JP5889912B2 - アラニニルメイタンシノール抗体コンジュゲート - Google Patents
アラニニルメイタンシノール抗体コンジュゲート Download PDFInfo
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- JP5889912B2 JP5889912B2 JP2013539981A JP2013539981A JP5889912B2 JP 5889912 B2 JP5889912 B2 JP 5889912B2 JP 2013539981 A JP2013539981 A JP 2013539981A JP 2013539981 A JP2013539981 A JP 2013539981A JP 5889912 B2 JP5889912 B2 JP 5889912B2
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Description
本出願は、2010年11月17日に出願された米国仮出願第61/414,535号の利益を主張し、それは参照によりその全体が援用される。
本発明は一般的に、治療又は診断の用途による抗体−薬剤コンジュゲートを形成するための、メイタンシノイド薬剤部分にコンジュゲートした抗体に関する。抗体はアラニニルメイタンシノイド薬剤リンカー試薬との結合のための反応性の遊離システインアミノ酸で操作することができる。本発明はまた、哺乳動物細胞、又は関連する病理学的状態のインビトロ、インサイツ、及びインビボでの診断または治療において、アラニニルメイタンシノイド抗体−薬剤コンジュゲート化合物を使用する方法にも関する。
抗体薬剤複合体(ADC)は、抗原発現腫瘍細胞に対して強力な細胞傷害性薬剤を標的とし、内部移行、そして薬剤の放出、及びそれによってそれらの抗腫瘍活性を増強することにより抗体と細胞傷害性薬剤の両方の理想的な特性を組み合わせた目的とされる化学療法分子である。所与の標的抗原に対するADCの開発の成功は、抗体の選択、リンカーの設計及び安定性、細胞毒性薬の効能及び抗体に対する薬とリンカーの結合様式の最適化に依存する。pHと酸化還元感度およびプロテアーゼ感受性についてのリンカーの特性は、内部移行と細胞毒性薬剤部分の放出に影響を与える。ADCのジスルフィド含有リンカーの細胞内の切断は、エンドソームとリソソームの酸化電位によって制限され、恐らくはエンドサイトーシス経路内の還元的開裂によっては放出されない(Austin et al (2005) Proc. Natl. Acad. Sci. USA 102(50):17987-17992)。還元開裂は、細胞膜で起こり得、遊離薬剤により腫瘍と影響を受けやすい正常細胞のバイスタンダー殺傷効果を付与する。薬剤の不適切な放出は毒性に寄与する可能性がある。ひとたび内在化すると、ADCの効力は、薬剤活性においてタンパク質分解消化に依存する。リンカーの安定性は、ADCの有効性及び毒性の両方で重要な役割を果たしている(Alley et al (2008) Bioconjugate Chem. 19:759-765)。mccなどの安定したリンカーは、不安定な、ジスルフィドリンカーよりも有効かつ安全であり、治療のウィンドウを拡大している。
本発明の一態様は、式Iのリンカー薬剤化合物から調製された式Ia及びIbの新規抗体−薬剤コンジュゲートを提供することである。
ここで:
Lは、
mは2、3、4、5または6;mは2、3、又は4;qは0又は1;pは1から4であり、Abは抗体である。
本発明の特定の実施態様に対して詳細に述べ、その例は、付随する構造と式に示される。本発明は説明される実施態様と併せて説明されるが、それらの実施態様に本発明を限定するものではないことが理解されるであろう。一方、本発明は、特許請求の範囲によって定義される本発明の範囲内に含まれ得る全ての代替、改変、および均等物を包含することを意図している。
特に明記しない限り、本明細書で使用する以下の用語と語句は、以下の意味を有することが意図される。
本発明の化合物は、野生型抗体又は親抗体の一以上のアミノ酸が、システインアミノ酸と置換される、システイン操作抗体を含む。抗体の任意の形態は、そのように操作、即ち変異導入されうる。例えば、親Fab抗体断片は、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(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(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。置換された(「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;又は0.8〜1.0の範囲内である。
(1)BMPR1B(骨形成タンパク質レセプタータイプIB型,Genbank受託番号NM_001203)
ten Dijke,P.,et al Science 264 (5155):101−104(1994),Oncogene 14 (11):1377−1382(1997));国際公開第2004063362号(請求項2);国際公開第2003042661号(請求項12);米国特許出願公開第2003134790−A1号(頁38−39);国際公開第2002102235号(請求項13;頁296);国際公開第2003055443号(頁91−92);国際公開第200299122号(実施例2;頁528−530);国際公開第2003029421号(請求項6);国際公開第2003024392号(請求項2;図112);国際公開第200298358号(請求項1;頁183);国際公開第200254940号(頁100−101);国際公開第200259377号(頁349−350);国際公開第200230268号(請求項27;頁376);国際公開第200148204号(実施例;図4)
NP_001194骨形成タンパク質レセプター,タイプIB/pid=NP_001194.1−
相互参照:MIM:603248;NP_001194.1;AY065994
Biochem. Biophys. Res. Commun. 255 (2), 283-288 (1999), Nature 395 (6699):288-291 (1998), Gaugitsch, H.W., et al (1992) J. Biol. Chem. 267 (16):11267-11273);国際公開第2004048938号(実施例2);国際公開第2004032842号(実施例IV);国際公開第2003042661号(請求項12);国際公開第2003016475号(請求項1);国際公開第200278524号(実施例2);国際公開第200299074号(請求項19;頁127−129);国際公開第200286443号(請求項27;頁222,393);国際公開第2003003906号(請求項10;頁293);国際公開第200264798号(請求項33;頁93−95);国際公開第200014228号(請求項5;頁133−136);米国特許出願公開第2003224454号(図3);国際公開第2003025138号(請求項12;頁150);
NP_003477溶質担体ファミリー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−ホモサピエンス
相互参照:MIM:600182;NP_003477.3;NM_015923;NM_003486_1
Cancer Res. 61 (15), 5857-5860 (2001), Hubert, R.S., et al (1999) Proc. Natl. Acad. Sci. U.S.A. 96 (25):14523-14528);国際公開第2004065577号(請求項6);国際公開第2004027049号(図1L);欧州特許第1394274号(実施例11);国際公開第2004016225号(請求項2);国際公開第2003042661号(請求項12);米国特許出願公開第2003157089号(実施例5);米国特許出願公開第2003185830号(実施例5);米国特許出願公開第2003064397号(図2);国際公開第200289747号(実施例5;頁618−619);国際公開第2003022995号(実施例9;図13A,実施例53;頁173,実施例2;図2A);
NP_036581 前立腺の6回膜貫通型上皮抗原
相互参照:MIM:604415;NP_036581.1;NM_012449_1
J. Biol. Chem. 276 (29):27371-27375 (2001));国際公開第2004045553号(請求項14);国際公開第200292836号(請求項6;図12);国際公開第200283866号(請求項15;頁116−121);米国特許出願公開第2003124140号(実施例16);相互参照:GI:34501467;AAK74120.3;AF361486_1
Yamaguchi, N., et al 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));国際公開第2003101283号(請求項14);(国際公開第2002102235号(請求項13;頁287−288);国際公開第2002101075号(請求項4;頁308−309);国際公開第200271928号(頁320−321);国際公開第9410312号(頁52−57);相互参照:MIM:601051;NP_005814.2;NM_005823_1
J. Biol. Chem. 277 (22):19665-19672 (2002), Genomics 62 (2):281-284 (1999), Feild, J.A., et al (1999) Biochem. Biophys. Res. Commun. 258 (3):578-582);国際公開第2004022778号(請求項2);欧州特許第1394274号(実施例11);国際公開第2002102235号(請求項13;頁326);欧州特許第875569号(請求項1;頁17−19);国際公開第200157188号(請求項20;頁329);国際公開第2004032842号(実施例IV);国際公開第200175177号(請求項24;頁139−140);
相互参照:MIM:604217;NP_006415.1;NM_006424_1
Nagase T., et al (2000) DNA Res. 7 (2):143-150);国際公開第2004000997号(請求項1);国際公開第2003003984号(請求項1);国際公開第200206339号(請求項1;頁50);国際公開第200188133号(請求項1;頁41−43,48−58);国際公開第2003054152号(請求項20);国際公開第2003101400号(請求項11);
受託番号:Q9P283;EMBL;AB040878;BAA95969.1.Genew;HGNC:10737;
相互参照:GI:37182378;AAQ88991.1;AY358628_1
Nakamuta M., et al Biochem. Biophys. Res. Commun. 177, 34-39, 1991; Ogawa Y., et al Biochem. Biophys. Res. Commun. 178, 248-255, 1991; Arai H., et al Jpn. Circ. J. 56, 1303-1307, 1992; Arai H., et al J. Biol. Chem. 268, 3463-3470, 1993; Sakamoto A., Yanagisawa M., et al Biochem. Biophys. Res. Commun. 178, 656-663, 1991; Elshourbagy N.A., et al J. Biol. Chem. 268, 3873-3879, 1993; Haendler B., et al J. Cardiovasc. Pharmacol. 20, s1-S4, 1992; Tsutsumi M., et al Gene 228, 43-49, 1999; Strausberg R.L., et al Proc. Natl. Acad. Sci. U.S.A. 99, 16899-16903, 2002; Bourgeois C., et al J. Clin. Endocrinol. Metab. 82, 3116-3123, 1997; Okamoto Y., et al Biol. Chem. 272, 21589-21596, 1997; Verheij J.B., et al Am. J. Med. Genet. 108, 223-225, 2002; Hofstra R.M.W., et al Eur. J. Hum. Genet. 5, 180-185, 1997; Puffenberger E.G., et al Cell 79, 1257-1266, 1994; Attie T., et al, Hum. Mol. Genet. 4, 2407-2409, 1995; Auricchio A., et al Hum. Mol. Genet. 5:351-354, 1996; Amiel J., et al Hum. Mol. Genet. 5, 355-357, 1996; Hofstra R.M.W., et al Nat. Genet. 12, 445-447, 1996; Svensson P.J., et al Hum. Genet. 103, 145-148, 1998; Fuchs S., et al Mol. Med. 7, 115-124, 2001; Pingault V., et al (2002) Hum. Genet. 111, 198-206;国際公開第2004045516号(請求項1);国際公開第2004048938号(実施例2);国際公開第2004040000号(請求項151);国際公開第2003087768号(請求項1);国際公開第2003016475号(請求項1);国際公開第2003016475号(請求項1);国際公開第200261087号(図1);国際公開第2003016494号(図6);国際公開第2003025138号(請求項12;頁144);国際公開第200198351号(請求項1;頁124−125);欧州特許第522868号(請求項8;図2);国際公開第200177172号(請求項1;頁297−299);米国特許出願公開第2003109676号;米国特許第6518404号(図3);米国特許第5773223号(請求項1a;Col 31−34);国際公開第2004001004号;
国際公開第2003104275号(請求項1);国際公開第2004046342号(実施例2);国際公開第2003042661号(請求項12);国際公開第2003083074号(請求項14;頁61);国際公開第2003018621号(請求項1);国際公開第2003024392号(請求項2;図93);国際公開第200166689号(実施例6);
相互参照:遺伝子座番号:54894;NP_060233.2;NM_017763_1
Lab. Invest. 82 (11):1573-1582 (2002));国際公開第2003087306号;米国特許出願公開第2003064397号(請求項1;図1);国際公開第200272596号(請求項13;頁54−55);国際公開第200172962号(請求項1;図4B);国際公開第2003104270号(請求項11);国際公開第2003104270号(請求項16);米国特許出願公開第2004005598号(請求項22);国際公開第2003042661号(請求項12);米国特許出願公開第2003060612号(請求項12;図10);国際公開第200226822号(請求項23;図2);国際公開第200216429号(請求項12;図10);
相互参照:GI:22655488;AAN04080.1;AF455138_1
Xu, X.Z., et al 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));米国特許出願公開第2003143557号(請求項4);国際公開第200040614号(請求項14;頁100−103);国際公開第200210382号(請求項1;図9A);国際公開第2003042661号(請求項12);国際公開第200230268号(請求項27;頁391);米国特許出願公開第2003219806号(請求項4);国際公開第200162794号(請求項14;図1A−D);
相互参照:MIM:606936;NP_060106.2;NM_017636_1
Ciccodicola, A., et al EMBO J. 8 (7):1987-1991 (1989), Am. J. Hum. Genet. 49 (3):555-565 (1991));米国特許出願公開第2003224411号(請求項1);国際公開第2003083041号(実施例1);国際公開第2003034984号(請求項12);国際公開第200288170号(請求項2;頁52−53);国際公開第2003024392号(請求項2;図58);国際公開第200216413号(請求項1;頁94−95,105);国際公開第200222808号(請求項2;図1);米国特許第5854399号(実施例2;Col 17−18);米国特許第5792616号(図2);
相互参照:MIM:187395;NP_003203.1;NM_003212_1
Fujisaku et al (1989) J. Biol. Chem. 264 (4):2118-2125); Weis J.J., et al J. Exp. Med. 167, 1047-1066, 1988; Moore M., et al Proc. Natl. Acad. Sci. U.S.A. 84, 9194-9198, 1987; Barel M., et al Mol. Immunol. 35, 1025-1031, 1998; Weis J.J., et al Proc. Natl. Acad. Sci. U.S.A. 83, 5639-5643, 1986; Sinha S.K., et al (1993) J. Immunol. 150, 5311-5320;国際公開第2004045520号(実施例4);米国特許出願公開第2004005538号(実施例1);国際公開第2003062401号(請求項9);国際公開第2004045520号(実施例4);国際公開第9102536号(図9.1−9.9);国際公開第2004020595号(請求項1);
受託番号:P20023;Q13866;Q14212;EMBL;M26004;AAA35786.1.
Proc. Natl. Acad. Sci. U.S.A. (2003) 100 (7):4126-4131, Blood (2002) 100 (9):3068-3076, Muller et al (1992) Eur. J. Immunol. 22 (6):1621-1625);国際公開第2004016225号(請求項2,図140);国際公開第2003087768号,米国特許出願公開第2004101874号(請求項1,頁102);国際公開第2003062401号(請求項9);国際公開第200278524号(実施例2);米国特許出願公開第2002150573号(請求項5,頁15);米国特許第5644033号;国際公開第2003048202号(請求項1,頁306及び309);国際公開第99/558658号,米国特許第6534482号(請求項13,図17A/B);国際公開第200055351号(請求項11,頁1145−1146);
相互参照:MIM:147245;NP_000617.1;NM_000626_1
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., et al (2001) Biochem. Biophys. Res. Commun. 280 (3):768-775;国際公開第2004016225号(請求項2);国際公開第2003077836号;国際公開第200138490号(請求項5;図18D−1−18D−2);国際公開第2003097803号(請求項12);国際公開第2003089624号(請求項25);
相互参照:MIM:606509;NP_110391.2;NM_030764_1
Coussens L., et al Science (1985) 230(4730):1132-1139); Yamamoto T., et al Nature 319, 230-234, 1986; Semba K., et al Proc. Natl. Acad. Sci. U.S.A. 82, 6497-6501, 1985; Swiercz J.M., et al J. Cell Biol. 165, 869-880, 2004; Kuhns J.J., et al J. Biol. Chem. 274, 36422-36427, 1999; Cho H.-S., et al Nature 421, 756-760, 2003; Ehsani A., et al (1993) Genomics 15, 426-429;国際公開第2004048938号(実施例2);国際公開第2004027049号(図1I);国際公開第2004009622;国際公開第2003081210;国際公開第2003089904号(請求項9);国際公開第2003016475号(請求項1);米国特許出願公開第2003118592号;国際公開第2003008537号(請求項1);国際公開第2003055439号(請求項29;図1A−B);国際公開第2003025228号(請求項37;図5C);国際公開第200222636号(実施例13;頁95−107);国際公開第200212341号(請求項68;図7);国際公開第200213847号(頁71−74);国際公開第200214503号(頁114−117);国際公開第200153463号(請求項2;頁41−46);国際公開第200141787号(頁15);国際公開第200044899号(請求項52;図7);国際公開第200020579号(請求項3;図2);米国特許第5869445号(請求項3;Col 31−38);国際公開第9630514号(請求項2;頁56−61);欧州特許第1439393号(請求項7);国際公開第2004043361号(請求項7);国際公開第2004022709号;国際公開第200100244号(実施例3;図4);
受託番号:P04626;EMBL;M11767;AAA35808.1.EMBL;M11761;AAA35808.1.
Barnett T., et al Genomics 3, 59-66, 1988; Tawaragi Y., et al Biochem. Biophys. Res. Commun. 150, 89-96, 1988; Strausberg R.L., et al Proc. Natl. Acad. Sci. U.S.A. 99:16899-16903, 2002;国際公開第2004063709;欧州特許第1439393号(請求項7);国際公開第2004044178号(実施例4);国際公開第2004031238号;国際公開第2003042661号(請求項12);国際公開第200278524号(実施例2);国際公開第200286443号(請求項27;頁427);国際公開第200260317号(請求項2);
受託番号:P40199;Q14920;EMBL;M29541;AAA59915.1.EMBL;M18728;
Proc. Natl. Acad. Sci. U.S.A. 99 (26):16899-16903 (2002));国際公開第2003016475号(請求項1);国際公開第200264798号(請求項33;頁85−87);特公平5−003790号公報(図6−8);国際公開第9946284号(図9);
相互参照:MIM:179780;AAH17023.1;BC017023_1
Clark H.F., et al Genome Res. 13, 2265-2270, 2003; Mungall A.J., et al Nature 425, 805-811, 2003; Blumberg H., et al Cell 104, 9-19, 2001; Dumoutier L., et al J. Immunol. 167, 3545-3549, 2001; Parrish-Novak J., et al J. Biol. Chem. 277, 47517-47523, 2002; Pletnev S., et al (2003) Biochemistry 42:12617-12624; Sheikh F., et al (2004) J. Immunol. 172, 2006-2010;欧州特許第1394274号(実施例11);米国特許出願公開第2004005320号(実施例5);国際公開第2003029262号(頁74−75);国際公開第2003002717号(請求項2;頁63);国際公開第200222153号(頁45−47);米国特許出願公開第2002042366号(頁20−21);国際公開第200146261号(頁57−59);国際公開第200146232号(頁63−65);国際公開第9837193号(請求項1;頁55−59);
受託番号:Q9UHF4;Q6UWA9;Q96SH8;EMBL;AF184971;AAF01320.1.
Gary S.C., et al Gene 256, 139-147, 2000; Clark H.F., et al Genome Res. 13, 2265-2270, 2003; Strausberg R.L., et al Proc. Natl. Acad. Sci. U.S.A. 99, 16899-16903, 2002;米国特許出願公開第2003186372号(請求項11);米国特許出願公開第2003186373号(請求項11);米国特許出願公開第2003119131号(請求項1;図52);米国特許出願公開第2003119122号(請求項1;図52);米国特許出願公開第2003119126号(請求項1);米国特許出願公開第2003119121号(請求項1;図52);米国特許出願公開第2003119129号(請求項1);米国特許出願公開第2003119130号(請求項1);米国特許出願公開第2003119128号(請求項1;図52);米国特許出願公開第2003119125号(請求項1);国際公開第2003016475号(請求項1);国際公開第200202634号(請求項1);
Chan,J. and 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));国際公開第2003042661号(請求項12);国際公開第200053216号(請求項1;頁41);国際公開第2004065576号(請求項1);国際公開第2004020583号(請求項9);国際公開第2003004529号(頁128−132);国際公開第200053216号(請求項1;頁42);
相互参照:MIM:600997;NP_004433.2;NM_004442_1
米国特許出願公開第20040101899号(請求項2);国際公開第2003104399号(請求項11);国際公開第2004000221号(図3);米国特許出願公開第2003165504号(請求項1);米国特許出願公開第2003124140号(実施例2);米国特許出願公開第2003065143号(図60);国際公開第2002102235号(請求項13;頁299);米国特許出願公開第2003091580号(実施例2);国際公開第200210187号(請求項6;図10);国際公開第200194641号(請求項12;図7b);国際公開第200202624号(請求項13;図1A−1B);米国特許出願公開第2002034749号(請求項54;頁45−46);国際公開第200206317号(実施例2;頁320−321,請求項34;頁321−322);国際公開第200271928号(頁468−469);国際公開第200202587号(実施例1;図1);国際公開第200140269号(実施例3;頁190−192);国際公開第200036107号(実施例2;頁205−207);国際公開第2004053079号(請求項12);国際公開第2003004989号(請求項1);国際公開第200271928号(頁233−234,452−453);国際公開第0116318号;
Reiter R.E., et al Proc. Natl. Acad. Sci. U.S.A. 95, 1735-1740, 1998; Gu Z., et al Oncogene 19, 1288-1296, 2000; Biochem. Biophys. Res. Commun. (2000) 275(3):783-788;国際公開第2004022709号;欧州特許第1394274号(実施例11);米国特許出願公開第2004018553号(請求項17);国際公開第2003008537号(請求項1);国際公開第200281646号(請求項1;頁164);国際公開第2003003906号(請求項10;頁288);国際公開第200140309号(実施例1;図17);米国特許出願公開第2001055751号(実施例1;図1b);国際公開第200032752号(請求項18;図1);国際公開第9851805号(請求項17;頁97);国際公開第9851824号(請求項10;頁94);国際公開第9840403号(請求項2;図1B);
受託番号:O43653;EMBL;AF043498;AAC39607.1.
AAP14954脂肪腫HMGIC融合パートナー様タンパク質(fusion−partner−like protein)/pid=AAP14954.1 − ホモ・サピエンス
種:ホモサピエンス(ヒト)
国際公開第2003054152号(請求項20);国際公開第2003000842号(請求項1);国際公開第2003023013号(実施例3,請求項20);米国特許出願公開第2003194704号(請求項45);
相互参照:GI:30102449;AAP14954.1;AY260763_1
Thompson, J.S., et al Science 293 (5537), 2108-2111 (2001);国際公開第2004058309号;国際公開第2004011611;国際公開第2003045422号(実施例;頁32−33);国際公開第2003014294号(請求項35;図6B);国際公開第2003035846号(請求項70;頁615−616);国際公開第200294852号(Col 136−137);国際公開第200238766号(請求項3;頁133);国際公開第200224909号(実施例3;図3);
相互参照:MIM:606269;NP_443177.1;NM_052945_1;AF132600
Wilson et al (1991) J. Exp. Med. 173:137-146;国際公開第2003072036号(請求項1;図1);
相互参照:MIM:107266;NP_001762.1;NM_001771_1
;国際公開第9207574号(図1);米国特許第5644033号;Ha et al (1992) J. Immunol. 148(5):1526-1531; Mueller et al (1992) Eur. J. Biochem. 22:1621-1625; Hashimoto et al (1994) Immunogenetics 40(4):287-295; Preud'homme et al (1992) Clin. Exp. Immunol. 90(1):141-146; Yu et al (1992) J. Immunol. 148(2) 633-637; Sakaguchi et al (1988) EMBO J. 7(11):3457-3464;
国際公開第2004040000号;国際公開第2004015426号;米国特許出願公開第2003105292号(実施例2);米国特許第6555339号(実施例2);国際公開第200261087号(図1);国際公開第200157188号(請求項20,頁269);国際公開第200172830号(頁12−13);国際公開第200022129号(実施例1,頁152−153,実施例2,頁254−256);国際公開第9928468号(請求項1,頁38);米国特許第5440021号(実施例2,col 49−52);国際公開第9428931号(頁56−58);国際公開第9217497号(請求項7,図5);Dobner et al (1992) Eur. J. Immunol. 22:2795-2799; Barella et al (1995) Biochem. J. 309:773-779;
Tonnelle et al (1985) EMBO J. 4(11):2839-2847; Jonsson et al (1989) Immunogenetics 29(6):411-413; Beck et al (1992) J. Mol. Biol. 228:433-441; Strausberg et al (2002) Proc. Natl. Acad. Sci USA 99:16899-16903; Servenius et al (1987) J. Biol. Chem. 262:8759-8766; Beck et al (1996) J. Mol. Biol. 255:1-13; Naruse et al (2002) Tissue Antigens 59:512-519;国際公開第9958658号(請求項13,図15);米国特許第6153408号(Col 35−38);米国特許第5976551号(col 168−170);米国特許第6011146号(col 145−146);Kasahara et al (1989) Immunogenetics 30(1):66-68; Larhammar et al (1985) J. Biol. Chem. 260(26):14111-14119;
Le et al (1997) FEBS Lett. 418(1-2):195-199;国際公開第2004047749号;国際公開第2003072035号(請求項10);Touchman et al (2000) Genome Res. 10:165-173;国際公開第200222660号(請求項20);国際公開第2003093444号(請求項1);国際公開第2003087768号(請求項1);国際公開第2003029277号(頁82);
国際公開第2004042346号(請求項65);国際公開第2003026493号(頁51−52,57−58);国際公開第200075655号(頁105−106);Von Hoegen et al (1990) J. Immunol. 144(12):4870-4877; Strausberg et al (2002) Proc. Natl. Acad. Sci USA 99:16899-16903;
米国特許出願公開第2002193567号;国際公開第9707198号(請求項11,頁39−42);Miura et al (1996) Genomics 38(3):299-304; Miura et al (1998) Blood 92:2815-2822;国際公開第2003083047号;国際公開第9744452号(請求項8,頁57−61);国際公開第200012130号(頁24−26);
国際公開第2003077836号;国際公開第200138490号(請求項6,図18E−1−18−E−2);Davis et al (2001) Proc. Natl. Acad. Sci USA 98(17):9772-9777;国際公開第2003089624号(請求項8);欧州特許第1347046号(請求項1);国際公開第2003089624号(請求項7);
国際公開第2003024392号(請求項2,図97); Nakayama et al (2000) Biochem. Biophys. Res. Commun. 277(1):124-127;国際公開第2003077836号;国際公開第200138490号(請求項3,図18B−1−18B−2);
国際公開第2004074320号(配列番号810);特開2004−113151号公報(配列番号2,4,8);国際公開第2003042661号(配列番号580);国際公開第2003009814号(配列番号411);欧州特許第1295944号(頁69−70);国際公開第200230268号(頁329);国際公開第200190304号(配列番号2706);米国特許出願公開第2004249130号;米国特許出願公開第2004022727号;国際公開第2004063355号;米国特許出願公開第2004197325号;米国特許出願公開第2003232350号;米国特許出願公開第2004005563号;米国特許出願公開第2003124579号;Horie et al(2000)Genomics 67:146−152;Uchida et al (1999) Biochem. Biophys. Res. Commun. 266:593-602; Liang et al (2000) Cancer Res. 60:4907-12; Glynne-Jones et al (2001) Int J Cancer. Oct 15;94(2):178-84;
システインは抗HER2hu4D5Fabv8 Fab断片抗体の重鎖と軽鎖の各位置に導入された(米国特許第5821337号;Carter et al (1992) Proc. Natl. Acad. Sci., 89:4285-4289)。全440の重鎖変異と軽鎖変異は本明細書に記載の方法に従って調製された。チオール反応性はPHESELECTORアッセイに従って測定された。重鎖配列は連続番号付けシステムによって番号が付けられる。軽鎖配列は、カバット番号付けシステムに従う。軽鎖において、カバットと連続番号付けは同じ番号を表示する。
所定の条件下では、システイン操作抗体は、DTT(クリーランドの試薬、ジチオスレイトール)、又はTCEP(トリス(2−カルボキシエチル)ホスフィン塩酸塩;Getz et al (1999) Anal. Biochem. Vol 273:73-80; Soltec Ventures, Beverly, MA)等の還元剤で処理することにより、リンカー試薬とのコンジュゲーションのために反応性になりうる。CHO細胞で発現される完全長システイン操作モノクローナル抗体(チオMab)(Gomez et al (2010) Biotechnology and Bioeng. 105(4):748-760; Gomez et al (2010) Biotechnol. Prog. 26:1438-1445)が、新たに導入されたシステイン残基と培地中に存在するシステインの存在の間に形成する可能性のあるジスルフィド結合を還元するために、室温で一晩約50倍過剰のDTTにより還元された。還元されたチオMabは10mM酢酸ナトリウムpH5で希釈され、HiTrap SP FFカラム上にロードされ、150mM塩化ナトリウムを含む50mMのTris−Cl,pH 7.5で溶出した。ジスルフィド結合は、50mM Tris−Cl,pH 7.5中で室温で3時間、15培DHAAによる再酸化を行うことにより、親モノクローナル抗体中に存在するシステイン残基との間で再形成された。当技術分野で公知の他の酸化体、すなわち、酸化剤、及び酸化条件を使用することができる。周囲の空気酸化もまた有効である。この穏やかな、部分的な再酸化工程は、高い忠実度で効率的に鎖内ジスルフィドを形成する。コンジュゲーションを生じさせてチオMab抗体−薬剤コンジュゲートを形成するために、およそ1.5培過剰の薬剤−リンカー中間体、例えば5、8、14、18を添加し、混合し、室温で1時間放置した。コンジュゲーション混合物をHiTrap SP FFカラムにロードして溶出し、過剰の薬剤−リンカー中間体及び他の不純物を取り除いた。
本発明の抗体−薬剤コンジュゲート(ADC)薬剤部分(D)は、微小管阻害、有糸分裂阻害、トポイソメラーゼ阻害、又はDNAインターカレーションを含む任意の作用機序を通じて細胞毒性又は細胞増殖抑制作用を有するメイタンシノイド誘導体である。
本発明はNメチルアラニニルメイタンシノール薬剤−リンカー中間体化合物を包含し、ここでリンカーはC−3アラニニルメイタンシノイド部分に結合し、式Iを有する:
Lは、
Eは、
nは2、3、4、5、又は6であり;
mは2、3、又は4であり;及び
qは0又は1である。
で、nは2、3、4、5又は6である。典型的な実施態様は、図1及び実施例1のmal−mc−ala−May薬剤−リンカー中間体5であり、ここでEはマレイミドでnは5である。(S)−2−(メチルアミノ)プロパン酸(N−メチルS−アラニン)2による2,5−ジオキソピロリジン−1−イル 6−(2,5−ジオキソ−2,5−ジヒドロ−1H−ピロール−1−イル)ヘキサノエート 1のアシル化は、(S)−2−(6−(2,5−ジオキソ−2,5−ジヒドロ−1H−ピロール−1−イル)−N−メチルヘキサンアミド)プロパン酸3を与える。メイタンシノール4の3ヒドロキシルでの3とのカップリングはmal−hex−ala−May 5を与え、抗体−薬剤コンジュゲートのAb−hex−mc−ala−Mayを与えるための抗体とのコンジュゲーションの準備ができる。
;nは2、3、4、5、又は6であり;mは2、3、又は4であり;及びqは1である。典型的な実施態様は、図3及び実施例3のmal−PEG3−ala−May薬剤−リンカー中間体14であり、ここでEはマレイミドで、nは4,及びmは3である。アジピン酸から形成される、モノN−ヒドロキシスクシンイミド(NHS)エステル、6−(2,5−ジオキソピロリジン−1−イルオキシ)−6−オキソヘキサン酸9を、2,2’−(2,2’−オキシビス(エタン−2,1−ジイル)ビス(オキシ))ジエタンアミンと反応させて、1−アミノ−13−オキソ−3,6,9−トリオキサ−12−アザオクタデカン−18−オイック酸10を与える。メチル2,5−ジオキソ−2,5−ジヒドロ−1H−ピロール−1−カルボン酸により10のマレイミドが形成され、1−(2,5−ジオキソ−2,5−ジヒドロ−1H−ピロール−1−イル)−13−オキソ−3,6,9−トリオキサ−12−アゾオクタデカン−18−オイック酸11を与える。11のNHSエステルがN−ヒドロキシスクシンイミドとDCCにより形成され、2,5−ジオキソピロリジン−1−イル−1−(2,5−ジオキソ−2,5−ジヒドロ−1H−ピロール−1−イル)−13−オキソ−3,6,9−トリオキサ−12−アザオクタデカン18−オエート12を与える。(S)−2−(メチルアミノ)プロパン酸(N−メチルS−アラニン)2による12のアミド化は、(S)−1−(2,5−ジオキソ−2,5−ジヒドロ−1H−ピロール−1−イル)−19,20−ジメチル−13,18−ジオキソ−3,6,9−トリオキサ−12,19−ジアザヘニコサン−21−オイック酸13を与えた。メイタンシノール4の3ヒドロキシルでの13とのカップリングはmal−PEG3−ala−May薬剤−リンカー中間体14を与え、抗体−薬剤コンジュゲートのAb−mal−PEG3−ala−Mayを与えるための抗体とのコンジュゲーションの準備ができる。
本発明の抗体−薬剤コンジュゲートは、抗体の反応性システインチオール基へのリンカー部分を通して共有結合したN−メチルアラニニルメイタンシノール薬剤部分からなる。
ここでpは1、2、3、又は4である。抗体分子にチオール反応性リンカー部分を介してコンジュゲートさせることができる薬剤部分の数は、本明細書に記載の方法によって導入されたシステイン残基の数によって制限される。従って、式Iの薬剤−リンカー中間体から調製された典型的なADCは、1つ、2つ、3つ、又は4つの操作されたシステインアミノ酸を有する抗体を含む。
Lは、
nは2、3、4、5、又は6であり;
mは2、3、又は4であり;
qは0又は1であり;
pは1から4であり;及び
Abは抗体である。
一般に、抗体−薬剤コンジュゲート(ADC)の細胞毒性又は細胞増殖抑制効果は、細胞培養培地中で、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地中でADCの抗体に曝露し;その細胞を約6時間から約5日間のある期間にわたって培養し;細胞生存率を測定することにより測定される。細胞ベースのインビトロアッセイが、本発明のADCの生存率(増殖)、細胞毒性、及びアポトーシスの誘導(カスパーゼ活性化)を測定するために用いられる。
トラスツズマブ−mcc−DM1(トラスツズマブ エムタンシン(emtansine)、TMAb−MCC−DM1、T−DM1)は、抗体−薬剤コンジュゲート(CAS登録番号139504−50−0)で、次の構造を有する:
ここで、Trは、リンカー試薬スクシンイミジル4−(N−マレイミドメチル)(シクロヘキサン−1−カルボキシレートから形成された、マレイミドメチル)シクロヘキサン−1−カルボキシレートリンカー部分(mcc)を通して、メイタンシノイド薬剤部分DM1(米国特許第5208020号;米国特許第6441163号)に結合したトラスツズマブである。薬剤の抗体に対する比率又は薬剤負荷は、上記のトラスツズマブ−mcc−DM1の構造でpにより表され、1から約8の整数値の範囲である。薬剤負荷の値は1から8である。トラスツズマブ−mcc−DM1は、様々に負荷され結合した抗体−薬剤コンジュゲートの全混合物を含み、ここでは1、2、3、4、5、6、7、及び8の薬剤部分が抗体トラスツズマブに共有結合している(米国特許第7097840号;米国特許第2005/0276812号;米国特許第2005/0166993号)。
TMAb−mcc−DM1(6)と、DM1に共有結合したmpeo(2) hex (5)及びPEG3(3),(4),(7),(8)リンカーを持つ様々なチオMabコンジュゲート(実施例6)がMMTV−HER2 Fo5トラスツズマブ耐性乳腺腫瘍モデルで試験され、これらの結果を図5a、5b及び6に示した。MMTV−HER2 Fo5腫瘍移植片が、CRLのnu/nuマウスの番号2/3乳腺脂肪パッド中に移植された。腫瘍が平均体積で180mm3に達したとき、マウスが無作為化され、次いで試験の第0日にDM1コンジュゲートの1回の静脈内投与(10g/kg)が与えられた。
本発明の抗体−薬剤コンジュゲートは治療されるべき疾患に適した任意の経路で投与され得る。ADCは典型的には非経口的に、すなわち点滴、皮下、筋肉内、静脈内、皮内、髄腔内および硬膜外に投与される。
本発明の治療用抗体−薬剤コンジュゲート(ADC)の薬学的製剤は、典型的には、非経口投与、すなわちボーラス、静脈内、腫瘍内注射用に、薬学的に許容される非経口ビヒクルとともに単位用量の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−薬剤コンジュゲート(ADC)は、任意で凍結乾燥製剤または水溶液の形態で薬学的に許容される希釈剤、担体、賦形剤または安定剤(Remington's Pharmaceutical Sciences (1980) 16th edition, Osol, A. Ed.)と混合される。
本発明の抗体−薬剤コンジュゲートは、例えば腫瘍抗原の過剰発現によって特徴付けられる種々の疾患または障害を治療するために用いられ得る。典型的な病気または過剰増殖性疾患には、良性または悪性腫瘍、白血病及びリンパ系悪性腫瘍が含まれる。他には、神経細胞、グリア、星状、視床下部、マクロファージ、上皮性、間質性、胞胚腔(blastocoelic)、炎症性、血管新生及び自己免疫性を含む免疫に関する障害を含む。
本発明の他の実施態様において、上述した障害の治療に有用な物質を含む製造品又は「キット」が提供される。製造品は、容器とラベルまたは容器上にあるまたは容器に付属するパッケージ挿入物を含む。好適な容器は、例としてボトル、バイアル、シリンジ、ブリスター包装等を含む。容器はガラス又はプラスチックなどの様々な物質から形成されうる。容器は、疾患の治療のために有効である抗体−薬剤コンジュゲート(ADC)及び無菌のアクセスポートを有し得る(例えば、容器は皮下注射針による穴あきストッパーを有する静脈内溶液バッグ又はバイアルであってよい)。組成物中の少なくとも一の活性剤はADCである。ラベルまたはパッケージ挿入物は、組成物が選択される疾患、例えば癌の治療のために使用されることを示している。別法として、または加えて、製造品は、薬学的に許容されるバッファー、例えば注射用静菌水(BWFI)、リン酸緩衝化塩水、リンガー溶液およびデキストロース溶液を含む第二(または第三)の容器をさらに含んでもよい。これは、他のバッファー、希釈剤、フィルター、針、およびシリンジを含む、商業的およびユーザーの立場から望まれる他の物質をさらに含んでもよい。
(S)−2−(メチルアミノ)プロパン酸(N−メチルS−アラニン)2による2,5−ジオキソピロリジン−1−yl 6−(2,5−ジオキソ−2,5−ジヒドロ−1H−ピロール−1−イル)ヘキサノエート 1のアシル化は、(S)−2−(6−(2,5−ジオキソ−2,5−ジヒドロ−1H−ピロール−1−イル)−N−メチルヘキサンアミド)プロパン酸3を与える(図1a)。メイタンシノール4の3−ヒドロキシルで3とカップリングさせてmal−hex−ala−May 5を与える。MS[M+H]+843.5.1H NMR(400MHz,CD3OD):δ7.11(s,1H),6.76(s,2H),6.72−6.65(m,2H),6.60(dd,J=14.7,11.4Hz,1H),5.69(dd,J=14.9,9.1Hz,1H),5.49(q,J=6.7Hz,1H),4.65(dd,J=11.9,2.1Hz,1H),4.19(td,J=10.3,4.1Hz,1H),3.97(s,3H),3.62−3.55(m,2H),3.41−3.34(m,5H),3.23(d,J=12.7Hz,1H),3.20(s,3H),2.94(d,J=9.6Hz,1H),2.84(s,3H),2.72−2.62(m,1H),2.56−2.45(m,1H),2.33−2.23(m,1H),2.14(dd,J=14.1,1.8Hz,1H),1.68(s,3H),1.65−1.42(m,7H),1.29(d,J=6.8Hz,3H),1.28−1.25(m,2H),1.23(d,J=6.3Hz,3H),0.84(s,3H)。
(S)−2−(メチルアミノ)プロパン酸(N−メチルS−アラニン)2による2,5−ジオキソピロリジン−1−イル 6−(2ブロモアセトアミド)ヘキサノエート6のアシル化は、(S)−2−(6−(2ブロモアセトアミド)−N−メチルヘキサンアミド)プロパン酸7を与える(図2)。メイタンシノール4の3−ヒドロキシルで7とカップリングさせてbra−hex−ala−May 8を与える。
2,2’−(2,2’−オキシビス(エタン−2,1−ジイル)ビス(オキシ))ジエタンアミン(Chem−Impex,5.00g,0.0260mol)のTHF溶液(525mL)に4−ジメチルアミノピリジン(320mg、0.0026mol)が添加された。添加漏斗を使用して室温で、これに二炭酸ジ−tert−ブチル(5.68g,0.0260mol)のTHF溶液(100mL)が1時間にわたって添加された。(図3)。反応物は、最初は濁ったが、その後清澄となった。McReynolds K.D.et al.,(2002),Bioorg Med Chem,10:625に従い、反応物をさらに2時間撹拌し、次いで濃縮し、ISCO(0−20% MeOH/DCM)により精製し、tert−ブチル2−(2−(2−(2−アミノエトキシ)エトキシ)エトキシ)エチルカルバメートを淡黄色油として得た(2.70g,36%)。MS[M+H]+293.3.1H NMR(400MHz,CDCl3):δ5.79(s,1H),3.69−3.57(m,8H),3.56−3.47(m,4H),3.32−3.23(m,2H),2.84(t,J=5.1Hz,2H),1.44(s,9H)。
MS[M+H]+421.4.1H NMR(400MHz,CDCl3):δ10.55(s,1H),6.65(s,1H),5.27(s,1H),3.67−3.62(m,8H),3.60−3.52(m,4H),3.48−3.41(m,2H),3.35−3.23(m,2H),2.35(t,J=6.3Hz,3H),2.25(t,J=6.5Hz,2H),1.44(s,9H)。
2,2−ジメチル−4,18−ジオキソ−3,8,11,14−テトラオキサ−5,17−ジアザトリコサン−23−オイック酸9(321.8mg,0.7653mmol)を含有するバイアルに、1mLの塩化メチレンと1mLのトリフルオロ酢酸を添加した。反応物を30分間攪拌し、濃縮し、1−アミノ−13−オキソ−3,6,9−トリオキサ−12−アザオクタデカン−18−オイック酸10を得た(図3)。
軽鎖アミノ酸はKabatに従って番号付けされる(Kabat et al., Sequences of proteins of immunological interest, (1991) 5th Ed., US Dept of Health and Human Service, National Institutes of Health, Bethesda, MD)。重鎖アミノ酸は、Kabatシステムと記された場合を除いてEU番号付けシステムに従って番号付けされる(Edelman et al (1969) Proc. Natl. Acad of Sciences 63(1):78-85)。一文字アミノ酸略語が使用される。
実施例5の還元と再酸化法の後、システイン操作抗体をPBS(リン酸緩衝生理食塩水)緩衝液に溶解し、氷上で冷却した。マレイミド又はブロモ酢酸などのチオール反応性官能基を含む5、8、14及び18などのメイタンシノイド薬剤リンカー中間体の抗体あたりの操作されたシステインに対して約1.5モル当量がDMSOに溶解され、アセトニトリルと水で希釈され、PBS中で冷却され還元され再酸化された抗体に添加された。約1時間後、過剰のマレイミドを添加して反応を停止させ、未反応抗体のチオール基を覆った。反応混合物を遠心限外濾過により濃縮し、システイン操作トラスツズマブ抗体−薬剤コンジュゲートを精製し、PBS中でのG25樹脂を通する溶出によって脱塩し、無菌条件下で0.2μmのフィルターを通して濾過し、貯蔵のために凍結した。
上記の手順で、式Iの以下のシステイン操作型N−メチルアラニニルメイタンシノール抗体−薬剤コンジュゲートが調製された:
マレイミドDM1コンジュゲート,(2)LCV205Cチオ−TMAb−mpeo−DM1,平均薬剤付加DAR=1.7,及び(6)TMAb−mcc−DM1,平均薬剤付加DAR=3.4が、米国特許出願公開第2005/0276812号の実施例4の手順に従って調製され、それは参照により組み込まれる。
ADCの有効性は、以下のプロトコルを用いて細胞増殖アッセイにより測定した(CELLTITER GLOTM Luminescent Cell Viability Assay,Promega Corp.Technical Bulletin TB288; Mendoza et al (2002) Cancer Res. 62:5485-5488):
1.培地に約104細胞(SKBR−3,BT474,MCF7又はMDA−MB−468)を含む細胞培養物の100μlのアリコートを、96ウェルの不透明壁のプレートの各ウェルに沈着させた。
2.コントロールウェルは細胞無しで培地を含有して調製した。
3.ADCを実験ウェルに添加し、3−5日間インキュベートした。
4.プレートを約30分間室温にて平衡化した。
5.各ウェル中に存在する細胞培養培地の容積に等しい容積のCELLTITER GLOTM試薬を加えた。
6.内容物をオービタルシェーカーで2分間混合して細胞溶解を誘導した。
7.プレートは、発光シグナルを安定化させるために10分間室温でインキュベートした。
8.発光を記録し、RLU=相対発光単位としてグラフにて報告された。
データは、標準偏差誤差バーと共に、反復の各組について発光の平均値としてプロットされている。プロトコルはCELLTITER GLOTM発光細胞の変形である。
培地:SK−BR−3は50/50/10%FBS/グルタミン/250μg/mL G−418で生育し、OVCAR−3はRPMI/20%FBS/グルタミンで生育する。
Fo5マウス乳腺腫瘍モデルが、前述のように単一用量の静脈注射後に、(6)本発明のTMAb−mcc−DM1及び様々なチオ−TMAb−Mayのインビボ有効性を評価するために採用され(Phillips GDL, Li GM, Dugger DL, et al. Targeting HER2-Positive Breast Cancer with Trastuzumab-DM1, an Antibody-Cytotoxic Drug Conjugate. (2008) Cancer Res. 68:9280-90)、参照により本明細書に組み込まれる。Fo5モデルは、トランスジェニックマウスモデルであり、ヒトHER2遺伝子が、マウス乳腺腫瘍ウイルスプロモーター(MMTV−HER2)の転写制御下で乳腺上皮において過剰発現される。HER2過剰発現は乳腺腫瘍の自発的な増殖を引き起こす。これらの樹立動物(樹立#5[Fo5])の一匹の乳腺腫瘍は腫瘍断片(〜2×2mmの大きさ)の連続移植によってFVBマウスの後の世代に伝播される。すべての研究は、実験動物の管理と使用に関するガイドラインに従って実施された。各抗体−薬剤コンジュゲート(単一用量は、)研究の開始、及び移植後第14日に9匹の動物に静脈内投与した。初期腫瘍サイズは約200mm3の体積であった。本発明による抗体−薬剤コンジュゲートとコントロールによる時間の経過による腫瘍増殖阻害の測定は図5a、5b、及び6に示される。
明細書全体を通して引用された全ての特許、特許出願、及び参考文献は、出典明示により援用される。
Claims (25)
- nが5である、請求項2の化合物。
- nが4及びmが3である、請求項4の化合物。
- 抗体が、遊離システインアミノ酸を通してリンカー(L)にコンジュゲートしたシステイン操作抗体(Ab)である、請求項10の抗体−薬剤コンジュゲート。
- システイン操作抗体の遊離システインアミノ酸が重鎖のA118C(EU番号付け)である、請求項12の抗体−薬剤コンジュゲート。
- システイン操作抗体の遊離システインアミノ酸が軽鎖のV205C(Kabatの番号付け)である、請求項12の抗体−薬剤コンジュゲート。
- システイン操作抗体が遊離のシステインアミノ酸及び配列番号1−49から選択される重鎖の配列又は配列番号50−98から選択される軽鎖の配列を含み、該配列中のシステインが遊離のシステインアミノ酸である、請求項12の抗体−薬剤コンジュゲート。
- システイン操作抗体が
(i)システイン操作抗体をコードする核酸配列を変異誘発し;
(ii)システイン操作抗体を発現し;及び
(iii)システイン操作抗体を単離し精製すること
を含む工程により調製される請求項12に記載の抗体−薬剤コンジュゲート。 - システイン操作抗体が、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、ヒト化抗体、及びFab断片から選択される、請求項12に記載の抗体−薬剤コンジュゲート。
- システイン操作抗体が親抗体の一以上のアミノ酸残基を一以上の遊離システインアミノ酸と置換することを含む工程により調製され、親抗体が抗原に選択的に結合し、かつシステイン操作抗体が親抗体と同じ抗原に選択的に結合する、請求項12に記載の抗体−薬剤コンジュゲート。
- 抗体がレセプター(1)−(51):
(1)BMPR1B(骨形成タンパク質レセプタータイプIB型);
(2)E16(LAT1,SLC7A5);
(3)STEAP1(前立腺の6回膜貫通型上皮抗原);
(4)0772P(CA125,MUC16);
(5)MPF(MPF,MSLN,SMR,巨核球増強因子、メソテリン);
(6)Napi3b(NAPI−3B,NPTIIb,SLC34A2,溶質輸送体ファミリー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トランスポーター3b);
(7)Sema5b(FLJ10372,KIAA1445,Mm.42015,SEMA5B,SEMAG,セマフォリン 5b Hlog,セマドメイン(sema domain),7回トロンボスポンジン反復(1型及び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)5B);
(8)PSCA hlg(2700050C12Rik,C530008O16Rik,RIKEN cDNA 2700050C12,RIKEN cDNA 2700050C12 遺伝子);
(9)ETBR(エンドセリンタイプBレセプター);
(10)MSG783(RNF124,仮想タンパク質FLJ20315);
(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回膜貫通型上皮抗原2,6回膜貫通型前立腺タンパク質);
(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);
(13)CRIPTO(CR,CR1,CRGF,CRIPTO,TDGF1,奇形癌腫由来増殖因子);
(14)CD21(CR2(補体レセプター2)又はC3DR(C3d/エブスタインバーウイルスレセプター)又はHs.73792);
(15)CD79b(CD79B,CD79β,IGb(免疫グロブリン関連β),B29);
(16)FcRH2(IFGP4,IRTA4,SPAP1A(SH2ドメイン含有ホスファターゼアンカータンパク質1a),SPAP1B,SPAP1C);
(17)HER2;
(18)NCA;
(19)MDP;
(20)IL20Rα
(21)ブレビカン
(22)EphB2R;
(23)ASLG659;
(24)PSCA;
(25)GEDA;
(26)BAFF−R(B細胞活性化因子レセプター,BLySレセプター3,BR3);
(27)CD22(B細胞レセプターCD22−Bアイソフォーム);
(28)CD79a(CD79A,CD79α,免疫グロブリン関連α;
(29)CXCR5(バーキットリンパ腫レセプター1);
(30)HLA−DOB(MHCクラスII分子のベータサブユニット);
(31)P2X5(プリンレセプターP2Xリガンド開口型イオンチャネル5);
(32)CD72(B細胞分化抗原CD72,Lyb−2);
(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型膜タンパク質);
(34)FcRH1(Fcレセプター様タンパク質1);
(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);
(36)TENB2(推定上の膜貫通型プロテオグリカン);
(37)PMEL17(シルバーホモログ;SILV;D12S53E;PMEL17;(SI);(SIL);ME20;gp100);
(38)TMEFF1(EGF様及び2つのフォリスタチン様ドメインを有する膜貫通型タンパク質1;Tomoregulin−1;H7365;C9orf2;C9ORF2;U19878;X83961);
(39)GDNF−Ra1(GDNFファミリーレセプターアルファ1;GFRA1;GDNFR;GDNFRA;RETL1;TRNR1;RET1L;GDNFR−アルファ1;GFR−ALPHA−1;U95847;BC014962);
(40)Ly6E(リンパ球抗原6複合体、遺伝子座E;Ly67,RIG−E,SCA−2,TSA−1);
(41)TMEM46(シサホモログ2(アフリカツメガエル);SHISA2);
(42)Ly6G6D(リンパ球抗原6複合体、遺伝子座G6D;Ly6−D,MEGT1);
(43)LGR5(ロイシンリッチリピート含有Gタンパク質共役型受容体5;GPR49,GPR67);
(44)RET(retプロトオンコジーン;MEN2A;HSCR1;MEN2B;MTC1;(PTC);CDHF12;Hs.168114;RET51;RET−ELE1);
(45)LY6K(リンパ球抗原6複合体、遺伝子座K;LY6K;HSJ001348;FLJ35226);
(46)GPR19(Gタンパク質共役型受容体19;Mm.4787);
(47)GPR54(KISS1レセプター;KISS1R;GPR54;HOT7T175;AXOR12);
(48)ASPHD1(アスパラギン酸β−ヒドロキシラーゼドメイン含有1;LOC253982);
(49)チロシナーゼ(TYR;OCAIA;OCA1A;チロシナーゼ;SHEP3);
(50)TMEM118(リングフィンガータンパク質,膜貫通型2;RNFT2;FLJ14627);及び
(51)GPR172A(Gタンパク質共役型受容体172A;GPCR41;FLJ11856;D15Ertd747e)
の一以上に結合する、請求項10に記載の抗体−薬剤コンジュゲート。 - 請求項10〜19の何れか一項に記載の抗体−薬剤コンジュゲート化合物と薬学的に許容される希釈剤、担体又は賦形剤を含む薬学的組成物。
- 化学療法剤の治療的有効量を更に含む、請求項20の薬学的組成物。
- 請求項10〜19の何れか一項に記載の抗体−薬剤コンジュゲート化合物又は請求項20の薬学的組成物を含む、癌治療のための医薬。
- 抗体−薬剤コンジュゲート化合物と併用して、患者に化学療法剤が投与される、請求項22の医薬。
- 哺乳動物の癌の治療のための医薬の製造における、請求項10〜19の何れか一項に記載の抗体−薬剤コンジュゲート化合物の使用。
- 請求項10〜19の何れか一項に記載の抗体−薬剤コンジュゲート化合物;
容器;及び
パッケージ挿入物又は化合物が癌を治療するために使用することができることを示すラベルを含む製造品。
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PCT/US2011/061031 WO2012074757A1 (en) | 2010-11-17 | 2011-11-16 | Alaninyl maytansinol antibody conjugates |
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Families Citing this family (75)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
AU2011221226A1 (en) | 2010-02-23 | 2012-08-16 | Genentech, Inc. | Compositions and methods for the diagnosis and treatment of tumor |
EP2579897A1 (en) | 2010-06-08 | 2013-04-17 | Genentech, Inc. | Cysteine engineered antibodies and conjugates |
EA201790664A1 (ru) | 2010-12-20 | 2017-07-31 | Дженентек, Инк. | Антитела против мезотелина и иммуноконъюгаты |
KR20140010067A (ko) | 2011-02-15 | 2014-01-23 | 이뮤노젠 아이엔씨 | 컨쥬게이트의 제조방법 |
AR090549A1 (es) | 2012-03-30 | 2014-11-19 | Genentech Inc | Anticuerpos anti-lgr5 e inmunoconjugados |
AR090903A1 (es) | 2012-05-01 | 2014-12-17 | Genentech Inc | Anticuerpos e inmunoconjugados anti-pmel17 |
KR101718200B1 (ko) | 2012-05-21 | 2017-03-21 | 제넨테크, 인크. | 항-Ly6E 항체 및 면역접합체 및 사용 방법 |
MX2015001399A (es) | 2012-08-02 | 2015-09-07 | Genentech Inc | Anticuerpos anti-etbr e inmunoconjugados. |
RU2015106946A (ru) | 2012-08-02 | 2016-09-27 | Дженентек, Инк. | Антитела к рецептору эндотелина типа в (etbr) и их иммуноконъюгаты |
ES2716561T3 (es) * | 2012-09-26 | 2019-06-13 | Immunogen Inc | Métodos mejorados para la acilación de maitansinol |
KR101841818B1 (ko) | 2012-10-11 | 2018-03-26 | 다이이찌 산쿄 가부시키가이샤 | 항체-약물 콘주게이트 |
EP2910573B1 (en) | 2012-10-19 | 2020-02-19 | Daiichi Sankyo Company, Limited | Antibody-drug conjugate produced by binding through linker having hydrophilic structure |
CN103288957B (zh) | 2012-12-21 | 2015-01-28 | 百奥泰生物科技(广州)有限公司 | 一种抑制肿瘤生长的抗体药物衍生物及其制备方法和用途 |
CN104688740A (zh) * | 2012-12-21 | 2015-06-10 | 百奥泰生物科技(广州)有限公司 | 类美登素衍生物及其制备方法和用途 |
CN103333246B (zh) | 2012-12-21 | 2015-09-16 | 百奥泰生物科技(广州)有限公司 | 一种抗egfr受体的肿瘤生长抑制剂及其制备方法和用途 |
CN103333245B (zh) * | 2012-12-21 | 2015-03-18 | 百奥泰生物科技(广州)有限公司 | 一种针对细胞受体并抑制癌细胞生长的药物分子及其制备方法和用途 |
CN103254213B (zh) * | 2012-12-21 | 2015-02-25 | 百奥泰生物科技(广州)有限公司 | 类美登素酯的制备方法及用于所述方法的组合物 |
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 |
MX2015010146A (es) * | 2013-02-08 | 2016-05-31 | Novartis Ag | Sitios especificos para modificar anticuerpos para hacer inmunoconjugados. |
US9415118B2 (en) | 2013-03-13 | 2016-08-16 | Novartis Ag | Antibody drug conjugates |
US9498532B2 (en) | 2013-03-13 | 2016-11-22 | Novartis Ag | Antibody drug conjugates |
CA2902872A1 (en) * | 2013-03-15 | 2014-09-18 | Regeneron Pharmaceuticals, Inc. | Biologically active molecules, conjugates thereof, and therapeutic uses |
CA2922889A1 (en) | 2013-09-17 | 2015-03-26 | Genentech, Inc. | Methods of using anti-lgr5 antibodies |
CN105658237B (zh) | 2013-10-21 | 2021-03-09 | 基因泰克公司 | 抗Ly6E抗体及使用方法 |
CN105793268B (zh) * | 2013-12-02 | 2019-03-15 | 香港浸会大学 | 具有两个稠合大环的抗癌性美登木素类化合物 |
KR101941758B1 (ko) * | 2013-12-25 | 2019-01-24 | 다이이찌 산쿄 가부시키가이샤 | 항 trop2 항체-약물 컨쥬게이트 |
KR102465042B1 (ko) | 2014-01-31 | 2022-11-09 | 다이이찌 산쿄 가부시키가이샤 | 항-her2 항체-약물 접합체 |
CN104974252B (zh) * | 2014-04-01 | 2020-04-24 | 三生国健药业(上海)股份有限公司 | 一种抑制肿瘤生长的抗体-小分子药物偶联物及其制备方法和用途 |
KR102624244B1 (ko) | 2014-04-10 | 2024-01-11 | 다이이찌 산쿄 가부시키가이샤 | 항her3 항체-약물 콘주게이트 |
EP3130608B1 (en) | 2014-04-10 | 2019-09-04 | Daiichi Sankyo Co., Ltd. | (anti-her2 antibody)-drug conjugate |
RU2017107502A (ru) * | 2014-09-12 | 2018-10-12 | Дженентек, Инк. | Антитела и конъюгаты, сконструированные введением цистеина |
EP3193935A4 (en) * | 2014-09-16 | 2018-03-21 | Oncomed Pharmaceuticals, Inc. | Treatment of fibrotic diseases |
JP7029957B2 (ja) | 2014-10-03 | 2022-03-04 | エンジーンアイシー モレキュラー デリバリー ピーティーワイ リミテッド | インタクトな細菌由来のベシクルへの低分子化合物の充填の向上 |
WO2016149464A1 (en) | 2015-03-17 | 2016-09-22 | Regeneron Pharmaceuticals, Inc. | Amino acid acylation reagents and methods of using the same |
CN106267225B (zh) | 2015-05-29 | 2020-03-06 | 上海新理念生物医药科技有限公司 | 三马来酰亚胺型连接子及其应用 |
CN106279352B (zh) | 2015-05-29 | 2020-05-22 | 上海新理念生物医药科技有限公司 | 海兔毒素10的衍生物及其应用 |
HUE061408T2 (hu) | 2015-06-29 | 2023-06-28 | Daiichi Sankyo Co Ltd | Eljárás antitest-gyógyszer konjugátum szelektív elõállítására |
MA43345A (fr) | 2015-10-02 | 2018-08-08 | Hoffmann La Roche | Conjugués anticorps-médicaments de pyrrolobenzodiazépine et méthodes d'utilisation |
MA43354A (fr) | 2015-10-16 | 2018-08-22 | Genentech Inc | Conjugués médicamenteux à pont disulfure encombré |
MA45326A (fr) | 2015-10-20 | 2018-08-29 | Genentech Inc | Conjugués calichéamicine-anticorps-médicament et procédés d'utilisation |
WO2017165734A1 (en) * | 2016-03-25 | 2017-09-28 | Genentech, Inc. | Multiplexed total antibody and antibody-conjugated drug quantification assay |
WO2017214024A1 (en) | 2016-06-06 | 2017-12-14 | Genentech, Inc. | Silvestrol antibody-drug conjugates and methods of use |
EP3496763A1 (en) | 2016-08-11 | 2019-06-19 | Genentech, Inc. | Pyrrolobenzodiazepine prodrugs and antibody conjugates thereof |
GB201615725D0 (en) | 2016-09-15 | 2016-11-02 | Polytherics Ltd | Novel cytotoxic agents and conjugates thereof |
BR112019011794A2 (pt) | 2016-12-12 | 2019-10-29 | Daiichi Sankyo Co Ltd | composição farmacêutica, e, método terapêutico. |
US10864279B2 (en) | 2016-12-16 | 2020-12-15 | Industrial Technology Research Institute | Linker-drug and antibody-drug conjugate (ADC) employing the same |
JP6679762B2 (ja) | 2017-01-17 | 2020-04-15 | 第一三共株式会社 | 抗gpr20抗体及び抗gpr20抗体−薬物コンジュゲート |
TWI794230B (zh) | 2017-05-15 | 2023-03-01 | 日商第一三共股份有限公司 | 抗cdh6抗體及抗cdh6抗體-藥物結合物、以及其製造方法 |
CN107652219B (zh) | 2017-08-14 | 2021-06-08 | 上海新理念生物医药科技有限公司 | 四马来酰亚胺型连接子及其应用 |
AU2018327171B2 (en) | 2017-08-31 | 2023-03-09 | Daiichi Sankyo Company, Limited | Improved method for producing antibody-drug conjugate |
IL272964B2 (en) | 2017-08-31 | 2024-02-01 | Daiichi Sankyo Co Ltd | Production method for antibody-drug conjugates |
IL273387B2 (en) | 2017-09-20 | 2023-10-01 | Ph Pharma Co Ltd | Thylanstatin analogs |
AU2019270459A1 (en) | 2018-05-18 | 2020-12-03 | Daiichi Sankyo Co., Ltd. | Anti-MUC1 antibody-drug conjugate |
CN108949987B (zh) * | 2018-08-02 | 2021-03-16 | 青岛泱深生物医药有限公司 | Gpr19作为诊治宫颈癌的靶标 |
KR20210125034A (ko) | 2019-02-15 | 2021-10-15 | 우시 바이올로직스 아일랜드 리미티드 | 동질성이 개선된 항체-약물 콘쥬게이트의 제조방법 |
AU2020291014A1 (en) | 2019-06-13 | 2022-01-27 | Bolt Biotherapeutics, Inc. | Aminobenzazepine compounds, immunoconjugates, and uses thereof |
US11596693B2 (en) | 2019-08-07 | 2023-03-07 | Mabplex International Co., Ltd | Antibody-drug conjugates and uses thereof |
CN114630684A (zh) | 2019-09-03 | 2022-06-14 | 博尔特生物治疗药物有限公司 | 氨基喹啉化合物、免疫缀合物及其用途 |
AU2020359446A1 (en) | 2019-09-30 | 2022-04-21 | Bolt Biotherapeutics, Inc. | Amide-linked, aminobenzazepine immunoconjugates, and uses thereof |
KR20220088901A (ko) | 2019-10-25 | 2022-06-28 | 볼트 바이오테라퓨틱스 인코퍼레이티드 | 티에노아제핀 면역접합체, 및 이의 용도 |
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 |
CN111494645B (zh) * | 2020-05-20 | 2022-09-30 | 中国药科大学 | 抗人dll4人源化抗体与美登素生物碱dm1的偶联物及其制备方法与应用 |
US20230263903A1 (en) | 2020-08-13 | 2023-08-24 | Bolt Biotherapeutics, Inc. | Pyrazoloazepine immunoconjugates, and uses thereof |
US20220195066A1 (en) | 2020-12-11 | 2022-06-23 | Bolt Biotherapeutics, Inc. | Anti-cea immunoconjugates, and uses thereof |
CA3200056A1 (en) | 2020-12-11 | 2022-06-16 | Shelley Erin ACKERMAN | 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 |
AU2021398552A1 (en) | 2020-12-11 | 2023-06-29 | Bolt Biotherapeutics, Inc. | Anti-pd-l1 immunoconjugates, and uses thereof |
CA3200051A1 (en) | 2020-12-11 | 2022-06-16 | Shelley Erin ACKERMAN | Anti-cea immunoconjugates, and uses thereof |
AU2022245340A1 (en) | 2021-03-26 | 2023-11-09 | Bolt Biotherapeutics, Inc. | 2-amino-4-carboxamide-benzazepine immunoconjugates, and uses thereof |
TW202304520A (zh) | 2021-03-26 | 2023-02-01 | 美商博特生物治療公司 | 2-胺基-4-羧醯胺-苯并氮呯免疫結合物及其用途 |
EP4422697A1 (en) | 2021-10-29 | 2024-09-04 | Bolt Biotherapeutics, Inc. | Tlr agonist immunoconjugates with cysteine-mutant antibodies, and uses thereof |
WO2024137619A1 (en) | 2022-12-20 | 2024-06-27 | Bolt Biotherapeutics, Inc. | Anti-claudin, bis-benzimid azole sting agonist immunoconjugates, and uses thereof |
WO2024138128A2 (en) | 2022-12-23 | 2024-06-27 | Genentech, Inc. | Cereblon degrader conjugates, and uses thereof |
WO2024173384A1 (en) | 2023-02-14 | 2024-08-22 | Bolt Biotherapeutics, Inc. | Aza-benzazepine immunoconjugates, and uses thereof |
WO2024186626A1 (en) | 2023-03-03 | 2024-09-12 | Bolt Biotherapeutics, Inc. | Aza-bicyclic sting agonist immunoconjugates, and uses thereof |
Family Cites Families (263)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3896111A (en) | 1973-02-20 | 1975-07-22 | Research Corp | Ansa macrolides |
US4151042A (en) | 1977-03-31 | 1979-04-24 | Takeda Chemical Industries, Ltd. | Method for producing maytansinol and its derivatives |
US4137230A (en) | 1977-11-14 | 1979-01-30 | Takeda Chemical Industries, Ltd. | Method for the production of maytansinoids |
JPS5566585A (en) | 1978-11-14 | 1980-05-20 | Takeda Chem Ind Ltd | Novel maytansinoid compound and its preparation |
US4816567A (en) | 1983-04-08 | 1989-03-28 | Genentech, Inc. | Recombinant immunoglobin preparations |
JPS6098584A (ja) | 1983-11-02 | 1985-06-01 | Canon Inc | カメラ―体形vtr |
US5807715A (en) | 1984-08-27 | 1998-09-15 | The Board Of Trustees Of The Leland Stanford Junior University | Methods and transformed mammalian lymphocyte cells for producing functional antigen-binding protein including chimeric immunoglobulin |
US5583024A (en) | 1985-12-02 | 1996-12-10 | The Regents Of The University Of California | Recombinant expression of Coleoptera luciferase |
US5091178A (en) | 1986-02-21 | 1992-02-25 | Oncogen | Tumor therapy with biologically active anti-tumor antibodies |
WO1991002536A1 (en) | 1989-08-23 | 1991-03-07 | Scripps Clinic And Research Foundation | Compositions and methods for detection and treatment of epstein-barr virus infection and immune disorders |
US5208020A (en) | 1989-10-25 | 1993-05-04 | Immunogen Inc. | Cytotoxic agents comprising maytansinoids and their therapeutic use |
US5256643A (en) | 1990-05-29 | 1993-10-26 | The Government Of The United States | Human cripto protein |
AU9016591A (en) | 1990-10-25 | 1992-05-26 | Tanox Biosystems, Inc. | Glycoproteins associated with membrane-bound immunoglobulins as antibody targets on B cells |
US5440021A (en) | 1991-03-29 | 1995-08-08 | Chuntharapai; Anan | Antibodies to human IL-8 type B receptor |
US5543503A (en) | 1991-03-29 | 1996-08-06 | Genentech Inc. | Antibodies to human IL-8 type A receptor |
EP0577752B2 (en) | 1991-03-29 | 2007-07-11 | Genentech, Inc. | Human pf4a receptors and their use |
JP4124480B2 (ja) | 1991-06-14 | 2008-07-23 | ジェネンテック・インコーポレーテッド | 免疫グロブリン変異体 |
JP3050424B2 (ja) | 1991-07-12 | 2000-06-12 | 塩野義製薬株式会社 | ヒトエンドセリンリセプター |
US5264557A (en) | 1991-08-23 | 1993-11-23 | The United States Of America As Represented By The Department Of Health And Human Services | Polypeptide of a human cripto-related gene, CR-3 |
US6153408A (en) | 1991-11-15 | 2000-11-28 | Institut Pasteur And Institut National De La Sante Et De La Recherche Medicale | Altered major histocompatibility complex (MHC) determinant and methods of using the determinant |
US5976551A (en) | 1991-11-15 | 1999-11-02 | Institut Pasteur And Institut Nationale De La Sante Et De La Recherche Medicale | Altered major histocompatibility complex (MHC) determinant and method of using the determinant |
AU4025193A (en) | 1992-04-08 | 1993-11-18 | Cetus Oncology Corporation | Humanized C-erbB-2 specific antibodies |
IL107366A (en) | 1992-10-23 | 2003-03-12 | Chugai Pharmaceutical Co Ltd | Genes coding for megakaryocyte potentiator |
US5644033A (en) | 1992-12-22 | 1997-07-01 | Health Research, Inc. | Monoclonal antibodies that define a unique antigen of human B cell antigen receptor complex and methods of using same for diagnosis and treatment |
US5801005A (en) | 1993-03-17 | 1998-09-01 | University Of Washington | Immune reactivity to HER-2/neu protein for diagnosis of malignancies in which the HER-2/neu oncogene is associated |
US5869445A (en) | 1993-03-17 | 1999-02-09 | University Of Washington | Methods for eliciting or enhancing reactivity to HER-2/neu protein |
US5773223A (en) | 1993-09-02 | 1998-06-30 | Chiron Corporation | Endothelin B1, (ETB1) receptor polypeptide and its encoding nucleic acid methods, and uses thereof |
US5750370A (en) | 1995-06-06 | 1998-05-12 | Human Genome Sciences, Inc. | Nucleic acid encoding human endothlein-bombesin receptor and method of producing the receptor |
JPH08336393A (ja) | 1995-04-13 | 1996-12-24 | Mitsubishi Chem Corp | 光学活性なγ−置換−β−ヒドロキシ酪酸エステルの製造法 |
US5707829A (en) | 1995-08-11 | 1998-01-13 | Genetics Institute, Inc. | DNA sequences and secreted proteins encoded thereby |
US20020193567A1 (en) | 1995-08-11 | 2002-12-19 | Genetics Institute, Inc. | Secreted proteins and polynucleotides encoding them |
JP3646191B2 (ja) | 1996-03-19 | 2005-05-11 | 大塚製薬株式会社 | ヒト遺伝子 |
EP0910636A1 (en) | 1996-05-17 | 1999-04-28 | Schering Corporation | Human b-cell antigens, related reagents |
US5945511A (en) | 1997-02-20 | 1999-08-31 | Zymogenetics, Inc. | Class II cytokine receptor |
US20030185830A1 (en) | 1997-02-25 | 2003-10-02 | Corixa Corporation | Compositions and methods for the therapy and diagnosis of prostate cancer |
US7033827B2 (en) | 1997-02-25 | 2006-04-25 | Corixa Corporation | Prostate-specific polynucleotide compositions |
NZ337413A (en) | 1997-03-10 | 2003-02-28 | Univ California | Antibodies that bind to Prostate Stem Cell Antigen (PSCA) to treat prostate cancer. |
US6261791B1 (en) | 1997-03-10 | 2001-07-17 | The Regents Of The University Of California | Method for diagnosing cancer using specific PSCA antibodies |
US6541212B2 (en) | 1997-03-10 | 2003-04-01 | The Regents Of The University Of California | Methods for detecting prostate stem cell antigen protein |
US6555339B1 (en) | 1997-04-14 | 2003-04-29 | Arena Pharmaceuticals, Inc. | Non-endogenous, constitutively activated human protein-coupled receptors |
US6319688B1 (en) | 1997-04-28 | 2001-11-20 | Smithkline Beecham Corporation | Polynucleotide encoding human sodium dependent phosphate transporter (IPT-1) |
WO1998051805A1 (en) | 1997-05-15 | 1998-11-19 | Abbott Laboratories | Reagents and methods useful for detecting diseases of the prostate |
WO1998051824A1 (en) | 1997-05-15 | 1998-11-19 | Abbott Laboratories | Reagents and methods useful for detecting disease of the urinary tract |
US6602677B1 (en) | 1997-09-19 | 2003-08-05 | Promega Corporation | Thermostable luciferases and methods of production |
US20030060612A1 (en) | 1997-10-28 | 2003-03-27 | Genentech, Inc. | Compositions and methods for the diagnosis and treatment of tumor |
US20020034749A1 (en) | 1997-11-18 | 2002-03-21 | Billing-Medel Patricia A. | Reagents and methods useful for detecting diseases of the breast |
US6110695A (en) | 1997-12-02 | 2000-08-29 | The Regents Of The University Of California | Modulating the interaction of the chemokine, B Lymphocyte Hemoattractant, and its Receptor, BLR1 |
WO1999046284A2 (en) | 1998-03-13 | 1999-09-16 | The Burnham Institute | Molecules that home to various selected organs or tissues |
JP2002520000A (ja) | 1998-05-13 | 2002-07-09 | エピミューン, インコーポレイテッド | 免疫応答を刺激するための発現ベクターおよびそのベクターの使用方法 |
US20030064397A1 (en) | 1998-05-22 | 2003-04-03 | Incyte Genomics, Inc. | Transmembrane protein differentially expressed in prostate and lung tumors |
US20020187472A1 (en) | 2001-03-09 | 2002-12-12 | Preeti Lal | Steap-related protein |
WO2000012130A1 (en) | 1998-08-27 | 2000-03-09 | Smithkline Beecham Corporation | Rp105 agonists and antagonists |
JP4689781B2 (ja) | 1998-09-03 | 2011-05-25 | 独立行政法人科学技術振興機構 | アミノ酸輸送蛋白及びその遺伝子 |
AU5963699A (en) | 1998-10-02 | 2000-04-26 | Mcmaster University | Spliced form of (erb)b-2/neu oncogene |
WO2001057188A2 (en) | 2000-02-03 | 2001-08-09 | Hyseq, Inc. | Novel nucleic acids and polypeptides |
US20030091580A1 (en) | 2001-06-18 | 2003-05-15 | Mitcham Jennifer L. | Compositions and methods for the therapy and diagnosis of ovarian cancer |
US6962980B2 (en) | 1999-09-24 | 2005-11-08 | 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 |
US20020119158A1 (en) | 1998-12-17 | 2002-08-29 | Corixa Corporation | Compositions and methods for the therapy and diagnosis of ovarian cancer |
US6468546B1 (en) | 1998-12-17 | 2002-10-22 | Corixa Corporation | Compositions and methods for therapy and diagnosis of ovarian cancer |
US20030187196A1 (en) | 1998-12-30 | 2003-10-02 | Genentech, Inc. | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
CA2360396A1 (en) | 1998-12-30 | 2000-07-13 | Andrew M. Scharenberg | Characterization of a calcium channel family |
DE60044665D1 (de) | 1999-01-29 | 2010-08-26 | Corixa Corp | Her2/neu fusionsproteine |
GB9905124D0 (en) | 1999-03-05 | 1999-04-28 | Smithkline Beecham Biolog | Novel compounds |
AU3395900A (en) | 1999-03-12 | 2000-10-04 | Human Genome Sciences, Inc. | Human lung cancer associated gene sequences and polypeptides |
US7304126B2 (en) | 1999-05-11 | 2007-12-04 | Genentech, Inc. | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
WO2000075655A1 (fr) | 1999-06-03 | 2000-12-14 | Takeda Chemical Industries, Ltd. | Procede de criblage avec cd100 |
EP2977063A1 (en) * | 1999-06-25 | 2016-01-27 | Genentech, Inc. | Methods of treatment using anti-ErbB antibody-maytansinoid conjugates |
US7589172B2 (en) | 1999-07-20 | 2009-09-15 | Genentech, Inc. | PRO256 polypeptides |
US7297770B2 (en) | 1999-08-10 | 2007-11-20 | Genentech, Inc. | PRO6496 polypeptides |
US7294696B2 (en) | 1999-08-17 | 2007-11-13 | Genentech Inc. | PRO7168 polypeptides |
CA2380355A1 (en) | 1999-09-01 | 2001-03-08 | Genentech, Inc. | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
US20030129192A1 (en) | 1999-09-10 | 2003-07-10 | Corixa Corporation | Compositions and methods for the therapy and diagnosis of ovarian cancer |
US20030232056A1 (en) | 1999-09-10 | 2003-12-18 | Corixa Corporation | Compositions and methods for the therapy and diagnosis of ovarian cancer |
US20030206918A1 (en) | 1999-09-10 | 2003-11-06 | Corixa Corporation | Compositions and methods for the therapy and diagnosis of ovarian cancer |
US6750054B2 (en) | 2000-05-18 | 2004-06-15 | Lexicon Genetics Incorporated | Human semaphorin homologs and polynucleotides encoding the same |
ES2309012T3 (es) | 1999-10-29 | 2008-12-16 | Genentech, Inc. | Composiciones del anticuerpo anti-psca y a sus procedimientos contra celulas cancerigenas que expresen psca. |
EP1235847B1 (en) | 1999-11-29 | 2016-01-20 | The Trustees of Columbia University in the City of New York | ISOLATION OF FIVE NOVEL GENES CODING FOR NEW Fc RECEPTORS-TYPE MELANOMA INVOLVED IN THE PATHOGENESIS OF LYMPHOMA/MELANOMA |
WO2001040269A2 (en) | 1999-11-30 | 2001-06-07 | Corixa Corporation | Compositions and methods for therapy and diagnosis of breast cancer |
EP1568373A3 (en) | 1999-12-10 | 2005-12-21 | Epimmune Inc. | Inducing cellular immune responses to HER2/neu using peptide and nucleic acid compositions |
US6610286B2 (en) | 1999-12-23 | 2003-08-26 | Zymogenetics, Inc. | Method for treating inflammation using soluble receptors to interleukin-20 |
AU2458001A (en) | 1999-12-23 | 2001-07-03 | Zymogenetics Inc. | Method for treating inflammation |
DK1246846T3 (da) | 1999-12-23 | 2008-12-08 | Zymogenetics Inc | Oplöselig interleukin-20-receptor |
NZ502058A (en) | 1999-12-23 | 2003-11-28 | Ovita Ltd | Isolated mutated nucleic acid molecule for regulation of ovulation rate |
US20040001827A1 (en) | 2002-06-28 | 2004-01-01 | Dennis Mark S. | Serum albumin binding peptides for tumor targeting |
PT1240337E (pt) | 1999-12-24 | 2007-01-31 | Genentech Inc | Métodos e composições para prolongar as meias-vidas de eliminação de compostos bioactivos |
US7294695B2 (en) | 2000-01-20 | 2007-11-13 | Genentech, Inc. | PRO10268 polypeptides |
US20030224379A1 (en) | 2000-01-21 | 2003-12-04 | Tang Y. Tom | Novel nucleic acids and polypeptides |
WO2001053463A2 (en) | 2000-01-21 | 2001-07-26 | Corixa Corporation | COMPOUNDS AND METHODS FOR PREVENTION AND TREATMENT OF HER-2/neu ASSOCIATED MALIGNANCIES |
US20030186372A1 (en) | 2000-02-11 | 2003-10-02 | Genentech, Inc. | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
WO2001062794A2 (en) | 2000-02-22 | 2001-08-30 | Millennium Pharmaceuticals, Inc. | 18607, a human calcium channel |
US20030219806A1 (en) | 2000-02-22 | 2003-11-27 | Millennium Pharmaceuticals, Inc. | Novel 18607, 15603, 69318, 12303, 48000, 52920, 5433, 38554, 57301, 58324, 55063, 52991, 59914, 59921 and 33751 molecules and uses therefor |
US20040002068A1 (en) | 2000-03-01 | 2004-01-01 | Corixa Corporation | Compositions and methods for the detection, diagnosis and therapy of hematological malignancies |
US20040005561A1 (en) | 2000-03-01 | 2004-01-08 | Corixa Corporation | Compositions and methods for the detection, diagnosis and therapy of hematological malignancies |
AU2001245280A1 (en) | 2000-03-07 | 2001-09-17 | Hyseq, Inc. | Novel nucleic acids and polypeptides |
US7097840B2 (en) | 2000-03-16 | 2006-08-29 | Genentech, Inc. | Methods of treatment using anti-ErbB antibody-maytansinoid conjugates |
AU4941101A (en) | 2000-03-24 | 2001-10-08 | Fahri Saatcioglu | Novel prostate-specific or testis-specific nucleic acid molecules, polypeptides,and diagnostic and therapeutic methods |
WO2004043361A2 (en) | 2002-11-08 | 2004-05-27 | Genentech, Inc. | Compositions and methods for the treatment of natural killer cell related diseases |
WO2001072830A2 (de) | 2000-03-31 | 2001-10-04 | Ipf Pharmaceuticals Gmbh | Diagnostik- und arzneimittel zur untersuchung des zelloberflächenproteoms von tumor- und entzündungszellen sowie zur behandlung von tumorerkrankungen und entzündlichen erkrankungen vorzugsweise mit hilfe einer spezifischen chemokinrezeptor-analyse und der chemokinrezeptor-ligand-interaktion |
WO2001075177A2 (en) | 2000-04-03 | 2001-10-11 | The Government Of The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Tumor markers in ovarian cancer |
WO2001077172A2 (en) | 2000-04-07 | 2001-10-18 | Arena Pharmaceuticals, Inc. | Non-endogenous, constitutively activated known g protein-coupled receptors |
WO2001090304A2 (en) | 2000-05-19 | 2001-11-29 | Human Genome Sciences, Inc. | Nucleic acids, proteins, and antibodies |
US20020051990A1 (en) | 2000-06-09 | 2002-05-02 | Eric Ople | Novel gene targets and ligands that bind thereto for treatment and diagnosis of ovarian carcinomas |
CA2409776A1 (en) | 2000-06-16 | 2001-12-27 | Incyte Genomics, Inc. | G-protein coupled receptors |
US6540675B2 (en) | 2000-06-27 | 2003-04-01 | Rosedale Medical, Inc. | Analyte monitor |
EP1294885A2 (en) | 2000-06-30 | 2003-03-26 | Amgen, Inc. | B7-like molecules and uses thereof |
WO2002002587A1 (en) | 2000-06-30 | 2002-01-10 | Human Genome Sciences, Inc. | B7-like polynucleotides, polypeptides, and antibodies |
JP2004528003A (ja) | 2000-06-30 | 2004-09-16 | インサイト・ゲノミックス・インコーポレイテッド | 細胞外マトリクスおよび細胞接着分子 |
AU2002214531A1 (en) | 2000-07-03 | 2002-01-30 | Curagen Corporation | Proteins and nucleic acids encoding same |
US20040044179A1 (en) | 2000-07-25 | 2004-03-04 | Genentech, Inc. | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
EP1366158B1 (en) | 2000-07-28 | 2008-05-21 | Ulrich Wissenbach | Trp8 markers for cancer |
US7229623B1 (en) | 2000-08-03 | 2007-06-12 | Corixa Corporation | Her-2/neu fusion proteins |
US20020193329A1 (en) | 2000-08-14 | 2002-12-19 | Corixa Corporation | Compositions and methods for the therapy and diagnosis of Her-2/neu-associated malignancies |
WO2002013847A2 (en) | 2000-08-14 | 2002-02-21 | Corixa Corporation | Methods for diagnosis and therapy of hematological and virus-associated malignancies |
US6333410B1 (en) | 2000-08-18 | 2001-12-25 | Immunogen, Inc. | Process for the preparation and purification of thiol-containing maytansinoids |
JP2004520806A (ja) | 2000-08-24 | 2004-07-15 | ジェネンテック・インコーポレーテッド | 腫瘍の診断と治療のための組成物と方法 |
GB0020953D0 (en) | 2000-08-24 | 2000-10-11 | Smithkline Beecham Biolog | Vaccine |
EP1346040A2 (en) | 2000-09-11 | 2003-09-24 | Nuvelo, Inc. | Novel nucleic acids and polypeptides |
US20060073551A1 (en) | 2000-09-15 | 2006-04-06 | Genentech, Inc. | Pro4487 polypeptides |
US6613567B1 (en) | 2000-09-15 | 2003-09-02 | Isis Pharmaceuticals, Inc. | Antisense inhibition of Her-2 expression |
WO2002022153A2 (en) | 2000-09-15 | 2002-03-21 | Zymogenetics, Inc. | Use of a polypeptide comprising the extracellular domains of il-20rb for the treatment of inflammation |
UA83458C2 (uk) | 2000-09-18 | 2008-07-25 | Байоджен Айдек Ма Інк. | Виділений поліпептид baff-r (рецептор фактора активації в-клітин сімейства tnf) |
AU2001292724B2 (en) | 2000-09-18 | 2005-05-26 | Biogen Idec Ma Inc. | CRIPTO mutant and uses thereof |
WO2002030268A2 (en) | 2000-10-13 | 2002-04-18 | Eos Biotechnology, Inc. | Methods of diagnosis of prostate cancer, compositions and methods of screening for modulators of prostate cancer |
ATE432986T1 (de) | 2000-11-07 | 2009-06-15 | Zymogenetics Inc | Menschlicher rezeptor für tumor necrosis factor |
US20020150573A1 (en) | 2000-11-10 | 2002-10-17 | The Rockefeller University | Anti-Igalpha-Igbeta antibody for lymphoma therapy |
WO2002061087A2 (en) | 2000-12-19 | 2002-08-08 | Lifespan Biosciences, Inc. | Antigenic peptides, such as for g protein-coupled receptors (gpcrs), antibodies thereto, and systems for identifying such antigenic peptides |
EP1357828A2 (en) | 2001-01-12 | 2003-11-05 | University of Medicine and Dentistry of New Jersey | Bone morphogenetic protein-2 in the treatment and diagnosis of cancer |
US20030119133A1 (en) | 2001-01-16 | 2003-06-26 | Genentech, Inc. | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
US20030119119A1 (en) | 2001-01-16 | 2003-06-26 | Genentech, Inc. | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
US7754208B2 (en) | 2001-01-17 | 2010-07-13 | Trubion Pharmaceuticals, Inc. | Binding domain-immunoglobulin fusion proteins |
JP2005503760A (ja) | 2001-01-24 | 2005-02-10 | プロテイン デザイン ラブス, インコーポレイテッド | 乳癌の診断方法、組成物および乳癌のモジュレーターのスクリーニング方法 |
US20030073144A1 (en) | 2001-01-30 | 2003-04-17 | Corixa Corporation | Compositions and methods for the therapy and diagnosis of pancreatic cancer |
WO2002064798A1 (en) | 2001-02-12 | 2002-08-22 | Bionomics Limited | Dna sequences differentially expressed in tumour cell lines |
WO2002071928A2 (en) | 2001-03-14 | 2002-09-19 | Millennium Pharmaceuticals, Inc. | Nucleic acid molecules and proteins for the identification, assessment, prevention, and therapy of ovarian cancer |
US20040236091A1 (en) | 2001-03-28 | 2004-11-25 | Chicz Roman M. | Translational profiling |
WO2003008537A2 (en) | 2001-04-06 | 2003-01-30 | Mannkind Corporation | Epitope sequences |
US6820011B2 (en) | 2001-04-11 | 2004-11-16 | The Regents Of The University Of Colorado | Three-dimensional structure of complement receptor type 2 and uses thereof |
EP1414477B1 (en) | 2001-04-17 | 2015-06-10 | The Board Of Trustees Of The University Of Arkansas | Repeat sequences of the ca125 gene and their use for diagnostic interventions |
EP1463928A2 (en) | 2001-04-18 | 2004-10-06 | Protein Design Labs | Methods of diagnosis of lung cancer, compositions and methods of screening for modulators of lung cancer |
RS51635B (sr) | 2001-04-26 | 2011-08-31 | Biogen Idec Ma Inc. | Antitela koja blokiraju cripto i njihova upotreba |
WO2002089747A2 (en) | 2001-05-09 | 2002-11-14 | Corixa Corporation | Compositions and methods for the therapy and diagnosis of prostate cancer |
AU2002344326A1 (en) | 2001-05-11 | 2002-11-25 | Sloan-Kettering Institute For Cancer Research | Nucleic acid sequence encoding ovarian antigen, ca125, and uses thereof |
DE60234202D1 (de) | 2001-05-24 | 2009-12-10 | Zymogenetics Inc | Taci-immunoglobulin-fusionsproteine |
US6441163B1 (en) | 2001-05-31 | 2002-08-27 | Immunogen, Inc. | Methods for preparation of cytotoxic conjugates of maytansinoids and cell binding agents |
AU2002314901A1 (en) | 2001-06-04 | 2002-12-16 | Eos Biotechnology, Inc. | Methods of diagnosis and treatment of androgen-dependent prostate cancer, prostate cancer undergoing androgen-withdrawal, and androgen-independent prostate cancer |
WO2003000842A2 (en) | 2001-06-04 | 2003-01-03 | Curagen Corporation | Novel proteins and nucleic acids encoding same |
AU2002310256A1 (en) | 2001-06-05 | 2002-12-16 | Exelixis Inc. | Ppp2cs as modifiers of the p53 pathway and methods of use |
ATE483976T1 (de) | 2001-06-05 | 2010-10-15 | Exelixis Inc | Gfats als modifikatoren des p53-wegs und verwendungsverfahren |
US7235358B2 (en) | 2001-06-08 | 2007-06-26 | Expression Diagnostics, Inc. | Methods and compositions for diagnosing and monitoring transplant rejection |
WO2002101075A2 (en) | 2001-06-13 | 2002-12-19 | Millennium Pharmaceuticals, Inc. | Novel genes, compositions, kits, and methods for identification, assessment, prevention, and therapy of cervical cancer |
JP2005508144A (ja) | 2001-06-18 | 2005-03-31 | イオス バイオテクノロジー,インコーポレイティド | 卵巣癌の診断方法、卵巣癌のモジュレーターをスクリーニングする組成物及び方法 |
US7189507B2 (en) | 2001-06-18 | 2007-03-13 | Pdl Biopharma, Inc. | Methods of diagnosis of ovarian cancer, compositions and methods of screening for modulators of ovarian cancer |
AU2002322280A1 (en) | 2001-06-21 | 2003-01-21 | Millennium Pharmaceuticals, Inc. | Compositions, kits, and methods for identification, assessment, prevention, and therapy of breast cancer |
US20030108958A1 (en) | 2001-06-28 | 2003-06-12 | Rene De Waal Malefyt | Biological activity of AK155 |
US20030120040A1 (en) | 2001-06-29 | 2003-06-26 | Genentech, Inc. | Secreted and Transmembrane polypeptides and nucleic acids encoding the same |
WO2003004529A2 (en) | 2001-07-02 | 2003-01-16 | Licentia Ltd. | Ephrin-tie receptor materials and methods |
US20040076955A1 (en) | 2001-07-03 | 2004-04-22 | Eos Biotechnology, Inc. | Methods of diagnosis of bladder cancer, compositions and methods of screening for modulators of bladder cancer |
WO2003003984A2 (en) | 2001-07-05 | 2003-01-16 | Curagen Corporation | Novel proteins and nucleic acids encoding same |
US7446185B2 (en) | 2001-07-18 | 2008-11-04 | The Regents Of The University Of California | Her2/neu target antigen and use of same to stimulate an immune response |
US20030108963A1 (en) | 2001-07-25 | 2003-06-12 | Millennium Pharmaceuticals, Inc. | Novel genes, compositions, kit, and methods for identification, assessment, prevention and therapy of prostate cancer |
JP2005510208A (ja) | 2001-08-03 | 2005-04-21 | ジェネンテック・インコーポレーテッド | TACIs及びBR3ポリペプチドとその用途 |
AU2002324700A1 (en) | 2001-08-14 | 2003-03-03 | Bayer Ag | Nucleic acid and amino acid sequences involved in pain |
US20030092013A1 (en) | 2001-08-16 | 2003-05-15 | Vitivity, Inc. | Diagnosis and treatment of vascular disease |
AU2002313559A1 (en) | 2001-08-23 | 2003-03-10 | Oxford Biomedica (Uk) Limited | Genes |
AU2002357643A1 (en) | 2001-08-29 | 2003-04-14 | Vanderbilt University | The human mob-5 (il-24) receptors and uses thereof |
US20030124579A1 (en) | 2001-09-05 | 2003-07-03 | Eos Biotechnology, Inc. | Methods of diagnosis of ovarian cancer, compositions and methods of screening for modulators of ovarian cancer |
WO2003022995A2 (en) | 2001-09-06 | 2003-03-20 | Agensys, Inc. | Nucleic acid and corresponding protein entitled steap-1 useful in treatment and detection of cancer |
AU2002330039A1 (en) | 2001-09-17 | 2003-04-01 | Eos Biotechnology, Inc. | Methods of diagnosis of cancer compositions and methods of screening for modulators of cancer |
EP2143438B1 (en) | 2001-09-18 | 2011-07-13 | Genentech, Inc. | Compositions and methods for the diagnosis and treatment of tumors |
US20050004017A1 (en) | 2001-09-18 | 2005-01-06 | Yuval Reiss | Methods and compositions for treating hcap associated diseases |
CA2460621A1 (en) | 2001-09-19 | 2003-03-27 | Nuvelo, Inc. | Novel nucleic acids and polypeptides |
AU2002327792A1 (en) | 2001-09-28 | 2003-04-07 | Bing Yang | Diagnosis and treatment of diseases caused by mutations in cd72 |
AU2002362454A1 (en) | 2001-10-03 | 2003-04-14 | Origene Technologies, Inc. | Regulated breast cancer genes |
AU2002362436A1 (en) | 2001-10-03 | 2003-04-14 | Rigel Pharmaceuticals, Inc. | Modulators of lymphocyte activation and migration |
US20050123925A1 (en) | 2002-11-15 | 2005-06-09 | Genentech, Inc. | Compositions and methods for the diagnosis and treatment of tumor |
US20040241703A1 (en) | 2002-08-19 | 2004-12-02 | Genentech, Inc. | Compositions and methods for the diagnosis and treatment of tumor |
JP2005522986A (ja) | 2001-10-19 | 2005-08-04 | ジェネンテック・インコーポレーテッド | 炎症性腸疾患の診断と治療のための組成物と方法 |
AU2002356858A1 (en) | 2001-10-24 | 2003-05-06 | National Jewish Medical And Research Center | Structure of tall-1 and its cognate receptor |
JP4255382B2 (ja) | 2001-10-31 | 2009-04-15 | アルコン,インコーポレイテッド | 骨形成タンパク質(bmp)、bmpレセプターおよびbmp結合タンパク質ならびに緑内障の診断および処置におけるそれらの使用 |
WO2003042661A2 (en) | 2001-11-13 | 2003-05-22 | Protein Design Labs, Inc. | Methods of diagnosis of cancer, compositions and methods of screening for modulators of cancer |
US20030232350A1 (en) | 2001-11-13 | 2003-12-18 | Eos Biotechnology, Inc. | Methods of diagnosis of cancer, compositions and methods of screening for modulators of cancer |
US7344843B2 (en) | 2001-11-29 | 2008-03-18 | Serono Genetics Institute S.A. | Agonists and antagonists of prolixin for the treatment of metabolic disorders |
AU2002349784A1 (en) | 2001-12-03 | 2003-06-17 | Asahi Kasei Pharma Corporation | Nf-kappab activating genes |
EP1504099A4 (en) | 2001-12-10 | 2006-05-10 | Nuvelo Inc | NEW NUCLEIC ACIDS AND POLYPEPTIDES |
US20030134790A1 (en) | 2002-01-11 | 2003-07-17 | University Of Medicine And Dentistry Of New Jersey | Bone Morphogenetic Protein-2 And Bone Morphogenetic Protein-4 In The Treatment And Diagnosis Of Cancer |
US7452675B2 (en) | 2002-01-25 | 2008-11-18 | The Queen's Medical Center | Methods of screening for TRPM4b modulators |
US6790954B2 (en) | 2002-01-29 | 2004-09-14 | Immunogen, Inc. | Mutant Actinosynnema pretiosum strain with increased maytansinoid production |
AU2003224624B2 (en) | 2002-02-21 | 2008-08-28 | Duke University | Reagents and treatment methods for autoimmune diseases |
EP2388265A1 (en) | 2002-02-22 | 2011-11-23 | Genentech, Inc. | Compositions and methods for the treatment of immune related diseases |
AU2003213606A1 (en) | 2002-03-01 | 2003-10-13 | Exelixis, Inc. | MP53s AS MODIFIERS OF THE p53 PATHWAY AND METHODS OF USE |
US20050287147A1 (en) | 2002-05-15 | 2005-12-29 | Reinhard Ebner | Cancer-linked gene as target for chemotherapy |
EP2258712A3 (en) | 2002-03-15 | 2011-05-04 | Multicell Immunotherapeutics, Inc. | Compositions and Methods to Initiate or Enhance Antibody and Major-histocompatibility Class I or Class II-restricted T Cell Responses by Using Immunomodulatory, Non-coding RNA Motifs |
CA2486490A1 (en) | 2002-03-19 | 2003-12-31 | Curagen Corporation | Therapeutic polypeptides, nucleic acids encoding same, and methods of use |
WO2003081210A2 (en) | 2002-03-21 | 2003-10-02 | Sunesis Pharmaceuticals, Inc. | Identification of kinase inhibitors |
US7193069B2 (en) | 2002-03-22 | 2007-03-20 | Research Association For Biotechnology | Full-length cDNA |
EP1494693B1 (en) | 2002-03-22 | 2010-12-08 | Biogen Idec MA Inc. | Cripto-specific antibodies |
AU2003245239A1 (en) | 2002-03-25 | 2003-11-03 | Uab Research Foundation | FC receptor homolog, reagents, and uses thereof |
AU2003222103A1 (en) | 2002-03-28 | 2003-10-13 | Idec Pharmaceuticals Corporation | Novel gene targets and ligands that bind thereto for treatment and diagnosis of colon carcinomas |
US20030194704A1 (en) | 2002-04-03 | 2003-10-16 | Penn Sharron Gaynor | Human genome-derived single exon nucleic acid probes useful for gene expression analysis two |
JP2005534287A (ja) | 2002-04-05 | 2005-11-17 | アジェンシス, インコーポレイテッド | 癌の処置および検出において有用な98p4b6との名称の核酸および対応するタンパク質 |
US20040101874A1 (en) | 2002-04-12 | 2004-05-27 | Mitokor Inc. | Targets for therapeutic intervention identified in the mitochondrial proteome |
KR20040101502A (ko) | 2002-04-16 | 2004-12-02 | 제넨테크, 인크. | 종양의 진단 및 치료 방법 및 이를 위한 조성물 |
WO2003089904A2 (en) | 2002-04-17 | 2003-10-30 | Baylor College Of Medicine | Aib1 as a prognostic marker and predictor of resistance to encocrine therapy |
WO2003093444A2 (en) | 2002-05-03 | 2003-11-13 | Incyte Corporation | Transporters and ion channels |
WO2003101388A2 (en) | 2002-05-30 | 2003-12-11 | Bristol-Myers Squibb Company | Human solute carrier family 7 member 11 (hslc7a11) |
CA2488284A1 (en) | 2002-06-04 | 2003-12-11 | Avalon Pharmaceuticals, Inc. | Cancer-linked gene as target for chemotherapy |
WO2003101283A2 (en) | 2002-06-04 | 2003-12-11 | Incyte Corporation | Diagnostics markers for lung cancer |
DK1513934T3 (da) | 2002-06-06 | 2011-05-02 | Oncotherapy Science Inc | Gener og polypeptider relateret til humane coloncancersygdomme |
WO2003104270A2 (en) | 2002-06-06 | 2003-12-18 | Ingenium Pharmaceuticals Ag | Dudulin 2 genes, expression products, non-human animal model: uses in human hematological disease |
US20060228705A1 (en) | 2002-06-07 | 2006-10-12 | Reinhard Ebner | Cancer-linked gene as target for chemotherapy |
WO2003105758A2 (en) | 2002-06-12 | 2003-12-24 | Avalon Pharmaceuticals, Inc. | Cancer-linked gene as target for chemotherapy |
US20040022727A1 (en) | 2002-06-18 | 2004-02-05 | Martin Stanton | Aptamer-toxin molecules and methods for using same |
US20040249130A1 (en) | 2002-06-18 | 2004-12-09 | Martin Stanton | Aptamer-toxin molecules and methods for using same |
AU2003245615A1 (en) | 2002-06-20 | 2004-01-06 | The Regents Of The University Of California | Compositions and methods for modulating lymphocyte activity |
EP2365004B1 (en) | 2002-06-21 | 2016-01-06 | Johns Hopkins University School of Medicine | Membrane associated tumor endothelium markers |
AU2003281515A1 (en) | 2002-07-19 | 2004-02-09 | Cellzome Ag | Protein complexes of cellular networks underlying the development of cancer and other diseases |
JP2005533863A (ja) | 2002-07-25 | 2005-11-10 | ジェネンテック・インコーポレーテッド | Taci抗体とその用途 |
AU2003251471A1 (en) | 2002-08-06 | 2004-02-25 | Bayer Healthcare Ag | Diagnostics and therapeutics for diseases associated with human cxc chemokine receptor 5(cxcr5) |
JP2004121218A (ja) | 2002-08-06 | 2004-04-22 | Jenokkusu Soyaku Kenkyusho:Kk | 気管支喘息または慢性閉塞性肺疾患の検査方法 |
WO2004020583A2 (en) | 2002-08-27 | 2004-03-11 | Bristol-Myers Squibb Company | Polynucleotide predictor set for identifying protein tyrosine kinase modulators |
WO2004020595A2 (en) | 2002-08-29 | 2004-03-11 | Five Prime Therapeutics, Inc. | Novel human polypeptides encoded by polynucleotides |
AU2002951346A0 (en) | 2002-09-05 | 2002-09-26 | Garvan Institute Of Medical Research | Diagnosis of ovarian cancer |
US20040180354A1 (en) | 2002-09-06 | 2004-09-16 | Simard John J.L. | Epitope sequences |
AU2003300776A1 (en) | 2002-09-09 | 2004-05-25 | Omeros Corporation | G protein coupled receptors and uses thereof |
JP2004113151A (ja) | 2002-09-27 | 2004-04-15 | Sankyo Co Ltd | 癌遺伝子及びその用途 |
EP1554309A2 (en) | 2002-10-03 | 2005-07-20 | McGILL UNIVERSITY | Antibodies and cyclic peptides which bind cea (carcinoembryonic antigen) and their use as cancer therapeutics |
EP1570078A4 (en) | 2002-10-04 | 2006-09-13 | Van Andel Res Inst | MOLECULAR CLASSIFICATION OF RENAL TUMORS AND DISCOVERING NEW DIAGNOSTIC MARKERS |
CA2499300A1 (en) | 2002-10-31 | 2004-05-21 | Genentech, Inc. | Methods and compositions for increasing antibody production |
AU2003295511A1 (en) | 2002-11-13 | 2004-06-03 | Genentech, Inc. | Methods and compositions for diagnosing dysplasia |
AU2003294355A1 (en) | 2002-11-15 | 2004-06-15 | The Board Of Trustees Of The University Of Arkansas | Ca125 gene and its use for diagnostic and therapeutic interventions |
US8007804B2 (en) | 2002-11-15 | 2011-08-30 | Musc Foundation For Research Development | Complement receptor 2 targeted complement modulators |
WO2004046342A2 (en) | 2002-11-20 | 2004-06-03 | Biogen Idec Inc. | Novel gene targets and ligands that bind thereto for treatment and diagnosis of carcinomas |
AU2003294462C1 (en) | 2002-11-21 | 2011-06-30 | University Of Utah Research Foundation | Purinergic modulation of smell |
US20040253606A1 (en) | 2002-11-26 | 2004-12-16 | Protein Design Labs, Inc. | Methods of detecting soft tissue sarcoma, compositions and methods of screening for soft tissue sarcoma modulators |
WO2004053079A2 (en) | 2002-12-06 | 2004-06-24 | Diadexus, Inc. | Compositions, splice variants and methods relating to ovarian specific genes and proteins |
US20040157278A1 (en) | 2002-12-13 | 2004-08-12 | Bayer Corporation | Detection methods using TIMP 1 |
EP1581171B1 (en) | 2002-12-20 | 2012-06-27 | Abbott Biotherapeutics Corp. | Antibodies against gpr64 and uses thereof |
WO2004058309A1 (en) | 2002-12-23 | 2004-07-15 | Human Genome Sciences, Inc. | Neutrokine-alpha conjugate, neutrokine-alpha complex, and uses thereof |
WO2004063709A2 (en) | 2003-01-08 | 2004-07-29 | Bristol-Myers Squibb Company | Biomarkers and methods for determining sensitivity to epidermal growth factor receptor modulators |
US20050227301A1 (en) | 2003-01-10 | 2005-10-13 | Polgen | Cell cycle progression proteins |
US20050181375A1 (en) | 2003-01-10 | 2005-08-18 | Natasha Aziz | Novel methods of diagnosis of metastatic cancer, compositions and methods of screening for modulators of metastatic cancer |
WO2004065577A2 (en) | 2003-01-14 | 2004-08-05 | Bristol-Myers Squibb Company | Polynucleotides and polypeptides associated with the nf-kb pathway |
WO2004065576A2 (en) | 2003-01-15 | 2004-08-05 | Millennium Pharmaceuticals, Inc. | Methods and compositions for the treatment of urological disorder using differential expressed polypeptides |
AU2004205684A1 (en) | 2003-01-23 | 2004-08-05 | Genentech, Inc. | Methods for producing humanized antibodies and improving yield of antibodies or antigen binding fragments in cell culture |
WO2004074320A2 (en) | 2003-02-14 | 2004-09-02 | Sagres Discovery, Inc. | Therapeutic targets in cancer |
US20030224411A1 (en) | 2003-03-13 | 2003-12-04 | Stanton Lawrence W. | Genes that are up- or down-regulated during differentiation of human embryonic stem cells |
US7432088B2 (en) | 2003-05-08 | 2008-10-07 | Immunogen Inc. | Methods for the production of ansamitocins |
US8088387B2 (en) | 2003-10-10 | 2012-01-03 | Immunogen Inc. | Method of targeting specific cell populations using cell-binding agent maytansinoid conjugates linked via a non-cleavable linker, said conjugates, and methods of making said conjugates |
US7276497B2 (en) | 2003-05-20 | 2007-10-02 | Immunogen Inc. | Cytotoxic agents comprising new maytansinoids |
ZA200601182B (en) * | 2003-10-10 | 2007-04-25 | Immunogen Inc | Method of targeting specific cell populations using cell-binding agent maytansinoid conjugates linked via a non-cleavable linker, said conjugates, and methods of making said conjugates |
US7004206B2 (en) | 2004-01-29 | 2006-02-28 | Viken James P | Automatic fluid exchanger |
CN114053429A (zh) * | 2004-06-01 | 2022-02-18 | 健泰科生物技术公司 | 抗体-药物偶联物和方法 |
DK1791565T3 (en) | 2004-09-23 | 2016-08-01 | Genentech Inc | Cysteingensplejsede antibodies and conjugates |
US7301019B2 (en) | 2005-01-21 | 2007-11-27 | Immunogen, Inc. | Method for the preparation of maytansinoid esters |
US7598375B2 (en) | 2005-08-09 | 2009-10-06 | Millenium Pharmaceuticals, Inc. | Method of acylating maytansinol with chiral amino acids |
PL1945647T3 (pl) | 2005-11-08 | 2012-04-30 | Immunogen Inc | Procesy wytwarzania maytansinolu |
US20080149123A1 (en) * | 2006-12-22 | 2008-06-26 | Mckay William D | Particulate material dispensing hairbrush with combination bristles |
CN101687037B (zh) | 2007-05-08 | 2013-07-10 | 健泰科生物技术公司 | 半胱氨酸改造的抗muc16抗体和抗体药物偶联物 |
PE20090309A1 (es) | 2007-06-04 | 2009-04-18 | Wyeth Corp | Conjugado portador-caliqueamicina y un metodo de deteccion de caliqueamicina |
AU2008312457B2 (en) | 2007-10-19 | 2014-04-17 | Genentech, Inc. | Cysteine engineered anti-TENB2 antibodies and antibody drug conjugates |
KR20100137585A (ko) * | 2008-04-30 | 2010-12-30 | 이뮤노젠 아이엔씨 | 강력한 복합체 및 친수성 링커 |
KR20120080611A (ko) * | 2009-10-06 | 2012-07-17 | 이뮤노젠 아이엔씨 | 효능 있는 접합체 및 친수성 링커 |
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EP2640727B1 (en) | 2015-05-13 |
JP2013544253A (ja) | 2013-12-12 |
WO2012074757A1 (en) | 2012-06-07 |
EP2640727A1 (en) | 2013-09-25 |
CN103313990B (zh) | 2016-07-20 |
ES2544608T3 (es) | 2015-09-02 |
CA2816426A1 (en) | 2012-06-07 |
CN103313990A (zh) | 2013-09-18 |
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