their conjugates |
PT3134124T (pt) | 2014-04-25 | 2019-06-03 | Pf Medicament | Conjugado anticorpo-fármaco igf-1r e a sua utilização para o tratamento de cancro |
CA2946796C (en) | 2014-04-25 | 2019-10-22 | Pierre Fabre Medicament | Antibody-drug-conjugate and its use for the treatment of cancer |
JP6835591B2 (ja) | 2014-04-25 | 2021-02-24 | ピエール、ファーブル、メディカマン | Igf−1r抗体および癌処置のためのアドレッシングビヒクルとしてのその使用 |
UA119352C2 (uk) | 2014-05-01 | 2019-06-10 | Тева Фармасьютикалз Острейліа Пті Лтд | Комбінація леналідоміду або помалідоміду і конструкції анти-cd38 антитіло-атенуйований інтерферон альфа-2b та спосіб лікування суб'єкта, який має cd38-експресуючу пухлину |
JP6956630B2 (ja) | 2014-07-24 | 2021-11-02 | ジェネンテック, インコーポレイテッド | 薬剤の少なくとも1つのトリスルフィド結合を含むタンパク質中のチオール部分へのコンジュゲーション方法 |
TW201617368A (zh) | 2014-09-05 | 2016-05-16 | 史坦森特瑞斯公司 | 新穎抗mfi2抗體及使用方法 |
JP6531166B2 (ja) | 2014-09-10 | 2019-06-12 | メドイミューン・リミテッドMedImmune Limited | ピロロベンゾジアゼピン及びそのコンジュゲート |
EP3388449A3 (en) | 2014-09-12 | 2018-10-24 | F. Hoffmann-La Roche AG | Cysteine engineered antibodies and conjugates |
GB201416112D0 (en) | 2014-09-12 | 2014-10-29 | Medimmune Ltd | Pyrrolobenzodiazepines and conjugates thereof |
JP6622293B2 (ja) | 2014-09-12 | 2019-12-18 | ジェネンテック, インコーポレイテッド | アントラサイクリンジスルフィド中間体、抗体−薬物複合体、及び方法 |
EP3197500A1 (en) | 2014-09-17 | 2017-08-02 | Genentech, Inc. | Immunoconjugates comprising anti-her2 antibodies and pyrrolobenzodiazepines |
CR20170099A (es) | 2014-09-17 | 2017-07-19 | Genentech Inc | Pirrolobenzodiazepinas y conjugados de anticuerpos-disulfuro de las mismas |
MX2017004664A (es) | 2014-10-09 | 2017-06-30 | Genzyme Corp | Conjugados de farmacos de anticuerpos modificados mediante glicoingenieria. |
JP6784668B2 (ja) * | 2014-10-10 | 2020-11-11 | ファイザー・インク | 相乗的オーリスタチン組合せ |
KR102639037B1 (ko) | 2014-10-29 | 2024-02-20 | 테바 파마슈티컬즈 오스트레일리아 피티와이 엘티디 | 인터페론 α2b 변이체 |
AU2015352545B2 (en) | 2014-11-25 | 2020-10-15 | Adc Therapeutics Sa | Pyrrolobenzodiazepine-antibody conjugates |
RU2017118792A (ru) * | 2014-12-03 | 2019-01-09 | Дженентек, Инк. | Конъюгаты антитела к staphylococcus aureus с рифамицином и их применение |
MX2017007169A (es) | 2014-12-03 | 2018-05-02 | Genentech Inc | Compuestos de amina cuaternaria y conjugados de anticuerpofármaco de los mismos. |
KR20170086536A (ko) * | 2014-12-03 | 2017-07-26 | 제넨테크, 인크. | 항-스타필로코커스 아우레우스 항체 리파마이신 접합체 및 이의 용도 |
AU2015366284B2 (en) * | 2014-12-19 | 2021-07-22 | Ablynx N.V. | Cysteine linked nanobody dimers |
CN107667120B (zh) | 2015-03-17 | 2022-03-08 | 纪念斯隆-凯特林癌症中心 | 抗muc16抗体及其应用 |
GB201506389D0 (en) | 2015-04-15 | 2015-05-27 | Berkel Patricius H C Van And Howard Philip W | Site-specific antibody-drug conjugates |
GB201506402D0 (en) | 2015-04-15 | 2015-05-27 | Berkel Patricius H C Van And Howard Philip W | Site-specific antibody-drug conjugates |
GB201506411D0 (en) | 2015-04-15 | 2015-05-27 | Bergenbio As | Humanized anti-axl antibodies |
AU2015242213A1 (en) | 2015-07-12 | 2018-03-08 | Hangzhou Dac Biotech Co., Ltd | Bridge linkers for conjugation of cell-binding molecules |
US9839687B2 (en) | 2015-07-15 | 2017-12-12 | Suzhou M-Conj Biotech Co., Ltd. | Acetylenedicarboxyl linkers and their uses in specific conjugation of a cell-binding molecule |
GB201514928D0 (en) | 2015-08-21 | 2015-10-07 | King S College London | PDD compounds |
MA45326A (fr) | 2015-10-20 | 2018-08-29 | Genentech Inc | Conjugués calichéamicine-anticorps-médicament et procédés d'utilisation |
US9669106B2 (en) | 2015-10-26 | 2017-06-06 | Pierre Fabre Medicament | Conjugate of monomethyl auristatin F and trastuzumab and its use for the treatment of cancer |
JP6968790B2 (ja) | 2015-10-26 | 2021-11-17 | ピエール、ファーブル、メディカマン | Igf−1r発現癌の処置のための組成物 |
US20180362619A1 (en) | 2015-12-21 | 2018-12-20 | Bristol-Myers Squibb Company | Variant antibodies for site-specific conjugation |
SG11201805420SA (en) * | 2015-12-30 | 2018-07-30 | Kodiak Sciences Inc | Antibodies and conjugates thereof |
CN114478801A (zh) | 2016-01-25 | 2022-05-13 | 里珍纳龙药品有限公司 | 美登素类化合物衍生物、其偶联物和使用方法 |
GB201601431D0 (en) | 2016-01-26 | 2016-03-09 | Medimmune Ltd | Pyrrolobenzodiazepines |
GB201602356D0 (en) | 2016-02-10 | 2016-03-23 | Medimmune Ltd | Pyrrolobenzodiazepine Conjugates |
GB201602359D0 (en) | 2016-02-10 | 2016-03-23 | Medimmune Ltd | Pyrrolobenzodiazepine Conjugates |
AU2017228468B2 (en) | 2016-03-04 | 2019-12-05 | Genentech, Inc. | Process for the preparation of an antibody-rifamycin conjugate |
US20170315132A1 (en) | 2016-03-25 | 2017-11-02 | Genentech, Inc. | Multiplexed total antibody and antibody-conjugated drug quantification assay |
CA3019398A1 (en) | 2016-04-26 | 2017-11-02 | R.P. Scherer Technologies, Llc | Antibody conjugates and methods of making and using the same |
GB201607478D0 (en) | 2016-04-29 | 2016-06-15 | Medimmune Ltd | Pyrrolobenzodiazepine Conjugates |
US10918627B2 (en) | 2016-05-11 | 2021-02-16 | Massachusetts Institute Of Technology | Convergent and enantioselective total synthesis of Communesin analogs |
WO2017201449A1 (en) | 2016-05-20 | 2017-11-23 | Genentech, Inc. | Protac antibody conjugates and methods of use |
WO2017205741A1 (en) | 2016-05-27 | 2017-11-30 | Genentech, Inc. | Bioanalytical method for the characterization of site-specific antibody-drug conjugates |
JP7043425B2 (ja) | 2016-06-06 | 2022-03-29 | ジェネンテック, インコーポレイテッド | シルベストロール抗体-薬物コンジュゲート及び使用方法 |
EP3487522A4 (en) | 2016-07-19 | 2020-04-01 | Teva Pharmaceuticals Australia Pty Ltd | ANTI-CD47 COMBINATION THERAPY |
WO2018027204A1 (en) | 2016-08-05 | 2018-02-08 | Genentech, Inc. | Multivalent and multiepitopic anitibodies having agonistic activity and methods of use |
EP3515487B1 (en) | 2016-09-23 | 2023-07-19 | Regeneron Pharmaceuticals, Inc. | Bi specific anti-muc16-cd3 antibodies and anti-muc16 drug conjugates |
WO2018065501A1 (en) | 2016-10-05 | 2018-04-12 | F. Hoffmann-La Roche Ag | Methods for preparing antibody drug conjugates |
CN107789630A (zh) * | 2016-10-08 | 2018-03-13 | 四川百利药业有限责任公司 | 半胱氨酸改造的抗体‑毒素偶联物及其制备方法 |
GB201617466D0 (en) | 2016-10-14 | 2016-11-30 | Medimmune Ltd | Pyrrolobenzodiazepine conjugates |
KR102345175B1 (ko) | 2016-11-14 | 2021-12-31 | 항저우 디에이씨 바이오테크 씨오, 엘티디 | 결합 링커, 그러한 결합 링커를 함유하는 세포 결합 분자-약물 결합체, 링커를 갖는 그러한 결합체의 제조 및 사용 |
WO2018102682A1 (en) | 2016-12-01 | 2018-06-07 | Regeneron Pharmaceuticals, Inc. | Radiolabeled anti-pd-l1 antibodies for immuno-pet imaging |
BR112019016420A2 (pt) | 2017-02-08 | 2020-04-07 | Adc Therapeutics Sa | conjugados pirrolobenzodiazepina-anticorpo |
RU2759602C2 (ru) * | 2017-02-08 | 2021-11-16 | Пфайзер Инк. | Процесс крупномасштабного производства кэпированных и некэпированных цистеинов антител и их применение для конъюгации терапевтических белков |
LT3544636T (lt) | 2017-02-08 | 2021-06-25 | Adc Therapeutics Sa | Pirolobenzodiazepino-antikūno konjugatai |
GB201702031D0 (en) | 2017-02-08 | 2017-03-22 | Medlmmune Ltd | Pyrrolobenzodiazepine-antibody conjugates |
HUE059828T2 (hu) | 2017-04-18 | 2023-01-28 | Medimmune Ltd | Pirrolobenzodiazepin konjugátumok |
EP3612234B1 (en) | 2017-04-20 | 2024-03-13 | ADC Therapeutics SA | Combination therapy with an anti-axl antibody-drug conjugate |
KR20200014294A (ko) | 2017-04-26 | 2020-02-10 | 유레카 쎄라퓨틱스, 인코포레이티드 | 키메라 항체/t-세포 수용체 구축물 및 그의 용도 |
WO2018209239A1 (en) | 2017-05-11 | 2018-11-15 | Massachusetts Institute Of Technology | Potent agelastatin derivatives as modulators for cancer invasion and metastasis |
WO2018210824A1 (en) * | 2017-05-16 | 2018-11-22 | Universite De Strasbourg | Protein-drug conjugates and their use in the treatment of cancers |
BR112019026564A2 (pt) | 2017-06-14 | 2020-06-30 | Adc Therapeutics Sa | regimes de dosagem para a administração de um adc anti-cd19 |
AU2018288029B2 (en) * | 2017-06-19 | 2021-12-23 | Baili-Bio (Chengdu) Pharmaceutical Co., Ltd. | Antibody-drug conjugate having acidic self-stabilization junction |
CA3098491A1 (en) * | 2017-06-20 | 2018-12-27 | Sichuan Baili Pharm Co. Ltd | Screening of fixed-point coupling sites of cysteine-modified antibody-toxin conjugate (tdc) |
AU2018316532B2 (en) | 2017-08-18 | 2022-11-24 | Medimmune Limited | Pyrrolobenzodiazepine conjugates |
CN107583058B (zh) * | 2017-09-20 | 2020-09-18 | 厉保秋 | 一种t-2毒素-抗体缀合物及其用途 |
US11364303B2 (en) | 2017-09-29 | 2022-06-21 | Pfizer Inc. | Cysteine engineered antibody drug conjugates |
US10640508B2 (en) | 2017-10-13 | 2020-05-05 | Massachusetts Institute Of Technology | Diazene directed modular synthesis of compounds with quaternary carbon centers |
WO2019084030A1 (en) | 2017-10-24 | 2019-05-02 | Genentech, Inc. | (4-HYDROXYPYRROLIDIN-2-YL) -HYDROXAMATE COMPOUNDS AND METHODS OF USE |
EP3700901A1 (en) | 2017-10-24 | 2020-09-02 | Genentech, Inc. | (4-hydroxypyrrolidin-2-yl)-heterocyclic compounds and methods of use thereof |
WO2019100005A1 (en) * | 2017-11-18 | 2019-05-23 | De Magalhaes Nzola | Product and process for employing gc7 (n1-guanyl-1,7-diaminoheptane) based antigen binding conjugates in cancer therapy |
GB201803342D0 (en) | 2018-03-01 | 2018-04-18 | Medimmune Ltd | Methods |
WO2019183523A1 (en) | 2018-03-23 | 2019-09-26 | Genentech, Inc. | Hetero-bifunctional degrader compounds and their use as modulators of targeted ubiquination (vhl) |
GB201806022D0 (en) | 2018-04-12 | 2018-05-30 | Medimmune Ltd | Pyrrolobenzodiazepines and conjugates thereof |
CN108727499B (zh) * | 2018-04-24 | 2021-12-31 | 四川百利药业有限责任公司 | 半胱氨酸改造的抗体-毒素偶联物 |
CN108727498B (zh) * | 2018-04-24 | 2021-11-26 | 四川百利药业有限责任公司 | 半胱氨酸改造的抗体-毒素偶联物 |
CN108743966B (zh) * | 2018-04-24 | 2021-10-19 | 四川百利药业有限责任公司 | 半胱氨酸改造的抗体-毒素偶联物 |
CN108714220B (zh) * | 2018-04-24 | 2021-11-19 | 四川百利药业有限责任公司 | 半胱氨酸改造的抗体-毒素偶联物 |
WO2019236577A2 (en) | 2018-06-04 | 2019-12-12 | Intrexon Corporation | Muc16 specific chimeric antigen receptors and uses thereof |
GB201814281D0 (en) | 2018-09-03 | 2018-10-17 | Femtogenix Ltd | Cytotoxic agents |
WO2020055976A1 (en) | 2018-09-11 | 2020-03-19 | Genentech, Inc. | Tert-butyl (s)-2-(4-(phenyl)-6h-thieno[3,2-f][1,2,4]triazolo[4,3-a] [1,4]diazepin-6-yl) acetate derivatives and related compounds as bromodomain brd4 inhibitors for treating cancer |
CA3115136A1 (en) | 2018-10-19 | 2020-04-23 | Medimmune Limited | Pyrrolobenzodiazepine conjugates |
EP3866857A1 (en) | 2018-10-19 | 2021-08-25 | MedImmune Limited | Pyrrolobenzodiazepine conjugates |
CN113227119A (zh) | 2018-12-10 | 2021-08-06 | 基因泰克公司 | 用于与含Fc的蛋白质进行位点特异性缀合的光交联肽 |
CN113226472A (zh) | 2018-12-17 | 2021-08-06 | 雷维托普有限公司 | 双免疫细胞衔接物 |
GB201901197D0 (en) | 2019-01-29 | 2019-03-20 | Femtogenix Ltd | G-A Crosslinking cytotoxic agents |
EP3924378A4 (en) | 2019-02-15 | 2023-04-05 | WuXi Biologics Ireland Limited | METHODS FOR THE PRODUCTION OF ANTIBODY-DRUG CONJUGATES WITH IMPROVED HOMOGENEITY |
JP2022524880A (ja) | 2019-03-15 | 2022-05-10 | メドイミューン・リミテッド | がんの治療における使用のための、アゼチドベンゾジアゼピン二量体及びこれを含む複合体 |
CN113631196B (zh) | 2019-03-29 | 2024-03-15 | 免疫医疗有限公司 | 化合物及其缀合物 |
CN111825742B (zh) * | 2019-04-18 | 2024-01-30 | 陈铭 | Ctpa作为特种偶合剂用于氨基酸离子液体的多肽固相合成 |
US11535634B2 (en) | 2019-06-05 | 2022-12-27 | Massachusetts Institute Of Technology | Compounds, conjugates, and compositions of epipolythiodiketopiperazines and polythiodiketopiperazines and uses thereof |
GB201908128D0 (en) | 2019-06-07 | 2019-07-24 | Adc Therapeutics Sa | Pyrrolobenzodiazepine-antibody conjugates |
AU2020291014A1 (en) | 2019-06-13 | 2022-01-27 | Bolt Biotherapeutics, Inc. | Aminobenzazepine compounds, immunoconjugates, and uses thereof |
WO2021000067A1 (zh) | 2019-06-29 | 2021-01-07 | 杭州多禧生物科技有限公司 | 一种细胞结合分子-Tubulysin衍生物偶联物及其制备方法 |
US20220313835A1 (en) | 2019-09-03 | 2022-10-06 | Bolt Biotherapeutics, Inc. | Aminoquinoline compounds, immunoconjugates, and uses thereof |
MX2022003740A (es) | 2019-09-30 | 2022-05-02 | Bolt Biotherapeutics Inc | Inmunoconjugados de aminobenzazepina unidos a amida y usos de estos. |
US11912784B2 (en) | 2019-10-10 | 2024-02-27 | Kodiak Sciences Inc. | Methods of treating an eye disorder |
WO2021080608A1 (en) | 2019-10-25 | 2021-04-29 | Medimmune, Llc | Branched moiety for use in conjugates |
WO2021081407A1 (en) | 2019-10-25 | 2021-04-29 | Bolt Biotherapeutics, Inc. | Thienoazepine immunoconjugates, and uses thereof |
CN110922476A (zh) * | 2019-12-16 | 2020-03-27 | 蓝怡科技集团股份有限公司 | 一种生物素偶联抗体及其制备方法和应用 |
MX2022009052A (es) | 2020-01-22 | 2022-08-15 | Medimmune Ltd | Compuestos y conjugados de estos. |
TW202140076A (zh) | 2020-01-22 | 2021-11-01 | 英商梅迪繆思有限公司 | 化合物及其軛合物 |
JP2023524271A (ja) | 2020-05-08 | 2023-06-09 | ボルト バイオセラピューティクス、インコーポレーテッド | エラスターゼ-基質ペプチドリンカーイムノコンジュゲート、及びそれらの使用 |
GB2597532A (en) | 2020-07-28 | 2022-02-02 | Femtogenix Ltd | Cytotoxic compounds |
GB202011993D0 (en) | 2020-07-31 | 2020-09-16 | Adc Therapeutics Sa | ANTI-IL 13Ra2 antibodies |
WO2022036101A1 (en) | 2020-08-13 | 2022-02-17 | Bolt Biotherapeutics, Inc. | Pyrazoloazepine immunoconjugates, and uses thereof |
CA3193584A1 (en) | 2020-09-04 | 2022-03-10 | Novarock Biotherapeutics, Ltd. | Nectin-4 antibodies and uses thereof |
AR123480A1 (es) | 2020-09-11 | 2022-12-07 | Medimmune Ltd | Moléculas de unión terapéuticas |
IL303491A (en) | 2020-12-11 | 2023-08-01 | Bolt Biotherapeutics Inc | Anti-PD-L1 immunoconjugates and uses thereof |
US20220195066A1 (en) | 2020-12-11 | 2022-06-23 | Bolt Biotherapeutics, Inc. | Anti-cea immunoconjugates, and uses thereof |
WO2022125891A2 (en) | 2020-12-11 | 2022-06-16 | Bolt Biotherapeutics, Inc. | Anti-cea immunoconjugates, and uses thereof |
US20240091370A1 (en) | 2020-12-11 | 2024-03-21 | Bolt Biotherapeutics, Inc. | Anti-her2 immunoconjugates, and uses thereof |
CN116897054A (zh) | 2020-12-11 | 2023-10-17 | 博尔特生物治疗药物有限公司 | 抗her2免疫缀合物及其用途 |
EP4046996A1 (en) | 2021-02-19 | 2022-08-24 | Universität Bielefeld | Cryptophycin compounds and conjugates thereof |
CN114957476A (zh) * | 2021-02-23 | 2022-08-30 | 复旦大学 | 一种半胱氨酸工程化的结合人5t4的全人源纳米抗体 |
WO2022197877A1 (en) | 2021-03-19 | 2022-09-22 | Genentech, Inc. | Methods and compositions for time delayed bio-orthogonal release of cytotoxic agents |
EP4313162A1 (en) | 2021-03-26 | 2024-02-07 | Bolt Biotherapeutics, Inc. | 2-amino-4-carboxamide-benzazepine immunoconjugates, and uses thereof |
JP2024512056A (ja) | 2021-03-26 | 2024-03-18 | ボルト バイオセラピューティクス、インコーポレーテッド | 2-アミノ-4-カルボキサミド-ベンゾアゼピン免疫複合体、及びその使用 |
GB202105187D0 (en) | 2021-04-12 | 2021-05-26 | Medimmune Ltd | Pyrrolobenzodiazepine conjugates |
WO2023076599A1 (en) | 2021-10-29 | 2023-05-04 | Bolt Biotherapeutics, Inc. | Tlr agonist immunoconjugates with cysteine-mutant antibodies, and uses thereof |
WO2023083846A1 (en) | 2021-11-10 | 2023-05-19 | Astrazeneca Ab | Antibody molecules and conjugates |
WO2023088966A1 (en) | 2021-11-19 | 2023-05-25 | Adc Therapeutics Sa | Anti-psma conjugates |
US20230285580A1 (en) | 2021-11-19 | 2023-09-14 | Adc Therapeutics Sa | Anti-il-13ralpha2 conjugates |
TW202348252A (zh) | 2022-02-16 | 2023-12-16 | 英商梅迪繆思有限公司 | 用治療性結合分子治療癌症的組合療法 |
EP4230222A1 (en) | 2022-02-17 | 2023-08-23 | Oxsonics Limited | Combination therapy with an anti-axl antibody-pbd conjugate and nanocups |
WO2023160982A1 (en) | 2022-02-28 | 2023-08-31 | Adc Therapeutics Sa | Dosage regimen |
WO2023169896A1 (en) | 2022-03-09 | 2023-09-14 | Astrazeneca Ab | BINDING MOLECULES AGAINST FRα |
WO2023170216A1 (en) | 2022-03-11 | 2023-09-14 | Astrazeneca Ab | A SCORING METHOD FOR AN ANTI-FRα ANTIBODY-DRUG CONJUGATE THERAPY |
WO2024002938A1 (en) | 2022-06-27 | 2024-01-04 | Astrazeneca Ab | Combinations involving epidermal growth factor receptor tyrosine kinase inhibitors for the treatment of cancer |
WO2024052684A1 (en) | 2022-09-09 | 2024-03-14 | MyricX Pharma Limited | Antibody drug conjugate comprising nmt inhibitor and its use |
US20240165257A1 (en) | 2022-11-01 | 2024-05-23 | Heidelberg Pharma Research Gmbh | Anti-gucy2c antibody and uses thereof |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2005081711A2 (en) * | 2003-11-06 | 2005-09-09 | Seattle Genetics, Inc. | Monomethylvaline compounds capable of conjugation to ligands |
WO2006034488A2 (en) * | 2004-09-23 | 2006-03-30 | Genentech, Inc. | Cysteine engineered antibodies and conjugates |
WO2006132670A2 (en) * | 2004-11-12 | 2006-12-14 | Seattle Genetics, Inc. | Auristatins having an aminobenzoic acid unit at the n terminus |
Family Cites Families (33)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB8720833D0 (en) | 1987-09-04 | 1987-10-14 | Celltech Ltd | Recombinant dna product |
US5635483A (en) | 1992-12-03 | 1997-06-03 | Arizona Board Of Regents Acting On Behalf Of Arizona State University | Tumor inhibiting tetrapeptide bearing modified phenethyl amides |
US5780588A (en) | 1993-01-26 | 1998-07-14 | Arizona Board Of Regents | Elucidation and synthesis of selected pentapeptides |
ATE282630T1 (de) | 1993-10-01 | 2004-12-15 | Teikoku Hormone Mfg Co Ltd | Dolastatin-derivate |
GB9424449D0 (en) | 1994-12-02 | 1995-01-18 | Wellcome Found | Antibodies |
US5663149A (en) | 1994-12-13 | 1997-09-02 | Arizona Board Of Regents Acting On Behalf Of Arizona State University | Human cancer inhibitory pentapeptide heterocyclic and halophenyl amides |
US6037454A (en) | 1996-11-27 | 2000-03-14 | Genentech, Inc. | Humanized anti-CD11a antibodies |
AU743758B2 (en) | 1997-04-07 | 2002-02-07 | Genentech Inc. | Anti-VEGF antibodies |
US5994511A (en) * | 1997-07-02 | 1999-11-30 | Genentech, Inc. | Anti-IgE antibodies and methods of improving polypeptides |
US6753165B1 (en) | 1999-01-14 | 2004-06-22 | Bolder Biotechnology, Inc. | Methods for making proteins containing free cysteine residues |
US7083950B2 (en) | 1998-09-25 | 2006-08-01 | Regeneron Pharmaceuticals, Inc. | High affinity fusion proteins and therapeutic and diagnostic methods for use |
US20020119158A1 (en) | 1998-12-17 | 2002-08-29 | Corixa Corporation | Compositions and methods for the therapy and diagnosis of ovarian cancer |
US6858710B2 (en) | 1998-12-17 | 2005-02-22 | Corixa Corporation | Compositions and methods for the therapy and diagnosis of ovarian cancer |
US6884869B2 (en) | 2001-04-30 | 2005-04-26 | Seattle Genetics, Inc. | Pentapeptide compounds and uses related thereto |
WO2002092836A2 (en) | 2001-05-11 | 2002-11-21 | Sloan-Kettering Institute For Cancer Research | Nucleic acid sequence encoding ovarian antigen, ca125, and uses thereof |
US6441163B1 (en) | 2001-05-31 | 2002-08-27 | Immunogen, Inc. | Methods for preparation of cytotoxic conjugates of maytansinoids and cell binding agents |
US7803915B2 (en) | 2001-06-20 | 2010-09-28 | Genentech, Inc. | Antibody compositions for the diagnosis and treatment of tumor |
WO2003043583A2 (en) | 2001-11-20 | 2003-05-30 | Seattle Genetics, Inc. | Treatment of immunological disorders using anti-cd30 antibodies |
WO2003049704A2 (en) | 2001-12-11 | 2003-06-19 | University Of Massachusetts | Antibodies to treat cancer |
AU2002316365A1 (en) | 2002-06-21 | 2004-01-06 | Lewyn B. Boler Jr. | Device and system for coating a surface |
JP2006502110A (ja) | 2002-07-03 | 2006-01-19 | イミュノジェン・インコーポレーテッド | 非放出Muc1およびMuc16に対する抗体、およびその使用 |
ES2544527T3 (es) | 2002-07-31 | 2015-09-01 | Seattle Genetics, Inc. | Conjugados de fármacos y su uso para tratar el cáncer, una enfermedad autoinmune o una enfermedad infecciosa |
HUE034378T2 (en) | 2002-10-16 | 2018-02-28 | Purdue Pharma Lp | Cell-associated CA 125 / O722P binding antibodies and methods of use |
JP2006516189A (ja) | 2002-11-15 | 2006-06-29 | ザ ボード オブ トラスティーズ オブ ザ ユニバーシティ オブ アーカンソー | Ca125遺伝子、および診断および治療のためのその使用 |
WO2004072286A1 (ja) | 2003-01-23 | 2004-08-26 | Ono Pharmaceutical Co., Ltd. | ヒトpd−1に対し特異性を有する物質 |
ATE452147T1 (de) | 2004-02-19 | 2010-01-15 | Genentech Inc | Antikörper mit korrigierten cdr |
EP2286844A3 (en) | 2004-06-01 | 2012-08-22 | Genentech, Inc. | Antibody-drug conjugates and methods |
ES2690079T3 (es) * | 2004-09-03 | 2018-11-19 | Genentech, Inc. | Antagonistas anti-beta7 humanizados y utilizaciones para los mismos |
US8404803B2 (en) | 2005-03-31 | 2013-03-26 | Chugai Seiyaku Kabushiki Kaisha | Cancer-associated antigen analogue peptides and uses thereof |
KR101103108B1 (ko) * | 2005-06-20 | 2012-01-04 | 제넨테크, 인크. | 종양의 진단 및 치료를 위한 조성물 및 방법 |
WO2007008848A2 (en) | 2005-07-07 | 2007-01-18 | Seattle Genetics, Inc. | Monomethylvaline compounds having phenylalanine carboxy modifications at the c-terminus |
AR059900A1 (es) | 2006-03-17 | 2008-05-07 | Genentech Inc | Anticuerpos anti-tat226 e inmunoconjugados |
AU2008251608B2 (en) | 2007-05-08 | 2014-03-27 | Genentech, Inc. | Cysteine engineered anti-MUC16 antibodies and antibody drug conjugates |
-
2008
- 2008-05-07 AU AU2008251608A patent/AU2008251608B2/en not_active Ceased
- 2008-05-07 CN CN2008800230241A patent/CN101687037B/zh not_active Expired - Fee Related
- 2008-05-07 EP EP08747785A patent/EP2144628B1/en active Active
- 2008-05-07 AR ARP080101935A patent/AR066476A1/es unknown
- 2008-05-07 JP JP2010507620A patent/JP5290276B2/ja not_active Expired - Fee Related
- 2008-05-07 WO PCT/US2008/062903 patent/WO2008141044A2/en active Application Filing
- 2008-05-07 TW TW097116902A patent/TW200902554A/zh unknown
- 2008-05-07 CA CA002683568A patent/CA2683568A1/en not_active Abandoned
- 2008-05-07 US US12/116,457 patent/US7723485B2/en not_active Ceased
- 2008-05-07 CL CL200801334A patent/CL2008001334A1/es unknown
- 2008-05-07 PE PE2008000796A patent/PE20090245A1/es not_active Application Discontinuation
-
2015
- 2015-04-07 US US14/680,457 patent/USRE47194E1/en active Active
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2005081711A2 (en) * | 2003-11-06 | 2005-09-09 | Seattle Genetics, Inc. | Monomethylvaline compounds capable of conjugation to ligands |
WO2006034488A2 (en) * | 2004-09-23 | 2006-03-30 | Genentech, Inc. | Cysteine engineered antibodies and conjugates |
WO2006132670A2 (en) * | 2004-11-12 | 2006-12-14 | Seattle Genetics, Inc. | Auristatins having an aminobenzoic acid unit at the n terminus |
Non-Patent Citations (1)
Title |
---|
JPN6012069044; J. Biol. Chem., 2000, Vol.275, pp.30445-30450 * |
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EP2144628A2 (en) | 2010-01-20 |
US20080311134A1 (en) | 2008-12-18 |
AU2008251608B2 (en) | 2014-03-27 |
CL2008001334A1 (es) | 2008-09-22 |
PE20090245A1 (es) | 2009-03-17 |
CA2683568A1 (en) | 2008-11-20 |
USRE47194E1 (en) | 2019-01-08 |
AU2008251608A1 (en) | 2008-11-20 |
TW200902554A (en) | 2009-01-16 |
WO2008141044A2 (en) | 2008-11-20 |
CN101687037B (zh) | 2013-07-10 |
EP2144628B1 (en) | 2012-10-17 |
AR066476A1 (es) | 2009-08-19 |
JP5290276B2 (ja) | 2013-09-18 |
WO2008141044A3 (en) | 2008-12-31 |
US7723485B2 (en) | 2010-05-25 |
CN101687037A (zh) | 2010-03-31 |
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