JP4948413B2 - システイン操作抗体および結合体 - Google Patents
システイン操作抗体および結合体 Download PDFInfo
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- JP4948413B2 JP4948413B2 JP2007533692A JP2007533692A JP4948413B2 JP 4948413 B2 JP4948413 B2 JP 4948413B2 JP 2007533692 A JP2007533692 A JP 2007533692A JP 2007533692 A JP2007533692 A JP 2007533692A JP 4948413 B2 JP4948413 B2 JP 4948413B2
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- Prior art keywords
- antibody
- cysteine engineered
- cysteine
- amino acid
- drug conjugate
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- OGWKCGZFUXNPDA-UHFFFAOYSA-N vincristine Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(OC(C)=O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-UHFFFAOYSA-N 0.000 description 1
- 239000000052 vinegar Substances 0.000 description 1
- 235000021419 vinegar Nutrition 0.000 description 1
- GBABOYUKABKIAF-IELIFDKJSA-N vinorelbine Chemical compound C1N(CC=2C3=CC=CC=C3NC=22)CC(CC)=C[C@H]1C[C@]2(C(=O)OC)C1=CC([C@]23[C@H]([C@@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC GBABOYUKABKIAF-IELIFDKJSA-N 0.000 description 1
- 229960002066 vinorelbine Drugs 0.000 description 1
- CILBMBUYJCWATM-PYGJLNRPSA-N vinorelbine ditartrate Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O.OC(=O)[C@H](O)[C@@H](O)C(O)=O.C1N(CC=2C3=CC=CC=C3NC=22)CC(CC)=C[C@H]1C[C@]2(C(=O)OC)C1=CC([C@]23[C@H]([C@@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC CILBMBUYJCWATM-PYGJLNRPSA-N 0.000 description 1
- 238000012800 visualization Methods 0.000 description 1
- 229960001771 vorozole Drugs 0.000 description 1
- XLMPPFTZALNBFS-INIZCTEOSA-N vorozole Chemical compound C1([C@@H](C2=CC=C3N=NN(C3=C2)C)N2N=CN=C2)=CC=C(Cl)C=C1 XLMPPFTZALNBFS-INIZCTEOSA-N 0.000 description 1
- 210000003905 vulva Anatomy 0.000 description 1
- 201000005102 vulva cancer Diseases 0.000 description 1
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- 238000002424 x-ray crystallography Methods 0.000 description 1
- 125000001834 xanthenyl group Chemical group C1=CC=CC=2OC3=CC=CC=C3C(C12)* 0.000 description 1
- 229940075420 xanthine Drugs 0.000 description 1
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Images
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Description
本発明は一般に、反応性システイン残基を用いて操作された抗体に関し、そしてより具体的には、治療適用または診断適用を有する抗体に関する。システイン操作抗体は、化学療法薬物、毒素、アフィニティーリガンド(例えば、ビオチン)および検出標識(例えば、発蛍光団)と結合されていてもよい。本発明はまた、インビトロ、インサイチュ、および、インビボでの哺乳動物細胞または関連する病的状態の診断または処置のための抗体および抗体−薬物結合体化合物の使用方法に関する。
抗体療法は、癌を有する患者、免疫学的障害を有する患者および脈管由来障害を有する患者の標的化処置について確立されている。抗体を用いた癌の診断および処置の有効な細胞標的を見出す試みにおいて、研究者は、正常な非ガン細胞と比較して、癌細胞の表面に特異的に発現される、膜貫通ポリペプチドまたはさもなければ腫瘍関連ポリペチドを同定しようとした。このような腫瘍関連の細胞表面抗原ポリペチド、すなわち腫瘍関連抗原(TAA)の同定は、抗体ベースの治療法を介した破壊について癌細胞を特異的に標的とする能力をもたらした。
本発明の化合物は、親抗体の一つ以上のアミノ酸が遊離システインアミノ酸と置き換えられたシステイン操作抗体を含む。システイン操作抗体は、0.6〜1.0の範囲のチオール反応性値を有する一つ以上の遊離システインアミノ酸を含む。遊離システインアミノ酸は、親抗体において操作されていて、ジスルフィド架橋の一部ではない、システイン残基である。
(a)親抗体の一つ以上のアミノ酸残基をシステインによって置換する工程、および
(b)システイン操作抗体をチオール反応性試薬と反応させることにより、システイン操作抗体のチオール反応性を決定する工程。
(a)一つ以上のシステインアミノ酸を親抗体に導入して、システイン操作抗体を生成する工程;および
(b)チオール反応性試薬とのシステイン操作抗体のチオール反応性を決定する工程;
ここで、このシステイン操作抗体は、チオール反応性試薬との反応性が親抗体よりも高い。
(i)システイン操作抗体をコードする核酸配列に変異誘発する工程、
(ii)このシステイン操作抗体を発現させる工程;および
(iii)このシステイン操作抗体を単離および精製する工程。
(i)システイン操作抗体とチオール反応性親和性試薬とを反応させて、親和性標識されたシステイン操作抗体を生成する工程;および
(ii)この親和性標識されたシステイン操作抗体の、捕捉媒体に対する結合を測定する工程。
(a)一つ以上のシステインアミノ酸を親抗体に導入してシステイン操作抗体を生成する工程;
(b)このシステイン操作抗体をチオール反応性親和性試薬と反応させて、親和性標識されたシステイン操作抗体を生成する工程;および
(c)この親和性標識されたシステイン操作抗体の、捕捉媒体に対する結合を測定する工程;および
(d)チオール反応性試薬を用いてシステイン操作抗体のチオール反応性を決定する工程。
(i)システイン操作抗体をコードする核酸配列に変異誘発する工程、
(ii)このシステイン操作抗体を発現させる工程;および
(iii)このシステイン操作抗体を単離および精製する工程。
(i)システイン操作抗体をチオール反応性親和性試薬と反応させて、親和性標識されたシステイン操作抗体を生成させる工程;および
(ii)この親和性標識されたシステイン操作抗体の、捕捉媒体に対する結合を測定する工程。
Ab−(L−D)p I
ここで、pは1、2、3、または4であり;このシステイン操作抗体は、親抗体の一つ以上のアミノ酸残基を一つ以上の遊離システインアミノ酸によって置換する工程を包含するプロセスにより調製される。薬物部分としては、マイタンシノイド、オーリスタチン、ドラスタチン、トリコテセン(trichothecene)、CC1065、カリケアマイシンおよび他のエンジイン(enediyne)抗生物質、タキサン、アントラサイクリン、ならびにそれらの立体異性体、同配体、類似体または誘導体が挙げられるが、これらに限定されない。例示的な薬物部分としては、DM1、MMAEおよびMMAFが挙げられる。
ABP−Ab−(L−D)p Ia。
ここで、本発明の特定の実施形態に対し、詳細な言及がなされる。特定の実施形態の例は、添付の構造および式において説明される。本発明は、列挙される実施形態に関連して記載されるが、本発明をこれらの実施形態に限定することを意図しないことが、理解される。反対に、本発明は、特許請求の範囲によって規定される本発明の範囲に含まれ得る、全ての代替物、改変および均等物を、網羅することが意図される。
他に言及されない限り、以下の用語および語句は、本明細書中で使用される場合、以下の意味を有することが意図される:
本明細書中で商品名が使用される場合、本出願人は、商品名の製品の処方物、ジェネリック医薬品およびこの商品名の製品の活性な薬学的成分を個々に包含することを意図する。
本発明の化合物は、野生型抗体もしくは親抗体の1つもしくはそれより多くのアミノ酸が、システインアミノ酸と置き換えられている、システイン操作抗体を含む。抗体の任意の形態は、こ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、システイン操作Fabを形成するように操作され得、本明細書中で「チオFab」と呼ばれる。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。一部位変異は、チオFabにおいて1つの操作システイン残基を生じ、一方、IgG抗体のダイマーの性質に起因して、一部位変異は、チオMabにおいて2つの操作システイン残基を生じる。置き換えられた(「操作された」)システイン(Cys)残基を有する変異体は、新規に導入された操作チオール基の反応性について評価される。チオール反応性値は、0から1.0の範囲の相対的な数値の項であり、任意のシステイン操作抗体について測定され得る。本発明のシステイン操作抗体のチオール反応性値は、0.6〜1.0;0.7〜1.0;もしくは0.8〜1.0の範囲内である。
(1)BMPR1B(骨形態形成タンパク質レセプター−IB型、Genbank登録番号NM_001203)
ten Dijke,P.ら Science 264(5155):101−104(1994)、Oncogene 14(11):1377−1382(1997));WO2004063362(請求項2);WO2003042661(請求項12);US2003134790−A1(38−39ページ);WO2002102235(請求項13、296ページ);WO2003055443(91−92ページ);WO200299122(実施例2、528−530ページ);WO2003029421(請求項6);WO2003024392(請求項2、図112);WO200298358(請求項1、183ページ);WO200254940(100−101ページ);WO200259377(349−350ページ);WO200230268(請求項27、376ページ);WO200148204(実施例、図4)NP_001194骨形態形成タンパク質レセプター、IB型/pid=NP_001194.1−
相互参照:MIM:603248、NP_001194.1;AY065994
(2)E16(LAT1、SLC7A5、Genbank登録番号NM_003486)
Biochem.Biophys.Res.Commun.255(2),283−288(1999),Nature 395(6699):288−291(1998),Gaugitsch、H.W.ら(1992)J.Biol.Chem.267(16):11267−11273);WO2004048938(実施例2);WO2004032842(実施例IV);WO2003042661(請求項12);WO2003016475(請求項1);WO200278524(実施例2);WO200299074(請求項19;127−129ページ);WO200286443(請求項27、222ページ、393ページ);WO2003003906(請求項10、293ページ);WO200264798(請求項33;93−95ページ);WO200014228(請求項5;133−136ページ);US2003224454(図3);WO2003025138(請求項12;150ページ);NP_003477溶質キャリアファミリー7(カチオン性アミノ酸輸送体、y+システム)、メンバー5/pid=NP_003477.3−Homo sapiens
相互参照:MIM:600182;NP_003477.3;NM_015923;NM_003486_1
(3)STEAP1(前立腺の6回膜貫通上皮抗原、Genbank登録番号NM_012449)
Cancer Res.61(15)5857−5860(2001),Hubert,R.S.ら(1999)Proc.Natl.Acad.Sci.U.S.A.96(25):14523−14528);WO2004065577(請求項6);WO2004027049(図1L);EP1394274(実施例11);WO2004016225(請求項2);WO2003042661(請求項12);US2003157089(実施例5);US2003185830(実施例5);US2003064397(図2);WO200289747(実施例5、618−619ページ);WO2003022995(実施例9;図13A;実施例53;173ページ、実施例2;図2A);NP_036581 前立腺の6回膜貫通上皮抗原
相互参照:MIM:604415;NP_036581.1;NM_012449_1
(4)0772P(CA125、MUC16、Genbank登録番号AF361486)
J.Biol.Chem.276(29):27371−27375(2001));WO2004045553(請求項14);WO200292836(請求項6、図12);WO200283866(請求項15;116−121ページ);US2003124140(実施例16);
相互参照:GI:34501467;AAK74120.3;AF361486_1
(5)MPF(MPF、MSLN、SMR、巨核球増強因子、メソテリン(mesothelin)、Genbank登録番号NM_005823)Yamaguchi,N.ら,Biol.Chem.269(2)805−808(1994)、Proc.Natl.Acad.Sci.U.S.A.96(20):11531−11536(1999)、Proc.Natl.Acad.Sci.U.S.A.93(1):136−140(1996)、J.Biol.Chem.270(37):21984−21990(1995));WO2003101283(請求項14);(WO2002102235(請求項13、287−288ページ);WO2002101075(請求項4、308−309ページ);WO200271928(320−321ページ);WO9410312(52−57ページ);相互参照:MIM:601051、NP_005814.2、NM_005823_1
(6)Napi3b(NAPI−3B、NPTIIb、SLC34A2、溶質キャリアファミリー34(リン酸ナトリウム)、メンバー2、II型ナトリウム依存性リン酸輸送体3b,Genbank登録番号NM_006424)
J.Biol.Chem.277(22):19665−19672(2002),Genomics 62(2):281−284(1999),Feild、J.A.ra(1999)Biochem.Biophys.Res.Commun.258(3):578−582);WO2004022778(請求項2);EP1394274(実施例11);WO2002102235(請求項13、326ページ);EP875569(請求項1、17−19ページ);WO200157188(請求項20;329ページ);WO2004032842(実施例IV);WO200175177(請求項24、139−140ページ);
相互参照:MIM:604217、NP_006415.1、NM_006424_1
(7)Sema5b(FLJ10372、KIAA1445、Mm.42015、SEMA5B、SEMAG、Semaphorin 5b Hlog、semaドメイン、7回トロンボスポンジン繰り返し(1型および1型様)、膜貫通ドメイン(TM)および短い細胞質ドメイン(セマフォリン(semaphorin))5B),Genbank登録番号AB040878)
Nagase T.ら(2000)DNA Res.7(2):143−150);WO2004000997(請求項1);WO2003003984(請求項1);WO200206339(請求項1、50ページ);WO200188133(請求項1、41−43ページ、48−58ページ);WO2003054152(請求項20);WO2003101400(請求項11);
登録:Q9P283;EMBL;AB040878;BAA95969.1.Genew;HGNC:10737;
(8)PSCA hlg(2700050C12Rik;C530008O16Rik;RIKEN cDNA 2700050C12;RIKEN cDNA 2700050C12遺伝子;Genbank登録番号AY358628);Rossら(2002)Cancer Res.62:2546−2553;US2003129192(請求項2);US2004044180(請求項12);US2004044179(請求項11);US2003096961(請求項11);US2003232056(実施例5);WO2003105758(請求項12);US2003206918(実施例5);EP1347046(請求項1);WO2003025148(請求項20);
相互参照:GI:37182378;AAQ88991.1;AY358628_1
(9)ETBR(エンドセリンB型レセプター、Genbank登録番号AY275463);
Nakamuta M.ら,Biochem.Biophys.Res.Commun.177,34−39,1991;Ogawa Y.ら,Biochem.Biophys.Res.Commun.178,248−255,1991;Arai H.ら,Jpn.Circ.J.56、1303−1307、1992;Arai H.ら,J.Biol.Chem.268、3463−3470、1993;Sakamoto A.,Yanagisawa M.ら,Biochem.Biophys.Res.Commun.178,656−663,1991;Elshourbagy N.A.ら,J.Biol.Chem.268、3873−3879、1993;Haendler B.ら,J.Cardiovasc.Pharmacol.20、s1−S4、1992;Tsutsumi M.ら,Gene 228、43−49、1999;Strausberg R.L.ら,Proc.Natl.Acad.Sci.U.S.A.99、16899−16903、2002;Bourgeois C.ら,J.Clin.Endocrinol.Metab.82,3116−3123,1997;Okamoto Y.ら,Biol.Chem.272、21589−21596、1997;Verheij J.B.ら,Am.J.Med.Genet.108,223−225,2002;Hofstra R.M.W.ら,Eur.J.Hum.Genet.5,180−185,1997;Puffenberger E.G.ら,Cell 79、1257−1266、1994;Attie T.ら,、Hum.Mol.Genet.4,2407−2409,1995;Auricchio A.ら,Hum.Mol.Genet.5:351−354,1996;Amiel J.ら,Hum.Mol.Genet.5,355−357,1996;Hofstra R.M.W.ら,Nat.Genet.12,445−447,1996;Svensson P.J.ら,Hum.Genet.103,145−148,1998;Fuchs S.ら,Mol.Med.7、115−124、2001;Pingault V.ら(2002)Hum.Genet.111,198−206;WO2004045516(請求項1)、WO2004048938(実施例2);WO2004040000(請求項151);WO2003087768(請求項1);WO2003016475(請求項1);WO2003016475(請求項1);WO200261087(図1);WO2003016494(図6);WO2003025138(請求項12、144ページ);WO200198351(請求項1、124−125ページ);EP522868(請求項8、図2);WO200177172(請求項1、297−299ページ);US2003109676;US6518404(図3);US5773223(請求項1a、Col31−34);WO2004001004;
(10)MSG783(RNF124、仮想タンパク質FLJ20315、Genbank登録番号NM_017763);
WO2003104275(請求項1);WO2004046342(実施例2);WO2003042661(請求項12);WO2003083074(請求項14、61ページ);WO2003018621(請求項1);WO2003024392(請求項2;図93);WO200166689(実施例6);
相互参照:LocusID:54894、NP_060233.2、NM_017763_1
(11)STEAP2(HGNC_8639、IPCA−1、PCANAP1、STAMP1、STEAP2、STMP、前立腺癌関連遺伝子1、前立腺癌関連タンパク質1、前立腺の6回膜貫通上皮抗原2、6回膜貫通前立腺タンパク質、Genbank登録番号AF455138)
Lab.Invest.82(11):1573−1582(2002));WO2003087306;US2003064397(請求項1、図1);WO200272596(請求項13;54−55ページ);WO200172962(請求項1;図4B);WO2003104270(請求項11);WO2003104270(請求項16);US2004005598(請求項22);WO2003042661(請求項12);US2003060612(請求項12;図10);WO200226822(請求項23;図2);WO200216429(請求項12;図10);
相互参照:GI:22655488;AAN04080.1;AF455138_1
(12)TrpM4(BR22450、FLJ20041、TRPM4、TRPM4B、一過性レセプター電位カチオンチャネル、サブファミリーM、メンバー4、Genbank登録番号NM_017636)
Xu,X.Z.ら,Proc.Natl.Acad.Sci.U.S.A.98(19):10692−10697(2001),Cell 109(3):397−407(2002),J.Biol.Chem.278(33):30813−30820(2003));US2003143557(請求項4);WO200040614(請求項14;100−103ページ);WO200210382(請求項1;図9A);WO2003042661(請求項12);WO200230268(請求項27;391ページ);US2003219806(請求項4);WO200162794(請求項14;図1A−D);
相互参照:MIM:606936;NP_060106.2;NM_017636_1
(13)CRIPTO(CR、CR1、CRGF、CRIPTO、TDGF1、奇形癌腫由来増殖因子、Genbank登録番号NP_003203またはNM_003212)
Ciccodicola,A.ら,EMBO J.8(7):1987−1991(1989),Am.J.Hum.Genet.49(3):555−565(1991));US2003224411(請求項1);WO2003083041(実施例1);WO2003034984(請求項12);WO200288170(請求項2;52−53ページ);WO2003024392(請求項2;図58);WO200216413(請求項1;94−95ページ、105ページ);WO200222808(請求項2;図1);US5854399(実施例2、Col17−18);US5792616(図2);
相互参照:MIM:187395;NP_003203.1;NM_003212_1
(14)CD21(CR2(補体レセプター2)またはC3DR(C3d/エプスタインバーウイルスレセプター)またはHs.73792 Genbank登録番号M26004)
Fujisakuら(1989)J.Biol.Chem.264(4):2118−2125);Weis J.J.ら,J.Exp.Med.167、1047−1066、1988;Moore M.ら,Proc.Natl.Acad.Sci.U.S.A.84、9194−9198、1987;Barel M.ら,Mol.Immunol.35,1025−1031,1998;Weis J.J.ら,Proc.Natl.Acad.Sci.U.S.A.83、5639−5643、1986;Sinha S.K.ら(1993)J.Immunol.150,5311−5320;WO2004045520(実施例4);US2004005538(実施例1);WO2003062401(請求項9);WO2004045520(実施例4);WO9102536(図9.1−9.9);WO2004020595(請求項1);
登録:P20023;Q13866;Q14212;EMBL;M26004;AAA35786.1.
(15)CD79b(CD79B、CD79β、IGb(免疫グロブリン関連β)、B29、Genbank登録番号NM_000626または11038674)
Proc.Natl.Acad.Sci.U.S.A.(2003)100(7):4126−4131、Blood(2002)100(9):3068−3076;Mullerら(1992)Eur.J.Immunol.22(6):1621−1625);WO2004016225(請求項2、図140);WO2003087768;US2004101874(請求項1、102ページ);WO2003062401(請求項9);WO200278524(実施例2);US2002150573(請求項5、15ページ);US5644033;WO2003048202(請求項1、306ページおよび309ページ);WO 99/558658;US6534482(請求項13、図17A/B);WO200055351(請求項11、1145−1146ページ);
相互参照:MIM:147245;NP_000617.1;NM_000626_1
(16)FcRH2(IFGP4、IRTA4、SPAP1A(SH2ドメインを含むホスファターゼアンカータンパク質1a)、SPAP1B、SPAP1C、Genbank登録番号NM_030764、AY358130)
Genome Res.13(10):2265−2270(2003)、Immunogenetics 54(2):87−95(2002)、Blood 99(8):2662−2669(2002)、Proc.Natl.Acad.Sci.U.S.A.98(17):9772−9777(2001)、Xu,M.J.ら(2001)Biochem.Biophys.Res.Commun.280(3):768−775;WO2004016225(請求項2);WO2003077836;WO200138490(請求項5、図18D−1−18D−2);WO2003097803(請求項12);WO2003089624(請求項25);
相互参照:MIM:606509、NP_110391.2、NM_030764_1
(17)HER2(ErbB2、Genbank登録番号M11730)
Coussens L.ら,Science(1985)230(4730):1132−1139)、Yamamoto T.ら,Nature 319、230−234、1986;Semba K.ら,Proc.Natl.Acad.Sci.U.S.A.82、6497−6501、1985;Swiercz J.M.ら,J.Cell Biol.165、869−880、2004;Kuhns J.J.ら,J.Biol.Chem.274、36422−36427、1999;Cho H.−S.ら,Nature 421、756−760、2003;Ehsani A.ら(1993)Genomics 15,426−429;WO2004048938(実施例2);WO2004027049(図1I);WO2004009622;WO2003081210;WO2003089904(請求項9);WO2003016475(請求項1);US2003118592;WO2003008537(請求項1);WO2003055439(請求項29、図1A−B);WO2003025228(請求項37、図5C);WO200222636(実施例13、95−107ページ);WO200212341(請求項68;図7);WO200213847(71−74ページ);WO200214503(114−117ページ);WO200153463(請求項2;41−46ページ);WO200141787(15ページ);WO200044899(請求項52;図7);WO200020579(請求項3;図2);US5869445(請求項3;Col31−38);WO9630514(請求項2;56−61ページ);EP1439393(請求項7);WO2004043361(請求項7);WO2004022709;WO200100244(実施例3;図4);
登録:P04626;EMBL;M11767;AAA35808.1.EMBL;M11761;AAA35808.1。
Barnett T.ら,Genomics 3、59−66、1988;Tawaragi Y.ら,Biochem.Biophys.Res.Commun.150,89−96,1988;Strausberg R.L.ら,Proc.Natl.Acad.Sci.U.S.A.99:16899−16903、2002;WO2004063709;EP1439393(請求項7);WO2004044178(実施例4);WO2004031238;WO2003042661(請求項12);WO200278524(実施例2);WO200286443(請求項27;427ページ);WO200260317(請求項2);
登録:P40199;Q14920;EMBL;M29541;AAA59915.1.EMBL;M18728;
(19)MDP(DPEP1、Genbank登録番号BC017023)
Proc.Natl.Acad.Sci.U.S.A.99(26):16899−16903(2002));WO2003016475(請求項1);WO200264798(請求項33;85−87ページ);JP05003790(図6−8);WO9946284(図9);
相互参照:MIM:179780;AAH17023.1;BC017023_1
(20)IL20Rα(IL20Ra、ZCYTOR7、Genbank登録番号AF184971);
Clark H.F.ら,Genome Res.13、2265−2270、2003;Mungall A.J.ら,Nature 425、805−811、2003;Blumberg H.ら,Cell 104、9−19、2001;Dumoutier L.ら,J.Immunol.167,3545−3549,2001;Parrish−Novak J.ら,J.Biol.Chem.277、47517−47523、2002;Pletnev S.ら(2003)Biochemistry 42:12617−12624;Sheikh F.ら(2004)J.Immunol.172,2006−2010;EP1394274(実施例11);US2004005320(実施例5);WO2003029262(74−75ページ);WO2003002717(請求項2;63ページ);WO200222153(45−47ページ);US2002042366(20−21ページ);WO200146261(57−59ページ);WO200146232(63−65ページ);WO9837193(請求項1;55−59ページ);
登録:Q9UHF4;Q6UWA9;Q96SH8;EMBL;AF184971;AAF01320.1。
Gary S.C.ら,Gene 256、139−147、2000;Clark H.F.ら,Genome Res.13、2265−2270、2003;Strausberg R.L.ら,Proc.Natl.Acad.Sci.U.S.A.99、16899−16903、2002;US2003186372(請求項11);US2003186373(請求項11);US2003119131(請求項1;図52);US2003119122(請求項1;図52);US2003119126(請求項1);US2003119121(請求項1;図52);US2003119129(請求項1);US2003119130(請求項1);US2003119128(請求項1;図52);US2003119125(請求項1);WO2003016475(請求項1);WO200202634(請求項1);
(22)EphB2R(DRT、ERK、Hek5、EPHT3、Tyro5、Genbank登録番号NM_004442)
Chan,J.およびWatt,V.M.,Oncogene 6(6)1057−1061(1991)Oncogene 10(5):897−905(1995),Annu.Rev.Neurosci.21:309−345(1998)、Int.Rev.Cytol.196:177−244 (2000));WO2003042661(請求項12);WO200053216(請求項1;41ページ);WO2004065576(請求項1);WO2004020583(請求項9);WO2003004529(128−132ページ);WO200053216(請求項1;42ページ);
相互参照:MIM:600997;NP_004433.2;NM_004442_1
(23)ASLG659(B7h、Genbank登録番号AX092328)
US20040101899(請求項2);WO2003104399(請求項11);WO2004000221(図3);US2003165504(請求項1);US2003124140(実施例2);US2003065143(図60);WO2002102235(請求項13;299ページ);US2003091580(実施例2);WO200210187(請求項6;図10);WO200194641(請求項12;図7b);WO200202624(請求項13;図1A−1B);US2002034749(請求項54;45−46ページ);WO200206317(実施例2;320−321ページ、請求項34;321−322ページ);WO200271928(468−469ページ);WO200202587(実施例1;図1);WO200140269(実施例3;ページ190−192);WO200036107(実施例2;205−207ページ);WO2004053079(請求項12);WO2003004989(請求項1);WO200271928(233−234ページ、452−453);WO 0116318;
(24)PSCA(前立腺の幹細胞抗原前駆体、Genbank登録番号AJ297436)
Reiter R.E.ら,Proc.Natl.Acad.Sci.U.S.A.95、1735−1740、1998;Gu Z.ら,Oncogene 19、1288−1296、2000;Biochem.Biophys.Res.Commun.(2000)275(3):783−788;WO2004022709;EP1394274(実施例11);US2004018553(請求項17);WO2003008537(請求項1);WO200281646(請求項1;164ページ);WO2003003906(請求項10;288ページ);WO200140309(実施例1;図17);US2001055751(実施例1;図1b);WO200032752(請求項18;図1);WO9851805(請求項17;97ページ);WO9851824(請求項10;94ページ);WO9840403(請求項2;図1B);
登録:O43653;EMBL;AF043498;AAC39607.1。
AAP14954脂肪腫HMGIC融合パートナー様タンパク質/pid=AAP14954.1−Homo sapiens 種:Homo Sapiens(ヒト)
WO2003054152(請求項20);WO2003000842(請求項1);WO2003023013(実施例3、請求項20);US2003194704(請求項45);
相互参照:GI:30102449;AAP14954.1;AY260763_1
(26)BAFF−R(B細胞活性化因子レセプター、BLySレセプター3、BR3、Genbank登録番号AF116456);
BAFFレセプター/pid=NP_443177.1−Homo sapiens
Thompson,J.S.ら,Science 293(5537)、2108−2111(2001);WO2004058309;WO2004011611;WO2003045422(実施例;32−33ページ);WO2003014294(請求項35;図6B);WO2003035846(請求項70;615−616ページ);WO200294852(Col136−137);WO200238766(請求項3;133ページ);WO200224909(実施例3;図3);
相互参照:MIM:606269;NP_443177.1;NM_052945_1;AF132600
(27)CD22(B細胞レセプターCD22−Bイソ型、BL−CAM、Lyb−8、Lyb8、SIGLEC−2、FLJ22814、Genbank登録番号AK026467);
Wilsonら(1991)J.Exp.Med.173:137−146;WO2003072036(請求項1;図1);
相互参照:MIM:107266;NP_001762.1;NM_001771_1
(28)CD79a(CD79A、CD79α、免疫グロブリン関連α、Igβ(CD79B)と共有結合的に相互作用して、IgM分子を有する結合体を表面に形成し、B細胞分化に関与するシグナルを伝達する、B細胞特異的タンパク質)pI:4.84、MW:25028 TM:2[P]Gene Chromosome:19q13.2、Genbank登録番号NP_001774.10)
WO2003088808;US20030228319;WO2003062401(請求項9);US2002150573(請求項4、ページ13−14);WO9958658(請求項13、図16);WO9207574(図1);US5644033;Haら(1992)J.Immunol.148(5):1526−1531;Muellerら(1992)Eur.J.Biochem.22:1621−1625;Hashimotoら(1994)Immunogenetics 40(4):287−295;Preud’hommeら(1992)Clin.Exp.Immunol.90(1):141−146;Yuら(1992)J.Immunol.148(2)633−637;Sakaguchiら(1988)EMBO J.7(11):3457−3464;
(29)CXCR5(バーキットリンパ腫レセプター1、CXCL13ケモカインにより活性化され、リンパ球遊走および体液性防御において機能し、HIV−2感染症およびおそらくエイズ、リンパ腫、ミエローマおよび白血病の発現で役割を果たす、Gタンパク質共役レセプター);372aa、pI:8.54 MW:41959 TM:7[P]Gene Chromosome:11q23.3、Genbank登録番号NP_001707.1)
WO2004040000;WO2004015426;US2003105292(実施例2);US6555339(実施例2);WO200261087(図1);WO200157188(請求項20、269ページ);WO200172830(12−13ページ);WO200022129(実施例1、152−153ページ、実施例2、254−256ページ);WO9928468(請求項1、38ページ);US5440021(実施例2、Col49−52);WO9428931(56−58ページ);WO9217497(請求項7、図5);Dobnerら(1992)Eur.J.Immunol.22:2795−2799;Barellaら(1995)Biochem.J.309:773−779;
(30)HLA−DOB(ペプチドを結合して、それらをCD4+Tリンパ球に提示する、MHCクラスII分子(Ia抗原)のβサブユニット);273aa、pI:6.56 MW:30820 TM:1[P]Gene Chromosome:6p21.3、Genbank登録番号NP_002111.1)
Tonnelleら(1985)EMBO J.4(11):2839−2847;Jonssonら(1989)Immunogenetics 29(6):411−413;Beckら(1992)J.Mol.Biol.228:433−441;Strausbergら(2002)Proc.Natl.Acad.Sci USA 99:16899−16903;Serveniusら(1987)J.Biol.Chem.262:8759−8766;Beckら(1996)J.Mol.Biol.255:1−13;Naruseら(2002)Tissue Antigens 59:512−519;WO9958658(請求項13、図15);US6153408(Col35−38);US5976551(Col168−170);US6011146(Col145−146);Kasaharaら(1989)Immunogenetics 30(1):66−68;Larhammarら(1985)J.Biol.Chem.260(26):14111−14119;
(31)P2X5(プリン作動性レセプターP2Xリガンド型イオンチャネル5(細胞外のATPによって作動するイオンチャネル)は、シナプス伝達および神経形成において関与し得、欠乏は、特発性不安定性膀胱の病態生理学に寄与し得る);422aa)、pI:7.63、MW:47206 TM:1[P]Gene Chromosome:17p13.3、Genbank登録番号NP_002552.2)
Leら(1997)FEBS Lett.418(1−2):195−199;WO2004047749;WO2003072035(請求項10);Touchmanら(2000)Genome Res.10:165−173;WO200222660(請求項20);WO2003093444(請求項1);WO2003087768(請求項1);WO2003029277(82ページ);
(32)CD72(B細胞分化抗原CD72、Lyb−2)、PROTEIN SEQUENCE Full maeaity...tafrfpd(1..359;359aa),pI:8.66、MW:40225 TM:1[P]Gene Chromosome:9p13.3,Genbank登録番号NP_001773.1)
WO2004042346(請求項65);WO2003026493(51−52、57−58ページ);WO200075655(105−106ページ);Von Hoegenら(1990)J.Immunol.144(12):4870−4877;Strausbergら(2002)Proc.Natl.Acad.Sci USA 99:16899−16903;
(33)LY64(リンパ球抗原64(RP105)、ロイシンリッチリピート(LRR)ファミリーのI型膜貫通タンパク質)は、B細胞活性化およびアポトーシスを調節し、機能の喪失は、全身性エリテマトーデス患者における疾患活性の上昇と関連している);661aa、pI:6.20、MW:74147 TM:1[P]Gene Chromosome:5q12、Genbank登録番号NP_005573.1)
US2002193567;WO9707198(請求項11、39−42ページ);Miuraら(1996)Genomics 38(3):299−304;Miuraら(1998)Blood 92:2815−2822;WO2003083047;WO9744452(請求項8、57−61ページ);WO200012130(24−26ページ);
(34)FcRH1(Fcレセプター様タンパク質1(C2型Ig様ドメインおよびITAMドメインを含む免疫グロブリンFcドメインについての推定上のレセプター)は、Bリンパ球分化において役割を有し得る、429aa、pI:5.28、MW:46925 TM:1[P]Gene Chromosome:1q21−1q22、Genbank登録番号NP_443170.1)
WO2003077836;WO200138490(請求項6、図18E−1−18−E−2);Davisら(2001)Proc.Natl.Acad.Sci USA 98(17):9772−9777;WO2003089624(請求項8);EP1347046(請求項1);WO2003089624(請求項7);
(35)IRTA2(免疫グロブリンスーパーファミリーレセプタートランスロケーション関連2(B細胞の発達およびリンパ腫生成において役割を有し得る推定上の免疫レセプター);トランスロケーションによるこの遺伝子の調節解除は、いくつかのB細胞悪性疾患において生じる;977aa、pI:6.88MW:106468 TM:1[P]Gene Chromosome:1q21、Genbank登録番号Human:AF343662、AF343663、AF343664、AF343665、AF369794、AF397453、AK090423、AK090475、AL834187、AY358085;マウス:AK089756、AY158090、AY506558、NP_112571.1 WO2003024392(請求項2、図97);Nakayamaら(2000)Biochem.Biophys.Res.Commun.277(1):124−127、WO2003077836、WO200138490(請求項3、図18B−1−18B−2);
(36)TENB2(TMEFF2、tomoregulin、TPEF、HPP1、TR、推定上の膜貫通プロテオグリカン、増殖因子およびフォリスタチンのEGF/ヒレグリンファミリーに関連する);374aa、NCBI登録:AAD55776、AAF91397、AAG49451、NCBI RefSeq:NP_057276;NCBI Gene:23671;OMIM:605734;SwissProt Q9UIK5;Genbank登録番号AF179274;AY358907、CAF85723、CQ782436 WO2004074320(配列番号810);JP2004113151(配列番号2、4、8);WO2003042661(配列番号580);WO2003009814(配列番号411);EP1295944(69−70ページ);WO200230268(329ページ);WO200190304(配列番号2706);US2004249130;US2004022727;WO2004063355;US2004197325;US2003232350;US2004005563;US2003124579;Horieら(2000)Genomics 67:146−152;Uchidaら(1999)Biochem.Biophys.Res.Commun.266:593−602;Liangら(2000)Cancer Res.60:4907−12;Glynne−Jonesら(2001)Int J Cancer.10月15日、94(2):178−84。
出発ポリペチドのアミノ酸配列改変体をコードするDNAは、当該分野で公知の様々な方法により調製される。これらの方法としては、ポリペチドをコードする予め調製したDNAの、部位特異的(またはオリゴヌクレオチド媒介)変異誘発、PCR変異誘発およびカセット変異誘発による調製が挙げられるがこれらに限定されない。組換え抗体の改変体は、制限フラグメントの操作によって、または、合成オリゴヌクレオチドを用いた重複伸張PCRによっても構築され得る。変異誘発プライマーは、システインコドン置換をコードする。標準的な変異誘発技術は、このような変異体システイン操作抗体をコードするDNAを生成するために使用され得る。一般的なガイダンスは、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に見出され得る。
PHESELECTOR(Phage ELISA for Selection of Reactive Thiols)アッセイは、ELISAファージ形式での抗体中の反応性システイン基の検出を可能にする。ウェル表面上で目的のタンパク質(例えば、抗体)をコーティングし、続いてファージ粒子とともにインキュベートし、次いでHRPで標識された二次抗体の吸光度を検出するプロセスは、実施例2において詳述される。ファージ上に提示される変異タンパク質は、迅速で頑強なハイ高いスループット様式でスクリーニングされ得る。システイン操作抗体のライブラリーが作製され得、そして抗体または他のタンパク質のランダムなタンパク質−ファージライブラリーから遊離Cys取り込みの適切に反応性の部位を同定するために同じアプローチを使用した結合選択を受け得る。この技術は、ファージ上に提示されたシステイン変異タンパク質を、親和性試薬またはチオール反応性でもあるレポーター基と反応させることを含む。図8は、HER2へのFabまたはチオFabの結合(上の図)およびビオチン化チオFabのストレプトアビジンへの結合(下の図)を示す概略図によって、PHESELECTOR Assayを図示する。
システイン操作抗体をコードするDNAは、従来の手順を用いて(例えば、マウス抗体の重鎖をコードする遺伝子および軽鎖をコードする遺伝子と特異的に結合し得るオリゴヌクレオチドプローブを用いることにより)容易に分離され、そして配列決定される。ハイブリドーマ細胞は、このようなDNAの供給源として役立つ。一旦単離されると、このDNAは、発現ベクター内に配置され得、次いで、この発現ベクターは、トランスフェクションしなければ抗体タンパク質を生成しない宿主細胞(例えば、E.coli細胞、サルのCOS細胞、チャイニーズハムスター卵巣(CHO)細胞、または他の哺乳動物宿主細胞(例えば、骨髄腫細胞)(US 5807715;US 2005/0048572;US 2004/0229310))へとトランスフェクションされて、組換え宿主細胞においてモノクローナル抗体の合成が得られる。hu4D5Fabv8システイン操作抗体の収率は、野生型hu4D5Fabv8と類似していた。抗体をコードするDNAの細菌中での組換え発現に関する総説としては、Skerraら(1993)Curr.Opinion in Immunol.5:256−262およびPlueckthun(1992)Immunol.Rev.130:151−188が挙げられる。
液体クロマトグラフィーエレクトロスプレー電離質量分析(LC−ESI−MS)による分析を、ビオチン結合体化Fabの正確な分子量決定のために用いた(Cole,R.B.Electro Spray Ionization Mass Spectrometry:Fundamentals,Instrumentation And Applications.(1997)Wiley,New York)。ビオチン化されたhu4D5Fabv8(A121C)ペプチドのアミノ酸配列を、トリプシン性消化、続いてLC−ESI−Tandem MS分析(表4、実施例3b)によって決定した。
1.完全に埋め込まれる(すなわち、10%未満の表面アクセシビリティー率の)アミノ酸残基は除去される。表1は、10%よりも高くアクセス可能である(表面アクセシビリティー率の)、hu4D5Fabv8の134残基(軽鎖)および151残基(重鎖)が存在することを示す。上位10個の最もアクセス可能なSer残基、Ala残基およびVal残基を、新しく操作されたCysによって抗体に最小の構造制約しか導入しない、他のアミノ酸よりもCysへのそれらの構造的類似性の近さに起因して選択した。他のシステイン置換部位もまたスクリーニングされ得、そして結合体化に有用であり得る。
本発明のシステイン操作抗体は、反応性システインチオール基によって抗体に結合した共有結合であり得る任意の標識部分と結合体化され得る(Singhら(2002)Anal.Biochem.304:147−15;Harlow E.およびLane,D.(1999)Using Antibodies:A Laboratory Manual,Cold Springs Harbor Laboratory Press,Cold Spring Harbor,NY;Lundblad R.L.(1991)Chemical Reagents for Protein Modification,第2版,CRC Press,Boca Raton,FL)。結合した標識は、以下のために機能し得る:(i)検出可能なシグナルを提供する;(ii)第2の標識と相互作用して、第1の標識または第2の標識によって提供される検出可能なシグナルを改変して、例えば、FRET(蛍光共鳴エネルギー転移)を与える;(iii)抗原またはリガンドとの相互作用を安定化するかまたは結合親和性を増加させる;(iv)電荷、疎水性、形状または他の物理的パラメータによる移動性(例えば、電気泳動易動度または細胞浸透性)に影響を及ぼす;または(v)捕捉部分を提供して、リガンド親和性、抗体/抗原結合またはイオン性錯体形成を改変する。
(a)ラジオアイソトープ(放射性核種)(例えば、3H、11C、14C、18F、32P、35S、64Cu、68Ga、86Y、99Tc、111In、123I、124I、125I、131I、133Xe、177Lu、211Atまたは213Bi)。ラジオアイソトープ標識抗体は、レセプターを標的とした画像化実験に有用である。抗体は、Current Protocols in Immunology、1巻および2巻、Coligenら編,Wiley−Interscience、New York、NY、Pubs.(1991)に記載されている技術を用いて、結合するか、キレート化するか、またはさもなければラジオアイソトープ金属を錯体化するリガンド試薬によって標識され得、ここで、この試薬は、抗体の操作されたシステインチオールと反応性である。金属イオンを錯体化し得るキレート化リガンドとしては、DOTA、DOTP、DOTMA、DTPAおよびTETA(Macrocyclics,Dallas,TX)が挙げられる。放射性核種は、本発明の抗体−薬物結合体との錯体形成を介して標的化され得る(Wuら(2005)Nature Biotechnology 23(9):1137−1146)。
(i)西洋ワサビペルオキシダーゼ(HRP)と、基質としての水素ペルオキシダーゼ(ここで、水素ペルオキシダーゼは、色素前駆体(例えば、オルトフェニレンジアミン(OPD)または3,3’,5,5’−テトラメチルベンジジン塩酸塩(TMB))を酸化する);
(ii)アルカリホスファターゼ(AP)と、色素形成性基質としてのパラ−ニトロフェニルホスフェート;および
(iii)β−D−ガラクトシダーゼ(β−D−Gal)と、色素形成性基質(例えば、p−ニトロフェニル−β−D−ガラクトシダーゼ)または蛍光発生性基質4−メチルウンベリフェリル−β−D−ガラクトシダーゼ。
ファージコートタンパク質に対するFabの融合がCysチオールアクセシビリティまたは反応性を潜在的に変更し得るので、上記のチオFab特性を、ファージの存在下で確立した。従って、チオFab構築物を、アルカリホスファターゼプロモーター(Changら(1987)Gene 55:189−196)下で発現ベクターにクローン化し、そしてチオFab発現を、ホスフェートを含まない培地中でE.coli細胞を増殖させることにより誘導した。チオFabを、Protein G SEPHAROSETMカラムにおいて精製し、そして還元型SDS−PAGEゲルおよび非還元型SDS−PAGEゲルにおいて分析した。これらの分析は、チオFabがそれらの反応性チオール基を保持したかまたは分子内ジスルフィド結合もしくは分子間ジスルフィド結合を形成することによって不活性になったかの評価を可能にする。チオFab L−V15C、チオFab L−V110C、チオFab H−A88CおよびチオFab H−A121Cを発現させ、そしてProtein−G SEPHAROSETMカラムクロマトグラフィーにより精製した(詳細については、方法のセクションを参照のこと)。精製されたタンパク質を、還元条件下(DTTあり)および非還元条件(DTTなし)においてSDS−PAGEゲルで分析した。BME(β−メルカプトエタノール)のような他の還元剤をゲルにおいて用いて、鎖間ジスルフィド基を切断し得た。主な(約90%)部分のチオFabがモノマー形態であり、その一方で、野生型hu4D5Fabv8は本質的にモノマー形態(47kDa)であることは、SDS−PAGEゲル分析から明白である。。
血漿タンパク質結合は、短命の分子の薬物動態特性を改善する有効な手段であり得る。アルブミンは、血漿において最も豊富なタンパク質である。血清アルブミン結合性ペプチド(ABP)は、組織取り込み、浸透および拡散の変更を含め、融合した活性ドメインタンパク質の薬力学を変更し得る。これらの薬力学的パラメータは、適切な血清アルブミン結合性ペプチド配列の特異的選択により調節され得る(US 20040001827)。一連のアルブミン結合性ペプチドは、ファージディスプレイスクリーニングにより確認された(Dennisら(2002)「Albumin Binding As A General Strategy For Improving The Pharmacokinetics Of Proteins」,J Biol Chem.277:35035−35043;WO 01/45746)。本発明の化合物は、以下によって教示されるABP配列を含む:(i)Dennisら(2002)J Biol Chem.277:35035−35043,Tables IIIおよびIV,35038頁;(ii)US 20040001827,[0076],配列番号9〜22;および(iii)WO 01/45746,12−13頁,配列番号z1〜z14。これらの全ては、本明細書中に参考として援用される。
CDKTHTGGGSQRLMEDICLPRWGCLWEDDF 配列番号1
QRLMEDICLPRWGCLWEDDF 配列番号2
QRLIEDICLPRWGCLWEDDF 配列番号3
RLIEDICLPRWGCLWEDD 配列番号4
DICLPRWGCLW 配列番号5。
上記の結果は、4つ全て(L−V15C、L−V110C、H−A88CおよびH−A121C)のチオFab(システイン操作Fab抗体)改変体が、標識試薬、リンカー試薬または薬物−リンカー中間体との部位特異的結合体化のために使用され得る反応性チオール基を有することを示す。L−V15Cは、比較的低い収率で、発現および精製され得る。しかしながら、L−V110C、H−A88CおよびH−A121C異型の発現収率および精製収率は、hu4D5Fabv8のものと類似していた。従って、これらの変異体は、さらなる分析のために使用され得、そして組換えられてFabあたり1個より多くのチオール基が得られ得る。この目的に向けて、軽鎖上の1つのチオール基および重鎖上の1つのチオール基を構築して、Fab分子あたり2個のチオール基を得た(L−V110C/H−A88CおよびL−V110C/H−A121C)。これらの2つの二重Cys改変体をE.coli発現系において発現させ、そして精製した。精製されたビオチン化ABP−チオFabの均質性は、単一Cys改変体の均一性と類似していることがわかった。
システインを、全長モノクローナル抗体であるトラスツズマブ(HERCEPTINR(登録商標)、Genentech Inc.)に、特定の残基において導入した。トラスツズマブの単一Cys変異体H−A88C、H−A121CおよびL−V110C、ならびにトラスツズマブの二重Cys変異体V110C−A121CおよびV110C−A121Cを、1mMのシステインを含んでいる培地中での一過性発酵によって、CHO(チャイニーズハムスター卵巣)細胞において発現させた。A88C変異体重鎖配列(450aa)は、配列番号6である。A121C変異体の重鎖配列(450aa)は、配列番号7である。V110C変異体の軽鎖配列(214aa)は、配列番号8である。
EVQLVESGGGLVQPGGSLRLSCAASGFNIKDTYIHWVRQAPGKGLEWVARIYPTNGYTRYADSVKGRFTISADTSKNTAYLQMNSLRCEDTAVYYCSRWGGDGFYAMDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 配列番号6
EVQLVESGGGLVQPGGSLRLSCAASGFNIKDTYIHWVRQAPGKGLEWVARIYPTNGYTRYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCSRWGGDGFYAMDYWGQGTLVTVSSCSTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 配列番号7
DIQMTQSPSSLSASVGDRVTITCRASQDVNTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQHYTTPPTFGQGTKVEIKRTCAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 配列番号8。
EVQLVESGGGLVQPGGSLRLSCAASGYTFTSYWMHWVRQAPGKGLEWVGFINPSTGYTDYNQKFKDRFTISADTSKNTAYLQMNSLRAEDTAVYYCTRRPKIPRHANVFWGQGTLVTVSSCSTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 配列番号28。
DVQLQESGPGLVNPSQSLSLTCTVTGYSITNDYAWNWIRQFPGNKLEWMGYINYSGYTTYNPSLKSRISITRDTSKNQFFLHLNSVTTEDTATYYCARWDGGLTYWGQGTLVTVSACSTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 配列番号39。
全長のIgGシステイン操作抗体(チオMab)のチオール反応性を、ビオチン化およびストレプトアビジン結合によって測定した。ウェスタンブロットアッセイを設定して、ビオチン−マレイミドと特異的に結合されたチオMabをスクリーニングした。このアッセイにおいて、抗体は還元型SDS−PAGEによって分析され、そして、ビオチンの存在は、ストレプトアビジン−HRPとともにインキュベートすることによって特異的にプローブされる。図18からわかるように、ストレプトアビジン−HRP相互作用は、どの操作されたcys改変体異型が使われたかに依存して重鎖または軽鎖のいずれかにおいて観察され、そして野生型については相互作用は見られない。このことは、チオMab改変体が、操作されたCys残基においてビオチンを特異的に結合したことを示す。図18は、固定された抗IgG−HRP(上のゲル)およびストレプトアビジン−HRP(下のゲル)への捕捉後の、還元したビオチン化チオ−IgG改変体の変性ゲル分析を示す。レーン1:3A5 H−A121C。レーン2:3A5 L−V110C。レーン3:2H9 H−A121C。レーン4:2H9 L−V110C。レーン5:抗EphB2R 2H9親、野生型。各変異体(レーン1〜4)を、選択性および親和性が保持されたことを示しているHRP検出を用いて抗IgGによって捕捉した(上図)。HRP検出を用いた固定されたストレプトアビジンによる捕捉(下図)は、重鎖および軽鎖上でのビオチンの位置を確認した。レーン1およびレーン3におけるシステイン操作抗体でのシステイン変異の位置は、重鎖である。レーン2およびレーン4におけるシステイン操作抗体でのシステイン変異の位置は、軽鎖である。システイン変異部位は、ビオチン−マレイミド試薬での結合体化を受ける。
抗ErbB2抗体4D5の様々なシステイン操作された軽鎖改変体Fabのスクリーニングは、図8のPHESELECTORアッセイによって測定したところ、0.6以上のチオール反応性値を有する多くの改変体を与えた(表7)。表7のチオール反応性値は、HC−A121C改変体の完全なビオチン化を仮定して100%と設定される重鎖4D5チオFab異型(HC−A121C)に対して正規化され、パーセント値として表される。
Ab−(L−D)p I
ここで、pは1、2、3、または4である。チオール反応性リンカー部分を介して抗体分子へと結合し得る薬物部分の数は、本明細書に記載される方法によって導入されるシステイン残基の数により制限される。従って、式Iの例示的なADCは、1、2、3、または4個の操作されたシステインアミノ酸を有する抗体を含む。
ABP−Ab−(L−D)p Ia
ここで、pは、1、2、3、または4である。
抗体−薬物結合体(ADC)の薬物部分(D)は、細胞傷害効果または細胞増殖抑制果を有する、任意の化合物、部分または基を含む。薬物部分としては、以下が挙げられる:(i)化学療法剤(これは、マイクロチューブリンインヒビター、有糸分裂インヒビター、トポイソメラーゼインヒビターまたはDNAインターカレーターとして機能し得る)、(ii)タンパク質毒素(これは、酵素的に機能し得る)、および(iii)ラジオアイソトープ。
「リンカー」(L)は、1以上の薬物部分(D)および抗体単位(Ab)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、薬物および抗体に結合させるための反応性官能基を有するリンカーを用いて、簡便に調製され得る。システイン操作された抗体(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−リンカー中間体の官能基と結合を形成し得る。
−Aa−Ww−Yy−
を有し、上記式において:
−A−は、抗体(Ab)のシステインチオールに共有結合し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する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、存在する場合、1つの抗体単位を1つのアミノ酸単位(−W−)に連結し得る。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の官能基と結合を形成し得る、遊離のシステインチオール基を有する。この実施形態の代表的なストレッチャー単位は、式IIIaおよびIIIbの括弧内に示され、ここで、Ab−、−W−、−Y−、−D、wおよびyは、上に定義されたとおりであり、そして、R17は、(CH2)r、C3−C8炭素環式、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炭素環式)、(C3−C8炭素環式)−(CH2)r、C3−C8複素環式、(CH2)r−(C3−C8複素環式)、−(C3−C8複素環式)−(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る;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る;そして、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、存在する場合、抗体(Ab)を、本発明のシステイン操作された抗体−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−)は、存在する場合(y=1または2)、アミノ酸単位が存在する場合(w=1〜12)に、アミノ酸単位(−Ww−)を薬物部分(D)に連結する。あるいは、スペーサー単位は、アミノ酸単位が存在しない場合、ストレッチャー単位を薬物部分に連結する。スペーサー単位はまた、アミノ酸単位もストレッチャー単位も存在しない場合(w、y=0)に、薬物部分を抗体単位に連結する。スペーサー単位は、2つの一般的な型のものである:自己犠牲型および非自己犠牲型。非自己犠牲型のスペーサー単位は、抗体−薬物結合体、または、薬物部分−リンカーの切断、特に、酵素的な切断の後に、スペーサー単位の一部または全体が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によって酵素的な切断を受けるとき、グリシン−グリシン−薬物部分、または、グリシン−薬物部分が、Ab−Aa−Ww−から切断される。1つの実施形態において、独立した加水分解反応が標的細胞内で生じて、グリシン−薬物部分の結合を切断し、そして、薬物を解放する。
別の実施形態において、リンカーLは、分枝の多官能性リンカー部分を通して、2以上の薬物部分を1つの抗体へと共有結合させるための、樹状型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;King(2002)Tetrahedron Letters 43:1987−1990)。樹状リンカーは、薬物対抗体の分子比、すなわち、ADCの効力に関連する負荷を高め得る。こうして、システイン操作された抗体が、1つのみの反応性のシステインチオール基を有する場合、多数の薬物部分が、樹状リンカーを介して結合され得る。
式IのADCは、当業者に公知の有機化学反応、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る:(1)共有結合を介して、抗体−リンカー中間体Ab−Lを形成するための、システイン操作された抗体のシステイン基のリンカー試薬との反応、その後の、活性化された薬物部分Dとの反応;および(2)共有結合を介して、薬物−リンカー中間体D−Lを形成するための、薬物部分の求核性基のリンカー試薬との反応、その後の、システイン操作された抗体のシステイン基との反応。結合体化方法(1)および(2)は、種々のシステイン操作された抗体、薬物部分およびリンカーを用いて行われ、式Iの抗体−薬物結合体を調製し得る。
一般に、抗体−薬物結合体(ADC)の細胞毒性または細胞増殖抑制活性は、レセプタータンパク質(例えば、HER2)を有する哺乳動物細胞を、細胞培養培地中のADCの抗体に暴露し;約6時間〜約5日間のある期間にわたって細胞を培養し;そして、細胞の生存度を測定することによって測定される。細胞ベースのインビトロアッセイを用いて、本発明のADCの生存度(増殖)、細胞傷害性、およびアポトーシスの誘導(カスパーゼの活性化)を測定した。
本発明の2つのアルブミン結合ペプチド−DM1(メイタンシノイド)−抗体−薬物結合体(ADC)のインビボでの有効性を、HER2を高度に発現するトランスジェニック外植マウスモデルによって測定した(図12、実施例10)。同種移植片を、Fo5 mmtvトランスジェニックマウスから増殖させた。このFo5 mmtvトランスジェニックマウスは、HERCEPTIN(登録商標)治療に対して、応答しないか、または、不完全に応答する。被験体を、ABP−rhuFab4D5−cys(軽鎖)−DM1;ABP−rhuFab4D5−cys(重鎖)−DM1;およびプラセボのPBS緩衝液コントロール(ビヒクル)で一回処置し、そして、3週間にわたってモニターして、腫瘍倍化時間、対数細胞殺傷、および腫瘍の縮小を測定した。
本発明の抗体−薬物結合体(ADC)は、処置される状態に適した適切な任意の経路で投与され得る。ADCは、代表的に、非経口的に(すなわち、注入、皮下、筋肉内、静脈内、皮内、クモ膜下腔内および硬膜外)投与され得る。
本発明の治療用抗体−薬物結合体(ADC)の薬学的処方物は、代表的に、非経口投与(すなわちボーラス注射、静脈内注射、腫瘍内注射)のために、薬学的に受容可能な非経口ビヒクルと共に、単位投薬注射可能形態で調製される。所望の程度の純度を有する抗体−薬物結合体(ADC)は、必要に応じて、薬学的に受容可能な希釈剤、キャリア、賦形剤もしくは安定化剤(Remington’s Pharmaceutical Sciences(1980)第16版,Osol,A.編)と、凍結乾燥処方物形態もしくは水溶液形態で混合される。
本発明の抗体−薬物結合体(ADC)は、種々の疾患もしくは障害(例えば、腫瘍抗原の過剰発現によって特徴付けられる疾患もしくは障害)を処置するために使用され得る。例示的な状態もしくは過剰増殖性障害としては、良性もしくは悪性の腫瘍;白血病およびリンパ性悪性疾患が挙げられる。他の障害としては、神経系障害、神経膠障害、星状細胞障害、視床下部障害、上皮障害、間質障害、胞胚腔障害、炎症性障害、脈管形成性障害および免疫障害(自己免疫障害を含む)が挙げられる。
本発明の抗体−薬物結合体(ADC)は、薬学的な組み合わせ処方物、もしくは組み合わせ治療としての投薬レジメンにおいて、抗癌特性を有する第2の化合物と組み合わされ得る。薬学的組み合わせ処方物もしくは投薬レジメンの第2の化合物は、組み合わせのADCに対して好ましくは補完的な活性を有し、それによって、互いに有害に作用しない。
本明細書中で記載されるADC化合物のインビボ代謝産物もまた、このような産物が新規かつ先行技術から自明でない範囲で、本発明の範囲内である。このような産物は、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、その代謝産物を生じるために十分な時間、哺乳動物に接触させる工程を包含するプロセスによって産生される、新規かつ非自明な化合物を含む。
本発明の別の実施形態において、システイン操作抗体は、放射性核種、蛍光色素、生物発光を引き起こす基質部分、化学発光を引き起こす部分、酵素および診断用途、薬力学用途および治療用途を有する画像化実験のための他の検出標識を有するシステインチオールを介して標識され得る。一般に、標識化システイン操作抗体(すなわち、「バイオマーカー」もしくは「プローブ」)は、生体(例えば、ヒト、げっ歯類もしくは他の小動物)、灌流された器官もしくは組織サンプルへの注射、輸液もしくは経口摂取によって投与される。プローブの分布は、時間経過にわたって検出され、そして画像によって表される。
本発明の別の実施形態において、上記の障害の処置のために有用な物質を含む製品もしくは「キット」が、提供される。製品は、容器およびこの容器上もしくはこの容器に伴うラベルもしくはパッケージ挿入物を含む。適切な容器としては、例えば、ビン、バイアル、シリンジ、パックなどが挙げられる。容器は、ガラスもしくはプラスチックのような、種々の材料から形成され得る。容器は、状態を処置するために有効な抗体−薬物結合体(ADC)組成物を維持し、そして、無菌アクセスポートを有し得る(例えば、この容器は、静脈内溶液バッグもしくは皮下注射針によって穿孔可能なストッパーを備えたバイアルであり得る)。この組み合わせ中の少なくとも1種の活性成分は、ADCである。ラベルもしくはパッケージ挿入物は、この組成物が、最適な状態(例えば癌)を処置するために使用されることを示す。あるいは、またはさらに、製品は、薬学的に受容可能な緩衝液(例えば注射のための静菌水(BWFI)、リン酸緩衝化生理食塩水、リンガー液およびデキストロース溶液)を含む第2(もしくは第3)の容器をさらに含み得る。これはさらに、商業的視点および使用者の視点から所望される他の物質を含み得、これらとしては、他の緩衝液、希釈剤、フィルター、針およびシリンジが挙げられる。
チオFab−ファージ(5×1012ファージ粒子)を、150倍過剰のビオチン−PEO−マレイミド((+)−ビオチニル−3−マレイミドプロピオンアミジル−3,6−ジオキサオクタインジアミン、Odaら(2001)Nature Biotechnology 19:379−382,Pierce Biotechnology,Inc.)と、3時間室温で反応させた。過剰なビオチン−PEO−マレイミドを、ビオチン−結合体化ファージから、PEG沈殿の繰り返し(3〜4回)によって除去した。システインチオール基と反応性である求電子性の基を有する他の市販のビオチン化試薬が、使用され得、これらとしては、ビオチン−BMCC、PEO−ヨードアセチルビオチン、ヨードアセチル−LC−ビオチン、およびビオチン−HPDP(Pierce Biotechnology,Inc.)、ならびにNα−(3−マレイミジルプロピオニル)ビオチシン(MPB,Molecular Probes,Eugene,OR)が挙げられる。ビオチン化二重官能性リンカー試薬およびビオチン化多重官能性リンカー試薬の他の商業的供給源としては、Molecular Probes,Eugene,ORおよびSigma,St.Louis,MOが挙げられる。
ウシ血清アルブミン(BSA)、erbB2細胞外ドメイン(HER2)およびストレプトアビジン(2μg/mlの100μl)を、Maxisorp 96ウェルプレート上に別個にコーティングした。0.5% Tween−20(PBS中)によるブロッキング後、ビオチン化hu4D5Fabv8−チオFab−ファージおよび非ビオチン化hu4D5Fabv8−チオFab−ファージ(2×1010ファージ粒子)を、1時間室温でインキュベートし、その後、西洋ワサビペルオキシダーゼ(HRP)標識化二次抗体(抗M13ファージコートタンパク質、pVIIIタンパク質)と共にインキュベートした。図8は、FabもしくはチオFabのHER2に対する結合(上)およびビオチン化チオFabのストレプトアビジンに対する結合(下)を示す略図によって、PHESELECTORアッセイを示す。
チオFabを、34B8、非サプレッサー(non−suppressor)E.coli株(Bacaら(1997)Journal Biological Chemistry 272(16):10678−84)における誘導において発現させた。回収した細胞ペレットを、PBS(リン酸緩衝化生理食塩水)中に再浮遊させ、細胞溶解全体を、マイクロフルイタイザー(microfluidizer)を通過させることによって行い、そしてチオFabを、タンパク質G SEPHAROSETM(Amersham)を用いる親和性クロマトグラフィーによって精製した。
ビオチン化hu4D5Fabv8(A121C)チオFabおよび野生型hu4D5Fabv8の酵素的フラグメント消化物を、液体クロマトグラフィーエレクトロスプレーイオン化質量分析(LS−ESI−MS)によって分析した。ビオチン化hu4D5Fabv8(A121C)の第1質量である48294.5と、野生型hu4D5Fabv8の第1質量である47737.0との間は、557.5質量単位であった。このフラグメントは、1つのビオチン−PEO−マレイミド部分(C23H36N5O7S2)の存在を示す。表4は、配列を確認する、フラグメント化値の割り当てを示す。
DMSO中に溶解した、薬物リンカー試薬であるマレイミドカプロイル−モノメチルアウリスタチン(auristatin)E(すなわち、MC−MMAE)を、アセトニトリルおよび水中に公知の濃度で希釈し、そして氷冷したリン酸緩衝化生理食塩水(PBS)中のABP−hu4D5Fabv8−(V110C)チオFabに添加する。約1時間後、過剰なマレイミドを添加して反応を止め、そして全ての未反応抗体チオール基をキャップする。反応混合物を、遠心限界濾過によって濃縮し、そしてABP−hu4D5Fabv8−(V110C)−MC−MMAEを、PBS中のG25樹脂を通した溶出によって精製しそして脱塩し、無菌条件下で0.2μmフィルターを通して濾過し、そして保存のために凍結する。
ABP−hu4D5Fabv8−(V110C)−MC−MMAFを、ABP−hu4D5Fabv8−(V110C)チオFabとMC−MMAFとの結合体化により、実施例4の手順に従って調製する。
ABP−hu4D5Fabv8−(A121C)−MC−val−cit−PAB−MMAEを、ABP−hu4D5Fabv8−(A121C)とMC−val−cit−PAB−MMAEとの結合体化により、実施例4の手順に従って調製する。
ABP−hu4D5Fabv8−(A121C)−MC−val−cit−PAB−MMAFは、ABP−hu4D5Fabv8−(A121C)とMC−val−cit−PAB−MMAFとの結合体化により、実施例4の手順に従って調製する。
hu4D5Fabv8−(V110C)チオFab上の遊離のシステインを、ビス−マレイミド試薬BM(PEO)4(Pierce Chemical)によって改変し、未反応のマレイミド基を抗体の表面上に残した。このことを、BM(PEO)4を50%エタノール/水混合物中に、10mMの濃度まで溶解し、そして10倍モル濃度過剰のBM(PEO)4を、リン酸緩衝化生理食塩水中約1.6mg/ml(10μM)の濃度のhu4D5Fabv8−(V110C)チオFabに添加し、そしてこれを1時間反応させることによって達成した。過剰なBM(PEO)4を、150mM NaCl緩衝液含有30mMクエン酸(pH6)中のゲル濾過(HiTrapカラム、Pharmacia)によって除去した。ジメチルアセトアミド(DMA)中に溶解した約10倍モル濃度過剰のDM1を、このhu4D5Fabv8−(V110C)チオFab−BMPEO中間体に添加した。また、ジメチルホルムアミド(DMF)を、薬物部分試薬を溶解するために使用し得る。この反応混合物を、一晩反応させ、その後、PBS中でゲル濾過もしくは透析を行って、未反応の薬物を除去した。PBS中、S200カラム上のゲル濾過を、高分子量凝集体を除去するために使用し、精製hu4D5Fabv8−(V110C)チオFab−BMPEO−DM1を提供した。
ADCの効力を、以下のプロトコール(CellTiter Glo発光細胞生存度アッセイ,Promega Corp.Technical Bulletin TB288;Mendozaら(2002)Cancer Res.62:5485−5488)を用いる細胞増殖アッセイによって測定した。
1. 約104個の細胞(SKBR−3、BT474、MCF7もしくはMDA−MB−468)を培地中に含む100μlの細胞培養物のアリコートを、96ウェルの不透明ウェルプレートの各ウェルに入れた。
2. 培地を含みそして細胞を含まないコントロールウェルを、調製した。
3. ADCを、実験ウェルに添加し、そして3〜5日間インキュベートした。
4. プレートを、30分間、室温に対して平衡化した。
5. 各ウェル中に存在する細胞培養培地の容量と同容量のCellTiter−Glo試薬を、添加した。
6. 内容物を、オービタルシェーカー(orbital shaker)上で2分間混合し、細胞溶解を誘導した。
7. このプレートを、室温で10分間インキュベートし、発光シグナルを安定化させた。
8. 発光を、RLU=相対発光単位のグラフに記録し、そして報告した。
1. プレートは、PC3/Muc16、PC3/neoの1000細胞/ウェル(50μL/ウェルの培地中)である。Ovcar3細胞を、2000細胞/ウェル(その培地の50μL中)でプレート培養するべきである(処方箋は以下)。細胞を、一晩接着させる。
2. ADCは、18μg/mlの作用濃度で開始して、培地中で1:3で連続希釈する(これにより、9μg/mlの最終濃度を生じる)。50μLの希釈したADCを、既にウェル中に存在する50μLの細胞および培地に添加する。
3. 72〜96時間インキュベートする(標準は72時間であるが、0μg/mL濃度を観察し、細胞が85〜95%コンフルーエントである時にアッセイを停止する)。
4. 100μL/ウェルのPromega Cell Titer Glo試薬を添加し、3分間振とうし、そしてルミノメーター上で読み取る。
培地:PC3/neoおよびPC3/MUC16は、50/50/10%FBS/グルタミン/250μg/mL中で増殖する。G−418 OVCAR−3は、RPMI/20%FBS/グルタミン中で増殖する。
トランスジェニック実験に適した動物は、Taconic(Germantown,N.Y.)のような標準的な商業的供給源から得られ得る。多くの系統が好適であるが、FVB雌性マウスが、腫瘍形成に対するその高い感受性ゆえに、好ましい。FVB雄を、交配のために使用し、そして精管切除したCD.1 studsを、偽妊娠を刺激するために使用した。精管切除したマウスは、任意の業者から得られ得る。創始マウス(founder)を、FVBマウスのいずれか、もしくは29/BL6×FVB p53異種接合マウスと交配した。p53対立遺伝子において異種接合性を有するマウスを、潜在的な腫瘍形成の増大のために使用した。しかし、これは、不必要であることが証明されている。しかし、いくつかのF1腫瘍は、混合した系統の腫瘍であった。創始腫瘍(founder 腫瘍)は、FVBのみである。いくらかの発達中の腫瘍を有する6匹の創始マウスを、同腹子なしで得た。
全長の、CHO細胞中で発現されるシステイン操作モノクローナル抗体(チオMabs)を、約50倍過剰のTCEP(トリ(2−カルボキシエチル)ホスフィン塩酸塩;Getzら(1999)Anal.Biochem.第273巻:73−80;Soltec Ventures,Beverly,MA)によって、3時間、37℃で還元した。還元型チオMab(図15)を、希釈し、そして10mM酢酸ナトリウム(pH5)中でHiTrap Sカラム上にローディングし、そして0.3M塩化ナトリウムを含有するPBSによって溶出した。溶出した還元型チオMabを、200nM硫酸銅(CuSO4)水溶液で、室温で一晩処理した。周囲の空気の酸化もまた、有効であった。
実施例11からの再酸化型(reoxidized)チオMab(チオ−トラスツズマブ(A121C)、チオ−2H9(A121C)、およびチオ−3A5(A121C)を含む)を、10倍過剰な薬物−リンカー中間体(BM(PEO)4−DM1)と合わせ、混合し、そして約1時間室温に静置して結合体化を起こさせ、そしてチオMab抗体−薬物結合体(チオ−トラスツズマブ(A121C)−BMPEO−DM1、チオ−2H9(A121C)−BMPEO−DM1、およびチオ−3A5(A121C)−BMPEO−DM1を含む)を形成した。結合体混合物を、ゲル濾過するか、またはHiTrap Sカラム上にローディングしそして溶出して、過剰な薬物−リンカー中間体および他の不純物を除去した。
Claims (46)
- 一つ以上の遊離システインアミノ酸を含むシステイン操作抗体であって、該システイン操作抗体は、親抗体の一つ以上のアミノ酸残基を、遊離システインアミノ酸残基によって置換する工程を包含するプロセスにより調製され、ここで、該親抗体は、抗原に選択的に結合し、該システイン操作抗体は、該親抗体と同じ抗原に選択的に結合し、該親抗体は、以下の配列:
重鎖の40位、88位、119位、121位、122位、175位および179位、または、軽鎖の15位、43位、110位、144位、153位、168位および205位のうち少なくとも一つが遊離システインアミノ酸残基によって置換されている、システイン操作抗体。 - 前記一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操作抗体。
- 前記親抗体の以下の位置:
軽鎖の15位、43位、110位、144位、153位、168位および205位のうち少なくとも一つが遊離システインアミノ酸残基によって置換されている、請求項1に記載のシステイン操作抗体。 - 前記一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操作抗体。
- 前記親抗体の以下の位置:
重鎖の40位、88位、119位、121位、122位、175位および179位のうち少なくとも一つが遊離システインアミノ酸残基によって置換されている、請求項1に記載のシステイン操作抗体。 - 前記一つ以上の遊離システインアミノ酸残基が、重鎖または軽鎖の可変領域の位置から選択される、請求項1に記載のシステイン操作抗体。
- 前記一つ以上の遊離システインアミノ酸残基が、定常領域の位置から選択される、請求項1に記載のシステイン操作抗体。
- 以下:
(i)前記システイン操作抗体をコードする核酸配列に変異誘発する工程;
(ii)該システイン操作抗体を発現させる工程;および
(iii)該システイン操作抗体を単離および精製する工程
を包含するプロセスにより調製される、請求項1に記載のシステイン操作抗体。 - 以下:
(i)前記システイン操作抗体をチオール反応性親和性試薬と反応させて、親和性標識されたシステイン操作抗体を生成する工程;および
(ii)該親和性標識されたシステイン操作抗体の、捕捉媒体に対する結合を測定する工程
をさらに包含する、請求項8に記載のシステイン操作抗体。 - 前記チオール反応性親和性試薬がビオチン部分およびマレイミド部分を含む、請求項9に記載のシステイン操作抗体。
- 前記捕捉媒体がストレプトアビジンを含む、請求項9に記載のシステイン操作抗体。
- 前記親抗体が、配列番号1、配列番号2、配列番号3、配列番号4および配列番号5から選択されるアルブミン結合性ペプチド(ABP)を含む融合タンパク質である、請求項1に記載のシステイン操作抗体。
- 配列番号6、配列番号7および配列番号8から選択されるアミノ酸配列を含む、請求項1に記載のシステイン操作抗体。
- 前記抗体が、捕捉標識、検出標識または固体支持体に共有結合している、請求項1に記載のシステイン操作抗体。
- 前記抗体が、フルオレセインタイプ、ローダミンタイプ、ダンシル、リサミン、シアニン、フィコエリトリン、テキサスレッドおよびそれらのアナログから選択される蛍光色素検出標識に共有結合している、請求項14に記載のシステイン操作抗体。
- 前記抗体が、3H、11C、14C、18F、32P、35S、64Cu、68Ga、86Y、99Tc、111In、123I、124I、125I、131I、133Xe、177Lu、211Atおよび213Biから選択される放射性核種検出標識に共有結合している、請求項14に記載のシステイン操作抗体。
- 前記抗体が、DOTA、DOTP、DOTMA、DTPAおよびTETAから選択されるキレートリガンドによって検出標識に共有結合している、請求項14に記載のシステイン操作抗体。
- 前記親抗体の以下の位置:
重鎖の119位、121位および175位のうち少なくとも一つが遊離システインアミノ酸残基によって置換されている、請求項1に記載のシステイン操作抗体。 - 前記親抗体の重鎖の121位が遊離システインアミノ酸残基によって置換されている、請求項1に記載のシステイン操作抗体。
- 一つ以上の遊離システインアミノ酸残基を含むシステイン操作抗体(Ab)と、マイタンシノイド、オーリスタチン、ドラスタチンおよびカリケアマイシンから選択される薬物部分(D)を含む抗体−薬物結合体化合物であって、該システイン操作抗体は、リンカー部分(L)によって一つ以上の遊離システインアミノ酸残基を通してDへと結合しており;該化合物は、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;該システイン操作抗体は、親抗体の一つ以上のアミノ酸残基を一つ以上の遊離システインアミノ酸残基によって置換する工程を包含するプロセスにより調製され、ここで、該親抗体は、抗原に選択的に結合し、該システイン操作抗体は、該親抗体と同じ抗原に選択的に結合し、該親抗体は、以下の配列:
重鎖の40位、88位、119位、121位、122位、175位および179位、または、軽鎖の15位、43位、110位、144位、153位、168位および205位のうち少なくとも一つが遊離システインアミノ酸残基によって置換されている、抗体−薬物結合体化合物。 - 前記親抗体の以下の位置:
重鎖の119位、121位および175位のうち少なくとも一つが遊離システインアミノ酸残基によって置換されている、請求項20に記載の抗体−薬物結合体化合物。 - 前記システイン操作抗体が、以下:
(a)親抗体の一つ以上のアミノ酸残基を遊離システインアミノ酸残基によって置換する工程;および
(b)該システイン操作抗体をチオール反応性試薬と反応させることによって該システイン操作抗体のチオール反応性を決定する工程
を包含するプロセスにより調製され、該システイン操作抗体は、該チオール反応性試薬との反応性が該親抗体よりも高い、請求項20に記載の抗体−薬物結合体化合物。 - 配列番号1、配列番号2、配列番号3、配列番号4および配列番号5から選択されるアルブミン結合性ペプチド(ABP)配列をさらに含む、請求項20に記載の抗体−薬物結合体化合物。
- pが1または2である、請求項20に記載の抗体−薬物結合体化合物。
- Lが、式:
−Aa−Ww−Yy−
を有し、ここで:
Aは、前記システイン操作抗体(Ab)のシステインチオールに共有結合し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し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20に記載の抗体−薬物結合体化合物。 - 以下の式:
- Wwがバリン−シトルリンである、請求項26に記載の抗体−薬物結合体化合物。
- R17が(CH2)5または(CH2)2である、請求項26に記載の抗体−薬物結合体化合物。
- R17が(CH2)5または(CH2)2である、請求項29に記載の抗体−薬物結合体化合物。
- Lがリンカー試薬SMCCまたはBMPEOから形成される、請求項20に記載の抗体−薬物結合体化合物。
- 前記薬物部分Dが、マイクロチューブリンインヒビター、有糸分裂インヒビター、トポイソメラーゼインヒビターおよびDNAインターカレーターから選択される、請求項20に記載の抗体−薬物結合体化合物。
- 前記薬物部分Dが、マイタンシノイド、オーリスタチン、ドラスタチンおよびカリケアマイシンから選択される、請求項20に記載の抗体−薬物結合体化合物。
- 前記親抗体の重鎖の121位が遊離システインアミノ酸残基によって置換されている、請求項20に記載の抗体−薬物結合化合物。
- 構造:
重鎖の40位、88位、119位、121位、122位、175位および179位、または、軽鎖の15位、43位、110位、144位、153位、168位および205位のうち少なくとも一つが遊離システインアミノ酸残基によって置換されている、抗体−薬物結合体化合物。 - 癌の処置において使用するための、請求項20に記載の抗体−薬物結合体化合物。
- 請求項20に記載の抗体−薬物結合体化合物またはその薬学的に受容可能な塩、および薬学的に受容可能な希釈液、キャリアまたは賦形剤を含む、薬学的組成物。
- 治療上有効量のさらなる化学療法剤をさらに含む、請求項43に記載の薬学的組成物。
- 請求項20に記載の抗体−薬物結合体化合物、
容器、および
該化合物を使用して癌を処置し得ることを示している、添付文書またはラベル
を備える、製品。 - 請求項20に記載の抗体−薬物結合体化合物を含む、癌の処置のための組成物。
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