TW201602111A - 吡咯并苯并二氮呯及其結合物 - Google Patents
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Abstract
本發明係關於一種化合物,該化合物係選自A:
□
B
□
C
□
及其鹽與溶劑合物。
Description
本發明係關於吡咯并苯并二氮呯(PBD),尤其具有不穩定N10保護基的吡咯并苯并二氮呯,該N10保護基呈連接至細胞結合劑的連接子形式。
一些吡咯并苯并二氮呯(PBD)具有識別及鍵結至DNA的特定序列的能力;較佳序列為PuGPu。在1965年(Leimgruber等人,J.Am.Chem.Soc.,87,5793-5795(1965);Leimgruber等人,J.Am.Chem.Soc.,87,5791-5793(1965))發現第一種PBD抗腫瘤抗生素、安麯黴素。此後,已報告多種天然存在的PBD,且對於各種類似物已研發超過10種合成途徑(Thurston等人,Chem.Rev. 1994,433-465(1994);Antonow,D.及Thurston,D.E.,Chem.Rev. 2011 111(4),2815-2864)。家族成員包括赤黴素(abbeymycin)(Hochlowski等人,J.Antibiotics,40,145-148(1987))、芝加黴素(chicamycin)(Konishi等人,J.Antibiotics,37,200-206(1984))、DC-81(日本專利58-180487;Thurston等人,Chem.Brit.,26,767-772(1990);Bose等人,Tetrahedron,48,751-758(1992))、混胺茴黴素(mazethramycin)(Kuminoto等人,J.Antibiotics,33,665-667(1980))、新茴黴素(neothramycin)A及B(Takeuchi等人,J.Antibiotics,29,93-96(1976))、坡咯黴素(porothramycin)(Tsunakawa等人,J. Antibiotics,41,1366-1373(1988))、普咯黴素(prothracarcin)(Shimizu等人,J.Antibiotics,29,2492-2503(1982);Langley及Thurston,J.Org.Chem.,52,91-97(1987))、西巴黴素(sibanomicin)(DC-102)(Hara等人,J.Antibiotics,41,702-704(1988);Itoh等人,J.Antibiotics,41,1281-1284(1988))、西伯利亞黴素(sibiromycin)(Leber等人,J.Am.Chem.Soc.,110,2992-2993(1988))及托馬黴素(tomamycin)(Arima等人,J.Antibiotics,25,437-444(1972))。PBD具有通式結構:
其在其芳族A環與吡咯并C環中的取代基之數目、類型與位置方面及在C環之飽和度方面可不同。在B環中在負責烷基化DNA之親電子中心之N10-C11位置處存在亞胺(N=C)、甲醇胺(NH-CH(OH))或甲醇胺甲醚(NH-CH(OMe))。所有已知天然產物在對掌性C11a位置處均具有(S)組態,該位置使其擁有自C環朝向A環檢視時之右旋扭轉。此給予其用於與B形式DNA之小溝等螺旋之適當的三維形狀,產生在結合位點處之緊密貼合(Kohn,In Antibiotics III.Springer-Verlag,New York,第3-11頁(1975);Hurley及Needham-VanDevanter,Acc.Chem.Res.,19,230-237(1986))。其在小溝中形成加合物之能力使其能夠干擾DNA加工,因此將其用作抗腫瘤劑。
尤其有利的吡咯并苯并二氮呯化合物由Gregson等人(Chem.Commun. 1999,797-798)描述作為化合物1,且由Gregson等人(J.Med.Chem. 2001,44,1161-1174)描述作為化合物4a。此亦稱為SG2000的化合物展示於下方:
WO 2007/085930描述具有用於連接至細胞結合劑(諸如抗體)之連接基團的二聚體PBD化合物之製備。連接子存在於連接二聚體之單體PBD單元之橋鍵中。
具有用於連接至細胞結合劑(諸如抗體)之連接基團的二聚體PBD化合物描述於WO 2011/130598中。將這些化合物中的連接子附著至可利用的N10位置中之一者,且一般藉由連接基團上之酶的作用來分裂該等連接子。
已建立抗體療法用於患有癌症、免疫及血管生成病症之患者的目標治療(Carter,P.(2006)Nature Reviews Immunology 6:343-357)。使用抗體-藥物結合物(ADC)(亦即免疫結合物)用於細胞毒性或細胞生長抑制劑(亦即在癌症之治療中殺滅或抑制腫瘤細胞之藥物)之局部傳遞、藥物部分至腫瘤之目標傳遞及其中之細胞內積聚,而此等未結合的藥物試劑之全身性投與可引起對正常細胞之不可接受的程度之毒性(Xie等人(2006)Expert.Opin.Biol.Ther.6(3):281-291;Kovtun等人(2006)Cancer Res.66(6):3214-3121;Law等人(2006)Cancer Res.66(4):2328-2337;Wu等人(2005)Nature Biotech.23(9):1137-1145;Lambert J.(2005)Current Opin.in Pharmacol.5:543-549;Hamann P.(2005)Expert Opin.Ther.Patents 15(9):1087-1103;Payne,G.(2003)Cancer Cell 3:207-212;Trail等人(2003)Cancer Immunol.Immunother.52:328-337;Syrigos及Epenetos(1999)Anticancer Research 19:605-614)。
進而尋求最大功效以及最小毒性。設計及精練ADC之工作已集
中於單株抗體(mAb)之選擇性以及藥物作用機制、藥物連接、藥物/抗體比率(負載量)及藥物釋放特性(Junutula等人,2008b Nature Biotech.,26(8):925-932;Dornan等人(2009)Blood 114(13):2721-2729;US 7521541;US 7723485;WO2009/052249;McDonagh(2006)Protein Eng.Design & Sel.19(7):299-307;Doronina等人(2006)Bioconj.Chem.17:114-124;Erickson等人(2006)Cancer Res.66(8):1-8;Sanderson等人(2005)Clin.Cancer Res.11:843-852;Jeffrey等人(2005)J.Med.Chem.48:1344-1358;Hamblett等人(2004)Clin.Cancer Res.10:7063-7070)。藥物部分可藉由包括微管蛋白結合、DNA結合、蛋白酶體及/或拓撲異構酶抑制之機制來賦予其細胞毒性及細胞生長抑制效應。一些細胞毒性藥物傾向於在結合至較大抗體或蛋白質受體配位體時為非活性的或弱活性的。
本發明人已研發具有連接基團的特定PBD二聚物,該等連接基團用於與細胞結合劑形成PBD結合物且尤其PBD抗體結合物。
在第一態樣中,本發明提供化合物A:
及其鹽與溶劑合物。
在第二態樣中,本發明提供化合物B:
及其鹽與溶劑合物。
在第三態樣中,本發明提供化合物C:
化合物A、B及C不同於先前所揭示的帶有具有C2-3內雙鍵之藥物連接子之PBD二聚體,在於其具有較小、較少親脂性C2取代基(例如4F-苯基、伸丙基)。因而,化合物A、B及C之結合物(參見下文)較不可能在合成後聚集。可藉由尺寸排外層析法(SEC)來量測結合物之此類凝聚。
化合物A及B分別包含碘乙醯胺及溴乙醯胺基團用於連接至細胞結合劑。
化合物C在第二亞胺基團上具有可分裂的保護基,以避免在其合成期間及最終產物中的交叉反應而避免形成甲醇胺及甲醇胺甲基醚。此保護亦避免分子中之反應性亞胺基團之存在。
全部三個化合物在各C環中具有兩個sp2中心,其可在DNA之小溝中達成比各C環中僅具有一個sp2中心的化合物之結合更強的結合。
本發明之第四態樣提供結合物,其具有式ConjAB:
ConjC:
其中CBA代表細胞結合劑。經由細胞結合劑上之游離S(活性巰基)連接至所示部分。
本發明提供具有經由PBD部分中之一者上之C2位置連接的連接子的PBD二聚體,該等PBD部分適合於形成經由該連接子結合至細胞結合劑之PBD二聚體。
本發明適用於提供PBD化合物至個體中的較佳位點。該結合物允許釋放不保留連接子之任何部分的活性PBD化合物。不存在可影響PBD化合物之反應性的殘端。由此ConjAB及ConjC將皆釋放化合物RelA:
在本發明中PBD二聚體與細胞結合劑(例如抗體)之間的特異性連接較佳為穩定的胞外連接。在轉移或傳遞至細胞中之前抗體-藥物結合物(ADC)較佳為穩定的且保持完整,亦即抗體保持連接至藥物部分。連接子在目標細胞外為穩定的且可能在細胞內以一定的有效速率分裂。有效連接子將:(i)維持抗體之特異性結合特性;(ii)允許結合物或藥物部分之細胞內傳遞;(iii)保持穩定且完整(亦即未分裂)直至已將結合物傳遞或轉移至其目標位點;及(iv)維持PBD藥物部分之細胞毒性、細胞殺滅效應或細胞生長抑制效應。可藉由諸如質譜、HPLC及分離/分析技術LC/MS之標準分析技術來量測ADC之穩定性。
化合物RelA之傳遞係藉由酶的作用在式ConjAB或ConjC之結合物之所需活化位點處實現,諸如藉由組織蛋白酶在連接基團上且尤其在纈胺酸-丙胺酸二肽部分上。
細胞結合劑可為任何種類的且包括胜肽及非胜肽。其可包括抗體或含有至少一個結合位點、淋巴因子、激素、激素模擬物、維生素、生長因子、營養轉移分子或任何其他細胞結合分子或物質之抗體
的片段。
在一個實施例中,細胞結合劑為包含4-30個、優選地6-20個鄰接胺基酸殘基之線性或環狀肽。在此實施例中,較佳的是將一個細胞結合劑連接至一個單體或二聚體吡咯并苯并二氮呯化合物。
在一個實施例中細胞結合劑包含結合整合素αvβ6之肽。肽可為對於αvβ6的選擇性超過XYS。
在一個實施例中,細胞結合劑包含A20FMDV-Cys多肽。A20FMDV-Cys具有序列:NAVPNLRGDLQVLAQKVARTC。或者,可使用A20FMDV-Cys序列之變異體,其中一個、兩個、三個、四個、五個、六個、七個、八個九個或十個胺基酸殘基由另一胺基酸殘基取代。此外,多肽可具有序列NAVXXXXXXXXXXXXXXXRTC。
在本文中術語「抗體」以最廣泛意義使用且尤其涵蓋單株抗體、多株抗體、二聚體、多聚體、多特異性抗體(例如雙特異性抗體)及抗體片段,只要其展現所需生物活性即可(Miller等人(2003)Jour.of Immunology 170:4854-4861)。抗體可為鼠類抗體、人類抗體、人類化抗體、嵌合抗體或源自其他物種。抗體為藉由免疫系統生成的蛋白質,其能夠識別且結合至特異性抗原。(Janeway,C.,Travers,P.,Walport,M.,Shlomchik(2001)Immuno Biology,第5版,Garland Publishing,New York)。目標抗原一般具有諸多由多個抗體上之CDR識別的結合位點(亦稱為抗原決定基)。特異性結合至不同抗原決定基之各抗體具有不同結構。由此,一個抗原可具有一個以上對應的抗體。抗體包括全長免疫球蛋白分子或全長免疫球蛋白分子之免疫活性部分,亦即含有免疫特異性結合所關注的目標或其部分之抗原的抗原結合位點之分子,此類目標包括(但不限於)癌細胞或產生與自體免疫
疾病相關的自體免疫抗體之細胞。免疫球蛋白可為免疫球蛋白分子之任何類型(例如IgG、IgE、IgM、IgD及IgA)、類別(例如IgG1、IgG2、IgG3、IgG4、IgA1及IgA2)或子類。免疫球蛋白可源自任何物種,包括人類、鼠類或兔來源。
「抗體片段」包含全長抗體之一部分,一般為其抗原結合或可變區。抗體片段之實例包括Fab、Fab'、F(ab')2及scFv片段;雙功能抗體;線性抗體;由Fab表現庫產生的片段、抗個體基因型(抗Id)抗體、CDR(互補決定區)及免疫特異性結合至癌細胞抗原之以上中之任一者的抗原決定基結合片段、病毒抗原或微生物抗原、單鏈抗體分子;及由抗體片段形成的多特異性抗體。
如本文所用之術語「單株抗體」係指自一群實質上均質之抗體獲得的抗體,亦即除以少量存在之有可能天然存在的突變以外構成該群之個別抗體為一致的。單株抗體為高度特異性的,其針對單個抗原位點。此外,與包括針對不同決定子(抗原決定基)的不同抗體之多株抗體製劑相反,各單株抗體針對抗原上之單個決定子。單株抗體為有利的,除其特異性以外,亦在於其可由其他抗體未經污染地合成。修飾語「單株」指示抗體之特徵為自實質上均質之抗體群獲得,且不應理解為需要藉由任何特定方法來產生該抗體。舉例而言,根據本發明使用的單株抗體可藉由首先由Kohler等人(1975)Nature 256:495描述之融合瘤方法來製得或可藉由重組DNA方法(參見US 4816567)來製得。亦可使用Clackson等人(1991)Nature,352:624-628;Marks等人(1991)J.Mol.Biol.,222:581-597中所描述之技術自噬菌體抗體庫或自攜有完全人類免疫球蛋白系統之轉基因小鼠(Lonberg(2008)Curr.Opinion 20(4):450-459)分離單株抗體。
本文中的單株抗體特定包括「嵌合」抗體以及此類抗體的片段,只要其呈現所需生物活性即可,在該等嵌合抗體中重鏈和/或輕
鏈之一部分與源自特定物種或屬於特定抗體類別或子類之抗體中的對應序列一致或同源,而該(等)鏈之其餘部分與源自另一物種或屬於另一抗體類別或子類的抗體中的對應序列一致或同源(US 4,816,567;及Morrison等人(1984)Proc.Natl.Acad.Sci.USA,81:6851-6855)。嵌合抗體包括「靈長類化」抗體,該等靈長類化抗體包含源自非人類靈長類(例如舊世界猴或猿)之可變域抗原結合序列及人類恆定區序列。
本文中「完整抗體」為包含VL與VH域以及輕鏈恆定域(CL)與重鏈恆定域(CH1、CH2及CH3)者。恆定域可為原生序列恆定域(例如人類原生序列恆定域)或其胺基酸序列變異體。完整抗體可具有一或多個「效應功能」,該等效應功能係指可歸因於抗體之Fc區(原生序列Fc區或胺基酸序列變異體Fc區)之彼等生物活性。抗體效應功能之實例包括C1q結合;補體依賴性細胞毒性;Fc受體結合;抗體依賴性細胞介導之細胞毒性(ADCC);吞噬作用;及細胞表面受體(諸如B細胞受體及BCR)之下調。
視其重鏈之恆定域之胺基酸序列而定,可將完整抗體分至不同「類別」。存在五種主要類別之完整抗體:IgA、IgD、IgE、IgG及IgM,且可將其中之若干者進一步劃分成「子類」(同型),例如IgG1、IgG2、IgG3、IgG4、IgA及IgA2。將對應於不同類別之抗體的重鏈恆定域分別稱為α、δ、ε、γ及μ。不同類別之免疫球蛋白的次單元結構及三維組態已為吾人所熟知。
減小非人類抗體或抗體片段之活體內免疫原性的技術包括稱為「人類化」者。
「人類化抗體」係指包含人類抗體之經修飾可變區之至少一部分的多肽,其中可變區之一部分、優選地實質上小於完整人類可變域之部分已由來自非人類物種之對應序列取代,且其中將經修飾的可變
區連接至另一蛋白質之至少另一部分、優選地人類抗體之恆定區。表述「人類化抗體」包括人類抗體,其中一或多個互補決定區(「CDR」)胺基酸殘基及/或一或多個構架區(「FW」或「FR」)胺基酸殘基由來自嚙齒動物或其他非人類抗體中之相似位點之胺基酸殘基取代。表述「人類化抗體」亦包括包含實質上具有人類免疫球蛋白之胺基酸序列的FR及實質上具有非人類免疫球蛋白之胺基酸序列的CDR之免疫球蛋白胺基酸序列變異體或其片段。
非人類(例如鼠類)抗體之「人類化」形式為含有源自非人類免疫球蛋白之最小序列之嵌合抗體。或者,以另一方式來看,人類化抗體為亦含有所選擇的來自非人類(例如鼠類)抗體之序列而非人類序列之人類抗體。人類化抗體可包括保守性胺基酸取代或來自一致或不同物種之非天然殘基,該等非天然殘基並不顯著更改其結合及/或生物活性。此類抗體為含有源自非人類免疫球蛋白之最小序列之嵌合抗體。
存在一系列人類化技術,包括『CDR移植』、『引導選擇』、『去免疫』、『重塑(resurfacing)』(亦稱為『鑲飾(veneering)』)、『複合抗體』、『人類鏈帶含量最佳化』及構架改組。
在此技術中,人類化抗體為人類免疫球蛋白(受者抗體),其中來自受者抗體之互補決定區(CDR)的殘基由來自非人類物種(供體抗體)之CDR的殘基置換(實際上將非人類CDR『移植』至人類構架上),其中非人類物種為諸如具有所需特性之小鼠、大鼠、駱駝、牛、山羊或兔。在一些情況下,人類免疫球蛋白之構架區(FR)殘基由對應非人類殘基置換(例如當特定FR殘基對抗原結合具有顯著影響時此可發生)。
此外,人類化抗體可包含在受者抗體中及在所引人的CDR或構架序列中均不存在之殘基。進行此等修飾以進一步精練且最大化抗體效能。一般而言,由此人類化抗體將包含至少一個可變域之全部,且在
一個態樣中將包含兩個可變域之全部,在可變域中高變環之全部或部份對應於非人類免疫球蛋白之高變環且FR區之全部或實質上全部為人類免疫球蛋白序列之FR區。人類化抗體視情況亦將包含免疫球蛋白恆定區(Fc)之至少一部分或人類免疫球蛋白之至少一部分。
方法由將對特定抗原決定基具有特異性之既定非人類抗體之VH或VL域與人類VH或VL庫合併及選擇特異性人類V域對抗所關注的抗原組成。隨後將此所選擇的人類VH與VL庫組合以生成完全人類VH×VL組合。該方法描述於Nature Biotechnology(N.Y.)12,(1994)899-903中。
在此方法中,在最終抗體分子內組合來自人類抗體之胺基酸序列之兩個或兩個以上片段。藉由在限制或避開最終複合抗體V區中之人類T細胞抗原決定基的組合中合併多個人類VH及VL序列片段來構造該等抗體分子。若需要,藉由使用避開T細胞抗原決定基之替代性片段交換V區片段來限制或避開T細胞抗原決定基,該等V區片段促成或編碼T細胞抗原決定基。此方法描述於美國2008/0206239 A1中。
此方法涉及自治療性抗體(或其他分子)之V區移除人類(或其他第二物種)T細胞抗原決定基。藉由(例如)與MHC結合基元之數據庫(諸如在www.wehi.edu.au代管的「基元」數據庫)比較來分析治療性抗體V區序列以獲得MHC第II類結合基元之存在。或者,可使用諸如由Altuvia等人(J.Mol.Biol.249 244-250(1995))設計的彼等方法之計算穿線法來鑑定MHC第II類結合基元;在此等方法中,測試來自V區序列之連續重疊胜肽以獲得其對MHC第II類蛋白質之結合能。隨後可將此數據與關於經成功呈遞之胜肽的其他序列特徵之資訊組合,該等序
列特徵為諸如兩親性、Rothbard基元及組織蛋白酶B與其他加工酶之分裂位點。
在已鑑定可能存在之第二物種(例如人類)T細胞抗原決定基後,藉由一或多個胺基酸之更改來消除該等第二物種T細胞抗原決定基。經修飾的胺基酸經常在T細胞抗原決定基自身內,但亦可使其在蛋白質之一級或二級結構上與抗原決定基鄰接(且因此可能在一級結構中並不鄰接)。最通常地,藉助於取代來進行更改,但在一些情況下添加或刪除胺基酸將為更適當的。
可藉由重組DNA技術完成全部更改,以使得可使用沿用已久的方法(諸如定點突變誘發)藉由來自重組宿主之表現來製備最終分子。然而,亦有可能使用蛋白質化學反應或分子更改之任何其他方式。
此方法涉及:(a)藉由構造非人類抗體可變區之三維模型來確定非人類(例如嚙齒動物)抗體(或其片段)之可變區的構形結構;(b)使用來自充足數量之非人類及人類抗體可變區重鏈及輕鏈之x射線結晶學結構的相關可行性分佈來生成序列比對以得到重鏈及輕鏈構架位置組,其中在充足數量之非人類抗體重鏈及輕鏈之98%中比對位置為一致的;(c)界定待人類化之非人類抗體,重鏈及輕鏈表面暴露胺基酸殘基組使用步驟(b)中所生成的構架位置組;(d)自人類抗體胺基酸序列鑑定重鏈及輕鏈表面暴露胺基酸殘基組,其與步驟(c)中所界定之表面暴露胺基酸殘基組最接近一致,其中來自人類抗體之重鏈及輕鏈為天然成對的或並非天然成對的;(e)在待人類化的非人類抗體之胺基酸序列中用步驟(d)中所鑑定的重鏈及輕鏈表面暴露胺基酸殘基組取代步驟(c)中所界定之重鏈及
輕鏈表面暴露胺基酸殘基組;(f)構造由步驟(e)中所指定之取代產生的非人類抗體之可變區之三維模型;(g)藉由比較步驟(a)與(f)中所構造之三維模型來鑑定來自步驟(c)或(d)中所鑑定之組的任何胺基酸殘基,該胺基酸殘基在待人類化之非人類抗體之互補決定區的任何殘基之任何原子之5埃內;及(h)使步驟(g)中所鑑定之任何殘基自人類胺基酸殘基變成原始非人類胺基酸殘基以藉此界定非人類抗體人類化的表面暴露胺基酸殘基組;其限制條件為無需首先進行步驟(a),但必須在步驟(g)之前進行步驟(a)。
該方法比較非人類序列與官能性人類生殖系基因譜系。選擇編碼與非人類序列一致或密切相關之典型結構之彼等人類基因。選擇CDR內之彼等經選擇的具有最高同源性之人類基因作為FR供體。最終,將非人類CDR移植至此等人類FR上。此方法描述於專利WO 2005/079479 A2中。
此方法比較非人類(例如小鼠)序列與人類生殖系基因之譜系,且評估差值作為人類鏈帶含量(HSC),該人類鏈帶含量以可能存在之MHC/T細胞抗原決定基之量來量化序列。隨後藉由最大化其HSC而非使用全域識別量測來人類化目標序列以生成多個不同人類化變異體(描述於Molecular Immunology,44,(2007)1986-1998中)。
將非人類抗體之CDR同構融合至包涵全部已知重鏈及輕鏈人類生殖系基因構架之cDNA庫。隨後藉由例如噬菌體顯示抗體庫之淘選來選擇人類化抗體。此描述於Methods 36,43-60(2005)中。
細胞結合劑之實例包括所描述之用於WO 2007/085930(將其併入本文中)中的彼等試劑。
用於本發明之實施例的腫瘤相關抗原及同源抗體列於以下。
Genbank寄存編號NM_001203
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Genbank寄存編號NP_001194
Genbank版本號NP_001194.1 GI:4502431
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ten Dijke,P.等人Science 264(5155):101-104(1994)、Oncogene 14 10(11):1377-1382(1997));WO2004/063362(請求項2);WO2003/042661(請求項12);US2003/134790-A1(第38-39頁);WO2002/102235(請求項13;第296頁);WO2003/055443(第91-92頁);WO2002/99122(實例2;第528-530頁);WO2003/029421(請求項6);WO2003/024392(請求項2;圖112);WO2002/98358(請求項1;第183頁);WO2002/54940(第100-101頁);WO2002/59377(第349-350頁);WO2002/30268(請求項27;第376頁);15 WO2001/48204(實例;圖4);NP_001194骨形態生成蛋白受體,IB型/pid=NP_001194.1;MIM:603248;AY065994
Genbank寄存編號NM_003486
Genbank版本號NM_003486.5 GI:71979931
Genbank記錄更新日期:2012年6月27日下午12:06
Genbank寄存編號NP_003477
Genbank版本號NP_003477.4 GI:71979932
Genbank記錄更新日期:2012年6月27日下午12:06
Biochem.Biophys.Res.Commun.255(2),283-288(1999)、Nature 395(6699):288-291(1998)、20 Gaugitsch,H.W.等人(1992)J.Biol.Chem.267(16):11267-11273);WO2004/048938(實例2);WO2004/032842(實例IV);WO2003/042661(請求項12);WO2003/016475(請求項1);WO2002/78524(實例2);WO2002/99074(請求項19;第127-129頁);WO2002/86443(請求項27;第222頁、第393頁);WO2003/003906(請求項10;第293頁);WO2002/64798(請求項33;第93-95頁);WO2000/14228(請求項5;第133-136頁);US2003/224454(圖3);25 WO2003/025138(請求項12;第150頁);NP_003477溶質載劑家族7(陽離子型胺基酸轉運體,y+系統),成員5/pid=NP_003477.3-智人;MIM:600182;NM_015923。
Genbank寄存編號NM_012449
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Genbank寄存編號NP_036581
Genbank版本號NP_036581.1 GI:9558759
Genbank記錄更新日期:2012年9月9日下午02:57
Cancer Res.61(15),5857-5860(2001)、Hubert,R.S.等人(1999)Proc.Natl.Acad.Sci.U.S.A.96(25):14523-14528);WO2004/065577(請求項6);WO2004/027049(圖1L);EP1394274(實例11);WO2004/016225(請求項2);WO2003/042661(請求項12);US2003/157089(實例5);US2003/185830(實例5);US2003/064397(圖2);WO2002/89747(實例5;第618-619頁);WO2003/022995(實例9;圖13A,35實例53;第173頁,實例2;圖2A);前列腺之六跨膜上皮抗原;MIM:604415。
Genbank寄存編號AF361486
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Genbank寄存編號AAK74120
Genbank版本號AAK74120.3 GI:34501467
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J.Biol.Chem.276(29):27371-27375(2001));WO2004/045553(請求項14);WO2002/92836(請求項6;圖12);WO2002/83866(請求項15;第116-121頁);US2003/124140(實例16);GI:34501467;
Genbank寄存編號NM_005823
Genbank版本號NM_005823.5 GI:293651528
Genbank記錄更新日期:2012年9月2日下午01:47
Genbank寄存編號NP_005814
Genbank版本號NP_005814.2 GI:53988378
Genbank記錄更新日期:2012年9月2日下午01:47
Yamaguchi,N.等人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 10(1):136-140(1996)、J.Biol.Chem.270(37):21984-21990(1995));WO2003/101283(請求項14);WO2002/102235(請求項13;第287-288頁);WO2002/101075(請求項4;第308-309頁);WO2002/71928(第320-321頁);WO94/10312(第52-57頁);IM:601051。
Genbank寄存編號NM_006424
Genbank版本號NM_006424.2 GI:110611905
Genbank記錄更新日期:2012年7月22日下午03:39
Genbank寄存編號NP_006415
Genbank版本號NP_006415.2 GI:110611906
Genbank記錄更新日期:2012年7月22日下午03:39
J.Biol.Chem.277(22):19665-19672(2002)、Genomics 62(2):281-284(1999)、Feild,J.A.等人(1999)Biochem.Biophys.Res.Commun.258(3):578-582);WO2004/022778(請求項2);EP1394274(實例11);WO2002/102235(請求項13;第20 326頁);EP0875569(請求項1;第17-19頁);WO2001/57188(請求項20;第329頁);WO2004/032842(實例IV);WO2001/75177(請求項24;第139-140頁);MIM:604217。
Genbank寄存編號AB040878
Genbank版本號AB040878.1 GI:7959148
Genbank記錄更新日期:2006年8月2日下午05:40
Genbank寄存編號BAA95969
Genbank版本號BAA95969.1 GI:7959149
Genbank記錄更新日期:2006年8月2日下午05:40
Nagase T.等人(2000)DNA Res.7(2):143-150);WO2004/000997(請求項1);WO2003/003984(請求項1);WO2002/06339(請求項1;第50頁);WO2001/88133(請求項1;第41-43頁,第48-58頁);WO2003/054152(請求項20);WO2003/101400(請求項11);寄存:30 Q9P283;Genew;HGNC:10737
Genbank寄存編號AY358628
Genbank版本號AY358628.1 GI:37182377
Genbank記錄更新日期:2009年12月1日上午04:15
Genbank寄存編號AAQ88991
Genbank版本號AAQ88991.1 GI:37182378
Genbank記錄更新日期:2009年12月1日上午04:15
Ross等人(2002)Cancer Res.62:2546-2553;US2003/129192(請求項2);US2004/044180(請求項12);US2004/044179 35(請求項11);US2003/096961(請求項11);US2003/232056(實例5);WO2003/105758 16(請求項12);US2003/206918(實例5);EP1347046(請求項1);WO2003/025148(請求項20);GI:37182378。
Genbank寄存編號AY275463
Genbank版本號AY275463.1 GI:30526094
Genbank記錄更新日期:2010年3月11日上午02:26
Genbank寄存編號AAP32295
Genbank版本號AAP32295.1 GI:30526095
Genbank記錄更新日期:2010年3月11日上午02:26
Nakamuta M.等人Biochem.Biophys.Res.Commun.177,34-39,1991;Ogawa Y.等人Biochem.Biophys.Res.Commun.178,248-255,
1991;Arai H.等人Jpn.Circ.J.56,1303-1307,1992;Arai H.等人J.Biol.Chem.268,3463-3470,1993;Sakamoto A.,Yanagisawa M.等人Biochem.Biophys.Res.Commun.178,656-663,1991;Elshourbagy N.A.等人J.Biol.Chem.268,3873-3879,1993;Haendler B.等人J.Cardiovasc.Pharmacol.20,s1-S4,1992;Tsutsumi M.等人Gene 228,43-49,1999;Strausberg R.L.等人Proc.Natl.Acad.Sci.U.S.A.99,16899-16903,2002;Bourgeois C.等人J.Clin.Endocrinol.Metab.82,3116-3123,1997;Okamoto Y.等人Biol.Chem.272,21589-21596,1997;Verheij J.B.等人Am.J.Med.Genet.108,223-225,2002;Hofstra R.M.W.等人Eur.J.Hum.Genet.5,180-185,1997;Puffenberger E.G.等人Cell 79,1257-1266,1994;Attie T.等人,Hum.Mol.Genet.4,2407-15 2409,1995;Auricchio A.等人Hum.Mol.Genet.5:351-354,1996;Armiel J.等人Hum.Mol.Genet.5,355-357,1996;Hofstra R.M.W.等人Nat.Genet.12,445-447,1996;Svensson P.J.等人Hum.Genet.103,145-148,1998;Fuchs S.等人Mol.Med.7,115-124,2001;Pingault V.等人(2002)Hum.Genet.111,198-206;WO2004/045516(請求項1);WO2004/048938(實例2);WO2004/040000(請求項151);WO2003/087768(請求項1);20 WO2003/016475(請求項1);WO2003/016475(請求項1);WO2002/61087(圖1);WO2003/016494(圖6);WO2003/025138(請求項12;第144頁);WO2001/98351(請求項1;第124-125頁);EP0522868(請求項8;圖2);WO2001/77172(請求項1;第297-299頁);US2003/109676;US6518404(圖3);US5773223(請求項1a;第31-34行);WO2004/001004。
Genbank寄存編號NM_017763
Genbank版本號NM_017763.4 GI:167830482
Genbank記錄更新日期:2012年7月22日上午12:34
Genbank寄存編號NP_060233
Genbank版本號NP_060233.3 GI:56711322
Genbank記錄更新日期:2012年7月22日上午12:34
WO2003/104275(請求項1);WO2004/046342(實例2);WO2003/042661(請求項12);WO2003/083074(請求項14;第61頁);WO2003/018621(請求項1);WO2003/024392(請求項2;圖93);WO2001/66689(實例6);LocusID:54894。
Genbank寄存編號AF455138
Genbank版本號AF455138.1 GI:22655487
Genbank記錄更新日期:2010年3月11日上午01:54
Genbank寄存編號AAN04080
Genbank版本號AAN04080.1 GI:22655488
Genbank記錄更新日期:2010年3月11日上午01:54
Lab.Invest.82(11):1573-1582(2002));WO2003/087306;US2003/064397(請求項1;圖1);WO2002/72596(請求項13;第54-55頁);WO2001/72962(請求項1;圖4B);35 WO2003/104270(請求項
11);WO2003/104270(請求項16);US2004/005598(請求項22);WO2003/042661(請求項12);US2003/060612(請求項12;圖10);WO2002/26822(請求項23;圖2);WO2002/16429(請求項12;圖10);GI:22655488。
Genbank寄存編號NM_017636
Genbank版本號NM_017636.3 GI:304766649
Genbank記錄更新日期:2012年6月29日上午11:27
Genbank寄存編號NP_060106
Genbank版本號NP_060106.2 GI:21314671
Genbank記錄更新日期:2012年6月29日上午11:27
Xu,X.Z.等人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));US2003/143557(請求項4);WO2000/40614(請求項14;第100-103頁);WO2002/10382(請求項1;圖9A);WO2003/042661(請求項12);WO2002/30268(請求項27;第391頁);US2003/219806(請求項4);WO2001/62794(請求項10 14;圖1A-D);MIM:606936。
Genbank寄存編號NM_003212
Genbank版本號NM_003212.3 GI:292494881
Genbank記錄更新日期:2012年9月23日下午02:27
Genbank寄存編號NP_003203
Genbank版本號NP_003203.1 GI:4507425
Genbank記錄更新日期:2012年9月23日下午02:27
Ciccodicola,A.等人EMBO J.8(7):1987-1991(1989)、Am.J.Hum.Genet.49(3):555-565(1991));US2003/224411(請求項1);WO2003/083041(實例1);WO2003/034984(請求項12);WO2002/88170(請求項2;第52-53頁);WO2003/024392(請求項2;圖58);WO2002/16413(請求項1;第94-95頁,105);WO2002/22808(請求項2;圖1);US5854399(實例2;第17-18行);US5792616(圖2);MIM:187395。
Genbank寄存編號M26004
Genbank版本號M26004.1 GI:181939
Genbank記錄更新日期:2010年6月23日上午08:47
Genbank寄存編號AAA35786
Genbank版本號AAA35786.1 GI:181940
Genbank記錄更新日期:2010年6月23日上午08:47
Fujisaku等人(1989)J.Biol.Chem.264(4):2118-2125);Weis J.J.
等人J.Exp.Med.167,1047-1066,1988;Moore M.等人Proc.Natl.Acad.Sci.U.S.A.84,9194-9198,1987;Barel M.等人Mol.Immunol.35,1025-1031,1998;Weis J.J.等人Proc.Natl.Acad.Sci.U.S.A.83,5639-5643,1986;Sinha S.K.等人(1993)J.Immunol.150,5311-5320;WO2004/045520(實例4);US2004/005538(實例1);WO2003/062401(請求項9);WO2004/045520(實例4);WO91/02536(圖9.1-9.9);WO2004/020595(請求項1);寄存:P20023;Q13866;Q14212;EMBL;M26004;AAA35786.1。
Genbank寄存編號NM_000626
Genbank版本號NM_000626.2 GI:90193589
Genbank記錄更新日期:2012年6月26日下午01:53
Genbank寄存編號NP_000617
Genbank版本號NP_000617.1 GI:11038674
Genbank記錄更新日期:2012年6月26日下午01:53
Proc.Natl.Acad.Sci.U.S.A.(2003)100(7):4126-4131、Blood(2002)100(9):3068-3076、Muller等人(1992)Eur.J.Immunol.22(6):1621-1625);WO2004/016225(請求項2,圖140);WO2003/087768、US2004/101874(請求項1,第102頁);WO2003/062401(請求項9);WO2002/78524(實例2);US2002/150573(請求項35 5,第15頁);US5644033;WO2003/048202(請求項1,第306頁及第309頁);WO 99/58658、US6534482(請求項13,圖17A/B);WO2000/55351(請求項11,第1145-1146頁);MIM:147245
Genbank寄存編號NM_030764
Genbank版本號NM_030764.3 GI:227430280
Genbank記錄更新日期:2012年6月30日上午12:30
Genbank寄存編號NP_110391
Genbank版本號NP_110391.2 GI:19923629
Genbank記錄更新日期:2012年6月30日上午12:30
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.等人(2001)Biochem.Biophys.Res.Commun.280(3):768-775;WO2004/016225(請求項2);WO2003/077836;WO2001/38490(請求項5;圖18D-1-18D-2);WO2003/097803(請求項12);10 WO2003/089624(請求項25);:MIM:606509。
Genbank寄存編號M11730
Genbank版本號M11730.1 GI:183986
Genbank記錄更新日期:2010年6月23日上午08:47
Genbank寄存編號AAA75493
Genbank版本號AAA75493.1 GI:306840
Genbank記錄更新日期:2010年6月23日上午08:47
Coussens L.等人Science(1985)230(4730):1132-1139);Yamamoto T.等人Nature 319,230-234,1986;Semba K.等人Proc.Natl.Acad.Sci.U.S.A.82,6497-6501,1985;Swiercz J.M.等人J.Cell Biol.165,869-15 880,2004;Kuhns J.J.等人J.Biol.Chem.274,36422-36427,1999;Cho H.-S.等人Nature 421,756-760,2003;Ehsani A.等人(1993)Genomics 15,426-429;WO2004/048938(請求項2);WO2004/027049(圖11);WO2004/009622;WO2003/081210;WO2003/089904(請求項9);WO2003/016475(請求項1);US2003/118592;WO2003/008537(請求項1);WO2003/055439(請求項29;圖1A-B);WO2003/025228(請求項37;圖5C);20 WO2002/22636(請求項13;第95-107頁);WO2002/12341(請求項68;圖7);WO2002/13847(第71-74頁);WO2002/14503(第114-117頁);WO2001/53463(請求項2;第41-46頁);WO2001/41787(第15頁);WO2000/44899(請求項52;圖7);WO2000/20579(請求項3;圖2);US5869445(請求項3;第31-38行);WO9630514(請求項2;第56-61頁);EP1439393(請求項7);WO2004/043361(請求項7);WO2004/022709;WO2001/00244 25(請求項3;圖4);寄存:P04626;EMBL;M11767;AAA35808.1.EMBL;M11761;AAA35808.1
Abbott:US20110177095
舉例而言,一種抗體,其包含與具有胺基酸序列SEQ ID NO:3(CDR-H1)、SEQ ID NO:4(CDR-H2)、SEQ ID NO:5(CDR-H3)、SEQ ID NO:104及/或SEQ ID NO:6(CDR-L1)、SEQ ID NO:7(CDR-L2)及SEQ ID NO:8(CDR-L3)之CDR具有總共至少80%序列一致性之CDR,
其中與具有SEQ ID NO:1之VH及SEQ ID NO:2之VL的抗體相比抗HER2抗體或抗HER2結合片段已減小免疫原性。
Biogen:US20100119511
舉例而言,ATCC寄存編號:PTA-10355,PTA-10356,PTA-10357,PTA-10358
舉例而言,結合至HER2之經純化的抗體分子,該抗體分子包含來自抗體之全部六個CDR或者與該等CDR一致或具有與該等CDR不超過兩個更改之CDR,該等CDR選自由BIIB71F10(SEQ ID NO:11,13)、BIIB69A09(SEQ ID NO:15,17);BIIB67F10(SEQ ID NO:19,21);BIIB67F11(SEQ ID NO:23,25)、BIIB66A12(SEQ ID NO:27,29)、BIIB66C01(SEQ ID NO:31,33)、BIIB65C10(SEQ ID NO:35,37)、BIIB65H09(SEQ ID NO:39,41)及BIIB65B03(SEQ ID NO:43,45)組成之群。
赫賽汀(Herceptin)(Genentech)-US6,054,297;ATCC寄存編號CRL-10463(Genentech)
帕妥珠單抗(Pertuzumab)(Genentech)
US20110117097
舉例而言,參見SEQ ID No.15及16、SEQ ID No.17及18、SEQ ID No.23及24以及ATCC寄存編號HB-12215、HB-12216、CRL 10463、HB-12697。
US20090285837
US20090202546
舉例而言,ATCC寄存編號:HB-12215、HB-12216、CRL 10463、HB-12698。
US20060088523
- 舉例而言,ATCC寄存編號:HB-12215、HB-12216
- 舉例而言,包含分別在SEQ ID NO.3及4中之可變輕胺基酸序列及可變重胺基酸序列之抗體。
- 舉例而言,包含選自SEQ ID NO.15及23之輕鏈胺基酸序列及選自SEQ ID NO.16及24之重鏈胺基酸序列的抗體
US20060018899
- 舉例而言,ATCC寄存編號:(7C2)HB-12215、(7F3)HB-12216、(4D5)CRL-10463、(2C4)HB-12697。
- 舉例而言,包含SEQ ID NO.23之胺基酸序列之抗體或其脫醯胺及/或氧化變異體。
US2011/0159014
- 舉例而言,具有包含SEQ ID NO:1之高變區的輕鏈可變結構域之抗體。
- 舉例而言,具有包含SEQ ID NO:2之高變區之重鏈可變結構域的抗體。
US20090187007
Glycotope:TrasGEX抗體http://www.glycotope.com/pipeline
舉例而言,參見國際聯合癌症學會(International Joint Cancer Institute)及長海醫院癌症中心(Changhai Hospital Cancer Cent):HMTI-Fc Ab-Gao J.等人BMB Rep.2009年10月31日;42(10):636-41。
Symphogen:US20110217305
中國協和幹細胞與基因工程(Union Stem Cell & Gene Engineering)-Liu HQ.等人,細胞與分子免疫學雜誌.2010年5月;26(5):456-8。
Genbank寄存編號M18728
Genbank版本號M18728.1 GI:189084
Genbank記錄更新日期:2010年6月23日上午08:48
Genbank寄存編號AAA59907
Genbank版本號AAA59907.1 GI:189085
Genbank記錄更新日期:2010年6月23日上午08:48
Barnett T.等人Genomics 3,59-66,1988;Tawaragi Y.等人Biochem.Biophys.Res.Commun.150,89-96,1988;Strausberg R.L.等人Proc.Natl.Acad.Sci.U.S.A.99:16899-16903,2002;WO2004/063709;EP1439393(請求項7);WO2004/044178(實例4);WO2004/031238;WO2003/042661(請求項12);WO2002/78524(實例2);WO2002/86443(請求項27;第427頁);WO2002/60317(請求項2);寄存:P40199;Q14920;EMBL;M29541;AAA59915.1.EMBL;M18728。
Genbank寄存編號BC017023
Genbank版本號BC017023.1 GI:16877538
Genbank記錄更新日期:2012年3月6日下午01:00
Genbank寄存編號AAH17023
Genbank版本號AAH17023.1 GI:16877539
Genbank記錄更新日期:2012年3月6日下午01:00
Proc.Natl.Acad.Sci.U.S.A.99(26):16899-16903(2002));
WO2003/016475(請求項1);WO2002/64798(請求項33;第85-87頁);JP05003790(圖6-8);WO99/46284(圖9);MIM:179780。
Genbank寄存編號AF184971
Genbank版本號AF184971.1 GI:6013324
Genbank記錄更新日期:2010年3月10日下午10:00
Genbank寄存編號AAF01320
Genbank版本號AAF01320.1 GI:6013325
Genbank記錄更新日期:2010年3月10日下午10:00
Clark H.F.等人Genome Res.13,2265-2270,2003;Mungall A.J.等人Nature 425,805-811,2003;Blumberg H.等人Cell 104,9-19,2001;Dumoutier L.等人J.Immunol.167,3545-3549,2001;Parrish-Novak J.等人J.Biol.Chem.277,47517-47523,2002;Pletnev S.等人(2003)10 Biochemistry 42:12617-12624;Sheikh F.等人(2004)J.Immunol.172,2006-2010;EP1394274(實例11);US2004/005320(實例5);WO2003/029262(第74-75頁);WO2003/002717(請求項2;第63頁);WO2002/22153(第45-47頁);US2002/042366(第20-21頁);WO2001/46261(第57-59頁);WO2001/46232(第63-65頁);WO98/37193(請求項1;第55-59頁);寄存:Q9UHF4;Q6UWA9;Q96SH8;EMBL;AF184971;AAF01320.1。
Genbank寄存編號AF229053
Genbank版本號AF229053.1 GI:10798902
Genbank記錄更新日期:2010年3月11日上午12:58
Genbank寄存編號AAG23135
Genbank版本號AAG23135.1 GI:10798903
Genbank記錄更新日期:2010年3月11日上午12:58
Gary S.C.等人Gene 256,139-147,2000;Clark H.F.等人Genome Res.13,2265-2270,2003;Strausberg R.L.等人Proc.Natl.Acad.Sci.U.S.A.99,16899-16903,2002;US2003/186372(請求項11);US2003/186373(請求項11);US2003/119131(請求項1;圖52);US2003/119122(請求項1;20圖52);US2003/119126(請求項1);US2003/119121(請求項1;圖52);US2003/119129(請求項1);US2003/119130(請求項1);US2003/119128(請求項1;圖52);US2003/119125(請求項1);WO2003/016475(請求項1);WO2002/02634(請求項1)
Genbank寄存編號NM_004442
Genbank版本號NM_004442.6 GI:111118979
Genbank記錄更新日期:2012年9月8日下午04:43
Genbank寄存編號NP_004433
Genbank版本號NP_004433.2 GI:21396504
Genbank記錄更新日期:2012年9月8日下午04:43
Chan,J.及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;第41頁);WO2004065576(請求項1);WO2004020583(請求項9);WO2003004529(第128-132頁);WO200053216(請求項1;第42頁);MIM:600997。
Genbank寄存編號AX092328
Genbank版本號AX092328.1 GI:13444478
Genbank記錄更新日期:2011年1月26日上午07:37
US2004/0101899(請求項2);WO2003104399(請求項11);WO2004000221(圖3);US2003/165504(請求項1);US2003/124140(實例2);US2003/065143(圖60);WO2002/102235(請求項13;第299頁);US2003/091580(實例2);WO2002/10187(請求項6;圖10);WO2001/94641(請求項12;圖7b);WO2002/02624(請求項13;圖1A-1B);US2002/034749(請求項54;第45-46頁);WO2002/06317(實例2;第320-321頁,請求項34;第321-322頁);WO2002/71928(第468-469頁);WO2002/02587(實例1;圖1);WO2001/40269(實例3;第190-192頁);WO2000/36107(實例2;第205-207頁);WO2004/053079(請求項12);WO2003/004989(請求項1);WO2002/71928(第233-234頁,第452-453頁);WO 01/16318。
Genbank寄存編號AJ297436
Genbank版本號AJ297436.1 GI:9367211
Genbank記錄更新日期:2011年2月1日上午11:25
Genbank寄存編號CAB97347
Genbank版本號CAB97347.1 GI:9367212
Genbank記錄更新日期:2011年2月1日上午11:25
Reiter R.E.等人Proc.Natl.Acad.Sci.U.S.A.95,1735-1740,1998;Gu Z.等人Oncogene 19,1288-1296,2000;Biochem.Biophys.Res.Commun.(2000)275(3):783-788;WO2004/022709;EP1394274(實例11);US2004/018553(請求項17);WO2003/008537(請求項1);WO2002/81646(請求項1;第164頁);WO2003/003906(請求項10;第288頁);WO2001/40309(實例1;圖17);US2001/055751(實例1;圖1b);WO2000/32752(請求項18;圖1);WO98/51805(請求項17;第97頁);WO98/51824(請求項10;第94頁);WO98/40403(請求項2;圖1B);寄存:O43653;EMBL;AF043498;AAC39607.1
Genbank寄存編號AY260763
Genbank版本號AY260763.1 GI:30102448
Genbank記錄更新日期:2010年3月11日上午02:24
Genbank寄存編號AAP14954
Genbank版本號AAP14954.1 GI:30102449
Genbank記錄更新日期:2010年3月11日上午02:24
AP14954脂肪瘤HMGIC融合搭配物類蛋白質/pid=AAP14954.1-智人(人類);WO2003/054152(請求項20);WO2003/000842(請求項1);WO2003/023013(實例3,請求項20);US2003/194704(請求項45);GI:30102449;
Genbank寄存編號AF116456
Genbank版本號AF116456.1 GI:4585274
Genbank記錄更新日期:2010年3月10日下午09:44
Genbank寄存編號AAD25356
Genbank版本號AAD25356.1 GI:4585275
Genbank記錄更新日期:2010年3月10日下午09:44
BAFF受體/pid=NP_443177.1-智人:Thompson,J.S.等人Science 293(5537),2108-2111(2001);WO2004/058309;WO2004/011611;WO2003/045422(實例;第32-33頁);WO2003/014294(請求項35;圖6B);WO2003/035846(請求項70;第615-616頁);WO2002/94852(第136-137行);WO2002/38766 25(請求項3;第133頁);WO2002/24909(實例3;圖3);MIM:606269;NP_443177.1;NM_052945_1;AF132600
Genbank寄存編號AK026467
Genbank版本號AK026467.1 GI:10439337
Genbank記錄更新日期:2006年9月11日下午11:24
Genbank寄存編號BAB15489
Genbank版本號BAB15489.1 GI:10439338
Genbank記錄更新日期:2006年9月11日下午11:24
Wilson等人(1991)J.Exp.Med.173:137-146;30 WO2003/072036(請求項1;圖1);IM:107266;NP_001762.1;NM_001771_1。
Genbank寄存編號X52785
Genbank版本號X52785.1 GI:29778
Genbank記錄更新日期:2011年2月2日上午10:09
Genbank寄存編號CAA36988
Genbank版本號CAA36988.1 GI:29779
Genbank記錄更新日期:2011年2月2日上午10:09
Stamenkovic I.等人,Nature 345(6270),74-77(1990)??
正式符號:CD22
其他別名:SIGLEC-2、SIGLEC2
其他名稱:B細胞受體CD22;B淋巴細胞細胞黏附分子;BL-CAM;CD22抗原;T細胞表面抗原Leu-14;唾液酸結合Ig類凝集素2;唾液酸結合Ig類凝集素2
G5/44(奧英妥珠單抗(Inotuzumab)):DiJoseph JF.等人Cancer Immunol Immunother.2005年1月;54(1):11-24。
依帕珠單抗(Epratuzumab)-Goldenberg DM.等人Expert Rev Anticancer Ther.6(10):1341-53,2006。
Genbank寄存編號NM_001783
Genbank版本號NM_001783.3 GI:90193587
Genbank記錄更新日期:2012年6月26日下午01:48
Genbank寄存編號NP_001774
Genbank版本號NP_001774.1 GI:4502685
Genbank記錄更新日期:2012年6月26日下午01:48
WO2003/088808、US2003/0228319;WO2003/062401(請求項9);US2002/150573(請求項4,第13-14頁);WO99/58658(請求項13,圖16);WO92/07574(圖1);US5644033;Ha等人(1992)J.Immunol.148(5):1526-1531;Müller等人(1992)Eur.J.Immunol..22:1621-1625;Hashimoto等人(1994)Immunogenetics 40(4):287-295;Preud'homme等人(1992)Clin.Exp.5 Immunol.90(1):141-146;Yu等人(1992)J.Immunol.148(2)633-637;Sakaguchi等人(1988)EMBO J.7(11):3457-3464
Genbank寄存編號NM_001716
Genbank版本號NM_001716.4 GI:342307092
Genbank記錄更新日期:2012年9月30日下午01:49
Genbank寄存編號NP_001707
Genbank版本號NP_001707.1 GI:4502415
Genbank記錄更新日期:2012年9月30日下午01:49
WO2004/040000;WO2004/015426;US2003/105292(實例2);US6555339(實例2);WO2002/61087(圖1);WO2001/57188(請求項20,第269頁);WO2001/72830(第12-13頁);WO2000/22129(實例1,第152-153頁,15實例2,第254-256頁);WO99/28468(請求項1第38頁);US5440021(實例2,第49-52行);WO94/28931(第56-58頁);WO92/17497(請求項7,圖5);Dobner等人(1992)Eur.J.Immunol.22:2795-2799;Barella等人(1995)Biochem.J.309:773-779 (30) HLA-DOB(結合胜肽且將胜肽呈遞至CD4+T淋巴細胞之MHC第II類分子(Ia抗原)之β次單元);273 aa,pI:6.56,MW:30820.TM:1[P]基因染色體:6p21.3
Genbank寄存編號NM_002120
Genbank版本號NM_002120.3 GI:118402587
Genbank記錄更新日期:2012年9月8日下午04:46
Genbank寄存編號NP_002111
Genbank版本號NP_002111.1 GI:4504403
Genbank記錄更新日期:2012年9月8日下午04:46
Tonnelle等人(1985)EMBO J.4(11):2839-2847;Jonsson等人(1989)Immunogenetics 29(6):411-413;Beck等人(1992)J.Mol.Biol.228:433-441;Strausberg等人(2002)Proc.Natl.Acad.Sci USA 99:16899-16903;Servenius等人(1987)J.Biol.Chem.262:8759-8766;Beck等人(1996)J.Mol.Biol.25 255:1-13;Naruse等人(2002)Tissue Antigens 59:512-519;WO99/58658(請求項13,圖15);US6153408(第35-38行);US5976551(第168-170行);US6011146(第145-146行);Kasahara等人(1989)Immunogenetics 30(1):66-68;Larhammar等人(1985)J.Biol.Chem.260(26):14111-14119 (31) P2X5(嘌呤受體P2X配位體閘控離子通道5,由細胞外ATP閘控之離子通道,其可能與突觸傳輸及神經生成有關,其缺乏可造成特發性逼尿肌不穩定之病理生理學);422 aa,pI:7.63,MW:47206 TM:1[P]基因染色體:17p13.3。
Genbank寄存編號NM_002561
Genbank版本號NM_002561.3 GI:325197202
Genbank記錄更新日期:2012年6月27日上午12:41
Genbank寄存編號NP_002552
Genbank版本號NP_002552.2 GI:28416933
Genbank記錄更新日期:2012年6月27日上午12:41
Le等人(1997)FEBS Lett.418(1-2):195-199;WO2004/047749;WO2003/072035(請求項10);Touchman等人(2000)Genome Res.10:165-173;WO2002/22660(請求項20);WO2003/093444(請求項1);WO2003/087768(請求項1);WO2003/029277(第82頁) (32) CD72(B細胞分化抗原CD72,Lyb-2);359 aa,pI:8.66,MW:40225,TM:15[P]基因染色體:9p13.3。
Genbank寄存編號NM_001782
Genbank版本號NM_001782.2 GI:194018444
Genbank記錄更新日期:2012年6月26日下午01:43
Genbank寄存編號NP_001773
Genbank版本號NP_001773.1 GI:4502683
Genbank記錄更新日期:2012年6月26日下午01:43
WO2004042346(請求項65);WO2003/026493(第51-52頁,第57-58頁);WO2000/75655(第105-106頁);Von Hoegen等人(1990)J.Immunol.144(12):4870-4877;Strausberg等人(2002)Proc.Natl.Acad.Sci USA 99:16899-16903。
Genbank寄存編號NM_005582
Genbank版本號NM_005582.2 GI:167555126
Genbank記錄更新日期:2012年9月2日下午01:50
Genbank寄存編號NP_005573
Genbank版本號NP_005573.2 GI:167555127
Genbank記錄更新日期:2012年9月2日下午01:50
US2002/193567;WO97/07198(請求項11,第39-42頁);Miura等人(1996)15 Genomics 38(3):299-304;Miura等人(1998)Blood 92:2815-2822;WO2003/083047;WO97/44452(請求項8,第57-61頁);WO2000/12130(第24-26頁)。
Genbank寄存編號NM_052938
Genbank版本號NM_052938.4 GI:226958543
Genbank記錄更新日期:2012年9月2日下午01:43
Genbank寄存編號NP_443170
Genbank版本號NP_443170.1 GI:16418419
Genbank記錄更新日期:2012年9月2日下午01:43
WO2003/077836;WO2001/38490(請求項6,圖18E-1-18-E-2);Davis等人(2001)Proc.Natl.Acad.Sci USA 98(17):9772-9777;WO2003/089624(請求項8);EP1347046(請求項1);WO2003/089624
(請求項7)。
Genbank寄存編號AF343662
Genbank版本號AF343662.1 GI:13591709
Genbank記錄更新日期:2010年3月11日上午01:16
Genbank寄存編號AAK31325
Genbank版本號AAK31325.1 GI:13591710
Genbank記錄更新日期:2010年3月11日上午01:16
AF343663、AF343664、AF343665、AF369794、AF397453、AK090423、AK090475、AL834187、AY358085;小鼠:AK089756、AY158090、AY506558;NP_112571.1;WO2003/024392(請求項2,圖97);Nakayama等人(2000)Biochem.Biophys.Res.Commun.277(1):124-127;WO2003/077836;WO2001/38490(請求項3,圖18B-1-18B-2)。
Genbank寄存編號AF179274
Genbank版本號AF179274.2 GI:12280939
Genbank記錄更新日期:2010年3月11日上午01:05
Genbank寄存編號AAD55776
Genbank版本號AAD55776.2 GI:12280940
Genbank記錄更新日期:2010年3月11日上午01:05
NCBI寄存:AAD55776、AAF91397、AAG49451、NCBI RefSeq:NP_057276;NCBI基因:23671;OMIM:605734;SwissProt Q9UIK5;AY358907、CAF85723、CQ782436;WO2004/074320;JP2004113151;WO2003/042661;WO2003/009814;EP1295944(第69-70頁);WO2002/30268(第329頁);WO2001/90304;US2004/249130;US2004/022727;WO2004/063355;US2004/197325;US2003/232350;5US2004/005563;US2003/124579;Horie等人(2000)Genomics 67:146-152;Uchida等人(1999)Biochem.Biophys.Res.Commun.266:593-602;Liang等人(2000)Cancer Res.60:4907-12;Glynne-Jones等人(2001)Int J Cancer.Oct 15;94(2):178-84。
Genbank寄存編號M99487
Genbank版本號M99487.1 GI:190663
Genbank記錄更新日期:2010年6月23日上午08:48
Genbank寄存編號AAA60209
Genbank版本號AAA60209.1 GI:190664
Genbank記錄更新日期:2010年6月23日上午08:48
Israeli R.S.等人Cancer Res.53(2),227-230(1993)
正式符號:FOLH1
其他別名:GIG27、FGCP、FOLH、GCP2、GCPII、NAALAD1、NAALAdase、PSM、PSMA、mGCP
其他名稱:N-乙醯化α連接酸性二肽酶1;N-乙醯化α連接酸性二肽酶I;NAALADase I;細胞生長抑制基因27蛋白質;葉酸多γ麩胺酸羧肽酶;麩胺酸羧化酶II;麩胺酸羧肽酶2;麩胺酸羧肽酶II;膜麩胺酸羧肽酶;前列腺特異性膜抗原變異體F;喋醯多γ麩胺酸羧肽酶抗體
US 7,666,425:具有以下ATCC參考號之由融合瘤產生的抗體:ATCC寄存編號HB-12101、ATCC寄存編號HB-12109、ATCC寄存編號HB-12127及ATCC寄存編號HB-12126。
Proscan:選自由8H12、3E11、17G1 29B4、30C1及20F2組成之群之單株抗體(US 7,811,564;Moffett S.等人Hybridoma (Larchmt)2007年12月;26(6):363-72)。
Cytogen:單株抗體7E11-C5(ATCC寄存編號HB 10494)及9H10-A4(ATCC寄存編號HB11430)-US 5,763,202
GlycoMimetics:NUH2-ATCC寄存編號HB 9762(US 7,135,301)
人類基因組科學:HPRAJ70-寄存編號97131(US 6,824,993);由cDNA純系(HPRAJ70)編碼之胺基酸序列寄存為美國菌種保存中心(「ATCC」)寄存號97131
Medarex:缺乏海藻糖基殘基之抗PSMA抗體-US 7,875,278
小鼠抗PSMA抗體包括3F5.4G6、3D7.1.1、4E10-1.14、3E11、
4D8、3E6、3C9、2C7、1G3、3C4、3C6、4D4、1G9、5C8B9、3G6、4C8B9及單株抗體。分泌3F5.4G6、3D7.1.1、4E10-1.14、3E11、4D8、3E6、3C9、2C7、1G3、3C4、3C6、4D4、1G9、5C8B9、3G6或4C8B9之融合瘤已公開寄存且描述於美國專利第6,159,508號中。相關融合瘤已公開寄存且描述於美國專利第6,107,090號中。此外,包括J591之人類化型式的人類化抗PSMA抗體進一步詳細描述於PCT公開案WO 02/098897中。
其他小鼠抗人類PSMA抗體已描述於此項技術中,諸如單株抗體107-1A4(Wang,S.等人(2001)Int.J.Cancer 92:871-876)及單株抗體2C9(Kato,K.等人(2003)Int.J.Urol.10:439-444)。
人類抗PSMA單株抗體之實例包括4A3、7F12、8C12、8A11、16F9、2A10、2C6、2F5及1C3抗體,如最初於PCT公開案WO 01/09192及WO 03/064606中及2005年2月18日申請之名為「Human Monoclonal Antibodies to Prostate Specific Membrane Antigen(PSMA)」的美國臨時申請案序列號60/654,125中所描述來分離且在結構上特徵化。VH胺基酸序列4A3、7F12、8C12、8A11、16F9、2A10、2C6、2F5及1C3分別展示於SEQ ID NO:1-9中。VL胺基酸序列4A3、7F12、8C12、8A11、16F9、2A10、2C6、2F5、及1C3分別展示於SEQ ID NO:10-18中。
其他人類抗PSMA抗體包括揭示於PCT公開案WO 03/034903及US申請案號2004/0033229中之抗體。
NW生物治療劑:選自由ATCC寄存編號為HB12060之3F5.4G6、ATCC寄存編號為HB12309之3D7-1.I.、ATCC寄存編號為HB12310之4E10-1.14、3E11(ATCC HB12488)、4D8(ATCC HB12487)、3E6(ATCC HB12486)、3C9(ATCC HB12484)、2C7(ATCC HB12490)、1G3(ATCC HB12489)、3C4(ATCC HB12494)、3C6(ATCC
HB12491)、4D4(ATCC HB12493)、1G9(ATCC HB12495)、5C8B9(ATCC HB12492)及3G6(ATCC HB12485)-參見US 6,150,508組成之群
PSMA Development Company/Progenics/Cytogen-Seattle Genetics:由以ATCC寄存編號PTA-3258寄存之融合瘤產生的單株抗體3.9或由以ATCC寄存編號PTA-3347寄存之融合瘤產生的單株抗體10.3-US 7850,971
PSMA Development Company-PSMA抗體之組合物(US 20080286284,表1)
本申請案為2003年3月21日申請之美國專利申請案序列號10/395,894之分案(US 7,850,971)
University Hospital Freiburg,Germany-單株抗體3/A12、3/E7及3/F11(WolfP.等人Prostate.2010年4月1日;70(5):562-9)。
Genbank寄存編號NM_001050
Genbank版本號NM_001050.2 GI:44890054
Genbank記錄更新日期:2012年8月19日下午01:37
Genbank寄存編號NP_001041
Genbank版本號NP_001041.1 GI:4557859
Genbank記錄更新日期:2012年8月19日下午01:37
Yamada Y.等人Proc.Natl.Acad.Sci.U.S.A.89(1),251-255(1992);Susini C.等人Ann Oncol.2006年12月;17(12):1733-42
正式符號:SSTR2
其他名稱:SRIF-1;SS2R;生長抑素受體型2
Genbank寄存編號D16827
Genbank版本號D16827.1 GI:487683
Genbank記錄更新日期:2006年8月1日下午12:45
Genbank寄存編號BAA04107
Genbank版本號BAA04107.1 GI:487684
Genbank記錄更新日期:2006年8月1日下午12:45
Yamada,Y.等人Biochem.Biophys.Res.Commun.195(2),844-852(1993)
正式符號:SSTR5
其他別名:SS-5-R
其他名稱:生長抑素受體次型5;生長抑素受體型5
Genbank寄存編號M14648 J02826 M18365
Genbank版本號M14648.1 GI:340306
Genbank記錄更新日期:2010年6月23日上午08:56
Genbank寄存編號AAA36808
Genbank版本號AAA36808.1 GI:340307
Genbank記錄更新日期:2010年6月23日上午08:56
Suzuki S.等人Proc.Natl.Acad.Sci.U.S.A.83(22),8614-8618(1986)
正式符號:ITGAV
其他別名:CD51、MSK8、VNRA、VTNR
其他名稱:由單株抗體L230鑑定之抗原;整合素αV;整合素αVβ3;整合素,αV(玻璃連結蛋白受體,α多肽,抗原CD51);玻璃連結蛋白受體次單元α
Genbank寄存編號NM_000888
Genbank版本號NM_000888.3 GI:9966771
Genbank記錄更新日期:2012年6月27日上午12:46
Genbank寄存編號NP_000879
Genbank版本號NP_000879.2 GI:9625002
Genbank記錄更新日期:2012年6月27日上午12:46
Sheppard D.J.等人Biol.Chem.265(20),11502-11507(1990)
正式符號:ITGB6
其他名稱:整合素β-6
Biogen:US 7,943,742-分別用ATCC寄存編號ATCC PTA-3649及ATCC PTA-3645寄存融合瘤純系6.3G9及6.8G6。
Biogen:US7,465,449-在一些實施例中,抗體包含與由融合瘤6.1A8、6.3G9、6.8G6、6.2B1、6.2B10、6.2A1、6.2E5、7.1G10、7.7G5或7.1C5產生之抗體相同的重鏈及輕鏈多肽序列。
Centocor(J&J):US7、550、142;US7,163,681
舉例而言,在US 7,550,142中-具有包含SEQ ID NO:7及SEQ ID NO:8中所展示之胺基酸序列的人類重鏈及人類輕鏈可變區之抗體。
Seattle Genetics:15H3(Ryan MC.等人Cancer Res 2012年4月15日;72(增刊8):4630)
Genbank寄存編號M17303
Genbank版本號M17303.1 GI:178676
基因銀行記錄更新日期:2010年6月23日上午08:47
Genbank寄存編號AAB59513
Genbank版本號AAB59513.1 GI:178677
基因銀行記錄更新日期:2010年6月23日上午08:47
Beauchemin N.等人Mol.Cell.Biol.7(9),3221-3230(1987)
正式符號:CEACAM5
其他別名:CD66e、CEA
其他名稱:胎糞抗原100
AstraZeneca-MedImmune:US 20100330103;US20080057063;US20020142359
- 例如具有互補決定區(CDR)之抗體,該等互補決定區具有以下序列:重鏈CDR1-DNYMH、CDR2-WIDPENGDTE YAPKFRG、CDR3-LIYAGYLAMD Y;及輕鏈CDR1-SASSSVTYMH、CDR2-STSNLAS、CDR3-QQRSTYPLT。
- 融合瘤806.077寄存為歐洲細胞培養物收集中心(ECACC)寄存編號96022936。
Research Corporation Technologies,Inc.:US5,047,507
Bayer Corporation:US6,013,772
BioAlliance:US7,982,017;US7,674,605
●US 7,674,605
- 包含來自SEQ ID NO:1之胺基酸序列的重鏈可變區序列及來自SEQ ID NO:2之胺基酸序列的輕鏈可變區序列之抗體。
- 包含來自SEQ ID NO:5之胺基酸序列的重鏈可變區序列及來自SEQ ID NO:6之胺基酸序列的輕鏈可變區序列之抗體。
Celltech Therapeutics Limited:US5,877,293
Dow Chemical Company:US5,472,693;US6,417,337;US6,333,405
US5,472,693-例如ATCC編號CRL-11215
US6,417,337-例如ATCC CRL-12208
US6,333,405-例如ATCC CRL-12208
Immunomedics,Inc:US7,534,431;US7,230,084;US7,300,644;
US6,730,300;US20110189085
- 具有輕鏈可變區之CDR的抗體包含:包含KASQDVGTSVA(SEQ ID NO:20)之CDR1;包含WTSTRHT(SEQ ID NO:21)之CDR2;及包含QQYSLYRS(SEQ ID NO:22)之CDR3;且該抗CEA抗體之重鏈可變區之CDR包含:包含TYWMS(SEQ ID NO:23)之CDR1;包含EIHPDSSTINYAPSLKD(SEQ ID NO:24)之CDR2;及包含LYFGFPWFAY(SEQ ID NO:25)之CDR3。
US20100221175;US20090092598;US20070202044;US20110064653;US20090185974;US20080069775。
Genbank寄存編號M35073
Genbank版本號M35073.1 GI:187553
Genbank記錄更新日期:2012年3月6日上午11:12
Genbank寄存編號AAA59589
Genbank版本號AAA59589.1 GI:553531
Genbank記錄更新日期:2012年3月6日上午11:12
Dean M.等人Nature 318(6044),385-388(1985)
正式符號:MET
其他別名:AUTS9、HGFR、RCCP2、c-Met
其他名稱:HGF受體;HGF/SF受體;SF受體;肝細胞生長因子受體;met原致癌基因酪胺酸激酶;原致癌基因c-Met;分散因子受
Abgenix/Pfizer:US20100040629
舉例而言,由美國菌種保存中心(ATCC)寄存編號為PTA-5026之融合瘤13.3.2產生的抗體;由ATCC寄存編號為PTA-5027之融合瘤9.1.2產生的抗體;由ATCC寄存編號為PTA-5028之融合瘤8.70.2產生的抗體;或由ATCC寄存編號為PTA-5029之融合瘤6.90.3產生的抗體。
Amgen/Pfizer:US20050054019
舉例而言,包含具有SEQ ID NO:2(其中X2為麩胺酸且X4為絲胺酸)中所列舉之胺基酸序列的重鏈及具有SEQ ID NO:4(其中X8為丙胺酸)中所列舉之胺基酸序列的輕鏈且不含訊號序列之抗體;包含具有SEQ ID NO:6中所列舉之胺基酸序列的重鏈及具有SEQ ID NO:8中所列舉之胺基酸序列的輕鏈且不含訊號序列之抗體;包含具有SEQ ID NO:10中所列舉之胺基酸序列的重鏈及具有SEQ ID NO:12中所列舉之胺基酸序列的輕鏈且不含訊號序列之抗體;或包含具有SEQ ID NO:14中所列舉之胺基酸序列的重鏈及具有SEQ ID NO:16中所列舉之胺基酸序列的輕鏈且不含訊號序列之抗體序。
Agouron Pharmaceuticals(現Pfizer):US20060035907
Eli Lilly:US20100129369
Genentech:US5,686,292;US20100028337;US20100016241;US20070129301;US20070098707;US20070092520、US20060270594;US20060134104;US20060035278;US20050233960;US20050037431
US 5,686,292-例如ATCC HB-11894及ATCC HB-11895
US 20100016241-例如ATCC HB-11894(融合瘤1A3.3.13)或HB-
11895(融合瘤5D5.11.6)
National Defense Medical Center,Taiwan:Lu RM.等人Biomaterials.2011年4月;32(12):3265-74。
Novartis:US20090175860
- 舉例而言,一種抗體,其包含重鏈4687之CDR1、CDR2及CDR3之序列的抗體,其中重鏈4687之CDR1、CDR2及CDR3之序列分別為SEQ ID NO:58的殘基26-35、50-65及98-102;及輕鏈5097之CDR1、CDR2及CDR3之序列,其中輕鏈5097之CDR1、CDR2及CDR3之序列為SEQ ID NO:37之殘基24-39、55-61及94-100。
Pharmacia Corporation:US20040166544
Pierre Fabre:US20110239316、US20110097262、US20100115639
Sumsung:US 20110129481-例如由寄存編號為KCLRF-BP-00219或寄存編號為KCLRF-BP-00223之融合瘤細胞產生的單株抗體。
Samsung:US 20110104176-例如由寄存編號為KCLRF-BP-00220之融合瘤細胞產生的抗體。
University of Turin Medical School:DN-30 Pacchiana G.等人J Biol Chem.2010年11月12日;285(46):36149-57
Van Andel Research Institute:Jiao Y.等人Mol Biotechnol.2005年9月;31(1):41-54。
Genbank寄存編號J05581
Genbank版本號J05581.1 GI:188869
Genbank記錄更新日期:2010年6月23日上午08:48
Genbank寄存編號AAA59876
Genbank版本號AAA59876.1 GI:188870
Genbank記錄更新日期:2010年6月23日上午08:48
Gendler S.J.等人J.Biol.Chem.265(25),15286-15293(1990)
正式符號:MUC1
其他別名:RP11-263K19.2、CD227、EMA、H23AG、KL-6、MAM6、MUC-1、MUC-1/SEC、MUC-1/X、MUC1/ZD、PEM、PEMT、PUM
其他名稱:DF3抗原;H23抗原;乳腺癌相關抗原DF3;癌相關黏蛋白;episialin;krebs von den Lungen-6;黏蛋白1,跨膜;黏蛋白-1;花生反應性泌尿黏蛋白;多形性上皮黏蛋白;腫瘤相關上皮黏蛋白;腫瘤相關上皮膜抗原;腫瘤相關黏蛋白
AltaRex-Quest Pharma Tech:US 6,716,966-例如由融合瘤ATCC編號PTA-975產生的Alt-1抗體。
AltaRex-Quest Pharma Tech:US7,147,850
CRT:5E5-Srensen AL.等人Glycobiology第16卷第2期第96-107頁,2006;HMFG2-Burchell J.等人Cancer Res.,47,5476-5482(1987)
Glycotope GT-MAB:GT-MAB 2.5-GEX(網站:http://www.glycotope.com/pipeline/pankomab-gex)
Immunogen:US7,202,346
- 舉例而言,抗體MJ-170:融合瘤細胞株MJ-170 ATCC寄存編號PTA-5286單株抗體MJ-171:融合瘤細胞株MJ-171 ATCC寄存編號PTA-5287;單株抗體MJ-172:融合瘤細胞株MJ-172 ATCC寄存編號PTA-5288;或單株抗體MJ-173:融合瘤細胞株MJ-173 ATCC寄存編號
PTA-5302
Immunomedics:US 6,653,104
Ramot Tel Aviv Uni:US7,897,351
Regents Uni.CA:US 7,183,388;US20040005647;US20030077676
Roche GlycArt:US8,021,856
Russian National Cancer Research Center:Imuteran-Ivanov PK.等人Biotechnol J.2007年7月;2(7):863-70
Technische Univ Braunschweig:(IIB6、HT186-B7、HT186-D11、HT186-G2、HT200-3A-C1、HT220-M-D1、HT220-M-G8)-Thie H.等人PLoS One.2011年1月14日;6(1):e15921
Genbank寄存編號X66839
Genbank版本號X66839.1 GI:1000701
Genbank記錄更新日期:2011年2月2日上午10:15
Genbank寄存編號CAA47315
Genbank版本號CAA47315.1 GI:1000702
Genbank記錄更新日期:2011年2月2日上午10:15
Pastorek J.等人Oncogene 9(10),2877-2888(1994)
正式符號:CA9
其他別名:CAIX、MN
其他名稱:CA-IX;P54/58N;RCC相關抗原G250;RCC相關蛋
白質G250;碳酸脫水酶IX;碳酸酐酶9;碳酸脫水酶;膜抗原MN;pMW1;腎細胞癌相關抗原G250
Abgenix/Amgen:US20040018198
親和抗體:抗CAIX親和抗體分子
(http://www.affibody.com/en/Product-Portfolio/Pipeline/)
Bayer:US7,462,696
Bayer/Morphosys:3ee9單株抗體-Petrul HM.等人Mol Cancer Ther.2012年2月;11(2):340-9
Harvard Medical School:抗體G10、G36、G37、G39、G45、G57、G106、G119、G6、G27、G40及G125。Xu C.等人PLoS One.2010年3月10日;5(3):e9625
Institute of Virology,Slovak Academy of Sciences(Bayer)-US5,955,075
- 舉例而言,M75-ATCC寄存編號HB 11128或MN12-ATCC寄存編號HB 11647
Institute of Virology,Slovak Academy of Sciences:US7,816,493
- 例如自融合瘤VU-M75分泌之M75單株抗體,融合瘤VU-M75以ATCC編號HB 11128寄存在美國菌種保存中心;或自融合瘤V/10-VU分泌之V/10單株抗體,融合瘤V/10-VU以寄存編號LMBP 6009CB寄存在位於Gent,Belgium之Universeit Gent的Laboratorium voor Moleculaire Bioloqie-Plasmidencollectie(LMBP)之International Depository Authority of the Belgian Coordinated Collection of Microorganisms(BCCM)。
Institute of Virology,Slovak Academy of Sciences US20080177046;US20080176310;US20080176258;US20050031623
Novartis:US20090252738
Wilex:US7,691,375-例如由融合瘤細胞株DSM ASC 2526產生的抗體。
Wilex:US20110123537;Rencarex:Kennett RH.等人Curr Opin Mol Ther.2003年2月;5(1):70-5
Xencor:US20090162382
Genbank寄存編號NM_201283
Genbank版本號NM_201283.1 GI:41327733
Genbank記錄更新日期:2012年9月30日下午01:47
Genbank寄存編號NP_958440
Genbank版本號NP_958440.1 GI:41327734
Genbank記錄更新日期:2012年9月30日下午01:47
Batra SK.等人Cell Growth Differ 1995;6:1251-1259。
US7,628,986及US7,736,644(Amgen)
舉例而言,選自由SEQ ID NO:142及變異體組成之群之重鏈可變區胺基酸序列以及選自由SEQ ID NO:144及變異體組成之群之輕鏈可變區胺基酸序列。
US20100111979(Amgen)
舉例而言,包含重鏈胺基酸序列之抗體,該重鏈胺基酸序列包含:由選自由抗體13.1.2(SEQ ID NO:138)、131(SEQ ID NO:2)、
170(SEQ ID NO:4)、150(SEQ ID NO:5)、095(SEQ ID NO:7)、250(SEQ ID NO:9)、139(SEQ ID NO:10)、211(SEQ ID NO:12)、124(SEQ ID NO:13)、318(SEQ ID NO:15)、342(SEQ ID NO:16)及333(SEQ ID NO:17)之CDR1區域的胺基酸序列組成之群之序列組成的CDR1;由選自由抗體13.1.2(SEQ ID NO:138)、131(SEQ ID NO:2)、170(SEQ ID NO:4)、150(SEQ ID NO:5)、095(SEQ ID NO:7)、250(SEQ ID NO:9)、139(SEQ ID NO:10)、211(SEQ ID NO:12)、124(SEQ ID NO:13)、318(SEQ ID NO:15)、342(SEQ ID NO:16)及333(SEQ ID NO:17)之CDR2區域的胺基酸序列組成之群之序列組成的CDR2;及由選自由抗體13.1.2(SEQ ID NO:138)、131(SEQ ID NO:2)、170(SEQ ID NO:4)、150(SEQ ID NO:5)、095(SEQ ID NO:7)、250(SEQ ID NO:9)、139(SEQ ID NO:10)、211(SEQ ID NO:12)、124(SEQ ID NO:13)、318(SEQ ID NO:15)、342(SEQ ID NO:16)及333(SEQ ID NO:17)之CDR3區域的胺基酸序列組成之群之序列組成的CDR3。
US20090240038(Amgen)
舉例而言,具有重鏈或輕鏈多肽中之至少一者的抗體包含與選自由以下各者組成之群之胺基酸序列至少90%一致之胺基酸序列:SEQ ID NO:2、SEQ ID NO:19、SEQ ID NO:142、SEQ ID NO:144及其任何組合。
US20090175887(Amgen)
舉例而言,具有選自由抗體13.1.2(SEQ ID NO:138)、131(SEQ ID NO:2)、170(SEQ ID NO:4)、150(SEQ ID NO:5)、095(SEQ ID NO:7)、250(SEQ ID NO:9)、139(SEQ ID NO:10)、211(SEQ ID
NO:12)、124(SEQ ID NO:13)、318(SEQ ID NO:15)、342(SEQ ID NO:16)及333(SEQ ID NO:17)之重鏈胺基酸序列組成之群之重鏈胺基酸序列的抗體。
US20090156790(Amgen)
舉例而言,具有重鏈多肽及輕鏈多肽之抗體,其中重鏈或輕鏈多肽中之至少一者包含與選自由以下各者組成之群之胺基酸序列至少90%一致的胺基酸序列:SEQ ID NO:2、SEQ ID NO:19、SEQ ID NO:142、SEQ ID NO:144及其任何組合。
US20090155282、US20050059087及US20050053608(Amgen)
舉例而言,選自由抗體13.1.2(SEQ ID NO:138)、131(SEQ ID NO:2)、170(SEQ ID NO:4)、150(SEQ ID NO:5)、095(SEQ ID NO:7)、250(SEQ ID NO:9)、139(SEQ ID NO:10)、211(SEQ ID NO:12)、124(SEQ ID NO:13)、318(SEQ ID NO:15)、342(SEQ ID NO:16)及333(SEQ ID NO:17)之重鏈胺基酸序列組成之群的抗體重鏈胺基酸序列。
MR1-1(US7,129,332;Duke)
舉例而言,具有SEQ ID NO 18之序列的變異體抗體,其在CDR3 VH中之S98P-T99Y及CDR3 VL中之F92W具有取代。
L8A4、H10、Y10(Wikstrand CJ.等人Cancer Res.1995年7月15日;55(14):3140-8;Duke)
US20090311803(Harvard University)
舉例而言,抗體重鏈可變區之SEQ ID NO:9及輕鏈可變區胺基酸序列之SEQ ID NO:3
US20070274991(EMD72000,亦稱為馬妥珠單抗(matuzumab);Harvard University)
舉例而言,輕鏈及重鏈各自之SEQ ID NO:3及9
US6,129,915(Schering)
舉例而言,SEQ.ID NO:1、2、3、4、5及6。
單株抗體CH12-Wang H.等人FASEB J.2012年1月;26(1):73-80(Shanghai Cancer Institute)。
RAbDMvIII-Gupta P.等人BMC Biotechnol.2010年10月7日;10:72(Stanford University Medical Center)。
單株抗體Ua30-Ohman L.等人Tumour Biol.2002年3月-4月;23(2):61-9(Uppsala University)。
Han DG.等人Nan Fang Yi Ke Da Xue Xue Bao.2010年1月;30(1):25-9(Xi'an Jiaotong University)。
Genbank寄存編號M_23197
Genbank版本號NM_23197.1 GI:180097
基因銀行記錄更新日期:2010年6月23日上午08:47
Genbank寄存編號AAA51948
Genbank版本號AAA51948.1 GI:188098
基因銀行記錄更新日期:2010年6月23日上午08:47
Simmons D.等人J.Immunol.141(8),2797-2800(1988)
正式符號:CD33
其他別名:SIGLEC-3、SIGLEC3、p67
其他名稱:CD33抗原(gp67);gp67;骨髓細胞表面抗原CD33;唾液酸結合Ig類凝集素3;唾液酸結合Ig類凝集素
H195(林妥珠單抗)-Raza A.等人Leuk Lymphoma.2009年8月;50(8):1336-44;US6,759,045(Seattle Genetics/Immunomedics)
單株抗體OKT9:Sutherland,D.R.等人Proc Natl Acad Sci USA 78(7):4515-45191981、Schneider,C.等人J Biol Chem 257,8516-8522(1982)
單株抗體E6:Hoogenboom,H.R.等人J Immunol 144,3211-3217(1990)
US 6,590,088(Human Genome Sciences)
舉例而言,SEQ ID NOs:1及2以及ATCC寄存編號97521
US7,557,189(Immunogen)
舉例而言,包含重鏈可變區及輕鏈可變區之抗體或其片段,該重鏈可變區包含三個具有SEQ ID NO:1-3之胺基酸序列CDR,該輕鏈可變區包含三個具有SEQ ID NO:4-6之胺基酸序列的CDR。
Genbank寄存編號NM_001178098
Genbank版本號NM_001178098.1 GI:296010920
Genbank記錄更新日期:2012年9月10日上午12:43
Genbank寄存編號NP_001171569
Genbank版本號NP_001171569.1 GI:296010921
Genbank記錄更新日期:2012年9月10日上午12:43
Tedder TF.等人J.Immunol.143(2):712-7(1989)
正式符號:CD19
其他別名:B4、CVID3
其他名稱:B淋巴細胞抗原CD19;B淋巴細胞表面抗原B4;T細胞表面抗原Leu-12;分化抗原CD19
Immunogen:HuB4-Al-Katib AM.等人Clin Cancer Res.2009年6月15日;15(12):4038-45。
4G7:Kügler M.等人Protein Eng Des Sel.2009年3月;22(3):135-47
舉例而言,Knappik,A.等人J Mol Biol 2000年2月;296(1):57-86之圖3中的序列
AstraZeneca/MedImmune:MEDI-551-Herbst R.等人J Pharmacol Exp Ther.2010年10月;335(1):213-22
Glenmark Pharmaceuticals:GBR-401-Hou S.等人Mol Cancer Ther 2011年11月10(會議摘要增刊)C164
US 7,109,304(Immunomedics)
舉例而言,包含hA19Vk(SEQ ID NO:7)之序列及hA19VH(SEQ ID NO:10)之序列的抗體
US 7,902,338(Immunomedics)
舉例而言,一種抗體或其抗原結合片段,其包含輕鏈互補決定區CDR序列SEQ ID NO:16(KASQSVDYDGDSYLN)之CDR1;SEQ ID NO:17(DASNLVS)之CDR2;及SEQ ID NO:18(QQSTEDPWT)之CDR3以及重鏈CDR序列SEQ ID NO:19(SYWMN)之CDR1;SEQ ID NO:20(QIWPGDGDTNYNGKFKG)之CDR2及SEQ ID NO:21(RETTTVGRYYYAMDY)之CDR3,且亦包含人類抗體構架(FR)及恆定區序列,其中一或多個構架區胺基酸殘基經母體鼠類抗體之對應構架區序列取代,且其中該等經取代FR殘基包含在重鏈可變區之Kabat殘
基91處用絲胺酸取代苯丙胺酸。
Medarex:MDX-1342-Cardarelli PM.等人Cancer Immunol Immunother.2010年2月;59(2):257-65。
MorphoSys/Xencor:MOR-208/XmAb-5574-Zalevsky J.等人Blood.2009年4月16日;113(16):3735-43
US 7,968,687(Seattle Genetics)
包含重鏈可變結構域及輕鏈可變結構域之抗體或抗原結合片段,該重鏈可變結構域包含SEQ ID NO:9之胺基酸序列,該輕鏈可變結構域包含SEQ ID NO:24之胺基酸序列。
4G7 chim-Lang P.等人Blood.2004年5月15日;103(10):3982-5(University of Tübingen)
舉例而言,US20120082664之圖6及SEQ ID No:80
Zhejiang University School of Medicine:2E8-Zhang J.等人J Drug Target.2010年11月;18(9):675-8
Genbank寄存編號NM_000417
Genbank版本號NM_000417.2 GI:269973860
Genbank記錄更新日期:2012年9月09日下午04:59
Genbank寄存編號NP_000408
Genbank版本號NP_000408.1 GI:4557667
Genbank記錄更新日期:2012年9月09日下午04:59
Kuziel W.A.等人J.Invest.Dermatol.94(6 SUPPL),27S-32S(1990)
正式符號:IL2RA
其他別名:RP11-536K7.1、CD25、IDDM10、IL2R、TCGFR
其他名稱:FIL-2受體次單元α;IL-2-RA;IL-2R次單元α;IL2-RA;TAC抗原;介白素-2受體次單元α;p55
US6,383,487(Novartis/UCL:Baxilisimab[Simulect])
US6,521,230(Novartis/UCL:Baxilisimab[Simulect])
舉例而言,具有抗原結合位點之抗體包含至少一個域,該域包含具有具有SEQ.ID.NO:7中之胺基酸序列的CDR1、具有SEQ.ID.NO:8中之胺基酸序列的CDR2及具有SEQ.ID.NO:9中之胺基酸序列的CDR3;或該等依序作為整體獲取之CDR1、CDR2及CDR3包含與依序作為整體獲取的SEQ.ID.NO:7、8及9至少90%一致之胺基酸序列。
Daclizumab-Rech AJ.等人Ann N Y Acad Sci.2009年9月;1174:99-106(Roche)
Genbank寄存編號M76125
Genbank版本號M76125.1 GI:292869
Genbank記錄更新日期:2010年6月23日上午08:53
Genbank寄存編號AAA61243
Genbank版本號AAA61243.1 GI:29870
Genbank記錄更新日期:2010年6月23日上午08:53
O'Bryan J.P.等人Mol.Cell.Biol.11(10),5016-5031(1991);Bergsagel P.L.等人J.Immunol.148(2),590-596(1992)
正式符號:AXL
其他別名:JTK11、UFO
其他名稱:AXL致癌基因;AXL轉型序列/基因;致癌基因AXL;酪胺酸蛋白激酶受體UFO
YW327.6S2-Ye X.等人Oncogene.2010年9月23日;29(38):5254-64(Genentech)。
BergenBio:BGB324(http://www.bergenbio.com/BGB324) (50) CD30-TNFRSF8(腫瘤壞死因子受體超家族,成員8)
Genbank寄存編號M83554
Genbank版本號M83554.1 GI:180095
Genbank記錄更新日期:2010年6月23日上午08:53
Genbank寄存編號AAA51947
Genbank版本號AAA51947.1 GI:180096
Genbank記錄更新日期:2010年6月23日上午08:53
Durkop H.等人Cell 68(3),421-427(1992)
正式符號:TNFRSF8
其他別名:CD30、D1S166E、Ki-1
其他名稱:CD30L受體;Ki-1抗原;細胞激素受體CD30;淋巴
細胞活化抗原CD30;腫瘤壞死因子受體超家族成員8
Genbank寄存編號Z29574
Genbank版本號Z29574.1 GI:471244
Genbank記錄更新日期:2011年2月02日上午10:40
Genbank寄存編號CAA82690
Genbank版本號CAA82690.1 GI:471245
Genbank記錄更新日期:2011年2月02日上午10:40
Laabi Y.等人Nucleic Acids Res.22(7),1147-1154(1994)
正式符號:TNFRSF17
其他別名:BCM、BCMA、CD269
其他名稱:B細胞成熟作用抗原;B細胞成熟作用因子;B細胞成熟作用蛋白質;腫瘤壞死因子受體超家族成員17
Fratta E.等人Mol Oncol.2011年4月;5(2):164-82;Lim SH.等人Am J Blood Res.2012;2(1):29-35。
Genbank寄存編號NM000149
Genbank版本號NM000149.3 GI:148277008
Genbank記錄更新日期:2012年6月26日下午04:49
Genbank寄存編號NP_000140
Genbank版本號NP_000140.1 GI:4503809
Genbank記錄更新日期:2012年6月26日下午04:49
Kukowska-Latallo,J.F.等人Genes Dev.4(8),1288-1303(1990)
正式符號:FUT3
其他別名:CD174、FT3B、FucT-III、LE、Les
其他名稱:Lewis FT;α(1,3/1,4)-海藻糖基轉移酶;Lewis血型α-4-海藻糖基轉移酶;海藻糖基轉移酶III;半乳糖苷3(4)-L-海藻糖基轉移酶
Genbank寄存編號NM175060
Genbank版本號NM175060.2 GI:371123930
Genbank記錄更新日期:2012年4月01日下午03:34
Genbank寄存編號NP_778230
Genbank版本號NP_778230.1 GI:28269707
Genbank記錄更新日期:2012年4月01日下午03:34
正式符號:CLEC14A
其他別名:UNQ236/PRO269、C14orf27、CEG1、EGFR-5
其他名稱:C型凝集素域家族14成員A;含有蛋白質之C1ECT及EGF類域;表皮生長因子受體5
Genbank寄存編號NM005347
Genbank版本號NM005347.4 GI:305855105
Genbank記錄更新日期:2012年9月30日下午01:42
Genbank寄存編號NP_005338
Genbank版本號NP_005338.1 GI:16507237
Genbank記錄更新日期:2012年9月30日下午01:42
Ting J.等人DNA 7(4),275-286(1988)
正式符號:HSPA5
其他別名:BIP、GRP78、MIF2
其他名稱:78kDa葡萄糖調節蛋白質;內質網腔Ca(2+)-結合蛋白grp78;免疫球蛋白重鏈結合蛋白
Genbank寄存編號L08096
Genbank版本號L08096.1 GI:307127
Genbank記錄更新日期:2012年6月23日上午08:54
Genbank寄存編號AAA36175
Genbank版本號AAA36175.1 GI:307128
Genbank記錄更新日期:2012年6月23日上午08:54
Goodwin R.G.等人Cell 73(3),447-456(1993)
正式符號:CD70
其他別名:CD27L、CD27LG、TNFSF7
其他名稱:CD27配位體;CD27-L;CD70抗原;Ki-24抗原;表面抗原CD70;腫瘤壞死因子(配位體)超家族,成員7;腫瘤壞死因子配位體超家族成員7
MDX-1411對抗CD70(Medarex)
h1F6(Oflazoglu,E.等人Clin Cancer Res.2008年10月1日;14(19):6171-80;Seattle Genetics)
舉例而言,參見US20060083736 SEQ ID NO:1、2、11及12以及圖1。
●5T4(參見下文第(63)項)
●CD25(參見上文第(48)項)
●CD32
○多肽
■Genbank寄存編號ABK42161
■Genbank版本號ABK42161.1 GI:117616286
■Genbank記錄更新日期:2007年7月25日下午03:00
●LGR5/GPR49
○核苷酸
■Genbank寄存編號NM_003667
■Genbank版本號NM_003667.2 GI:24475886
■Genbank記錄更新日期:2012年7月22日下午03:38
○多肽
■Genbank寄存編號NP_003658
■Genbank版本號NP_003658.1 GI:4504379
■Genbank記錄更新日期:2012年7月22日下午03:38
●Prominin/CD133
○核苷酸
■Genbank寄存編號NM_006017
■Genbank版本號NM_006017.2 GI:224994187
■Genbank記錄更新日期:2012年9月30日下午01:47
○多肽
■Genbank寄存編號NP_006008
■Genbank版本號NP_006008.1 GI:5174387
■Genbank記錄更新日期:2012年9月30日下午01:47
(Smith L.M.等人AACR 2010 Annual Meeting(摘要2590號);Gudas J.M.等人AACR 2010 Annual Meeting(摘要4393號)
抗AGS-5抗體:M6.131(Smith,L.M.等人AACR 2010 Annual Meeting(摘要2590號)
Genbank寄存編號AF005632
Genbank版本號AF005632.2 GI:4432589
Genbank記錄更新日期:2010年3月10日下午09:41
Genbank寄存編號AAC51813
Genbank版本號AAC51813.1 GI:2465540
Genbank記錄更新日期:2010年3月10日下午09:41
Jin-Hua P.等人Genomics 45(2),412-415(1997)
正式符號:ENPP3
其他別名:RP5-988G15.3、B10、CD203c、NPP3、PD-IBETA、PDNP3
其他名稱:E-NPP 3;dJ1005H11.3(磷酸二酯酶I/核苷酸焦磷酸酶3);dJ914N13.3(磷酸二酯酶I/核苷酸焦磷酸酶3);外核苷酸焦磷酸酶/磷酸二酯酶家族成員3;gp130RB13-6;磷酸二酯酶Iβ;磷酸二酯酶I/核苷酸焦磷酸酶3;磷酸二酯酶-Iβ
Genbank寄存編號NM_007244
Genbank版本號NM_007244.2 GI:154448885
Genbank記錄更新日期:2012年6月28日下午12:39
Genbank寄存編號NP_009175
Genbank版本號NP_009175.2 GI:154448886
Genbank記錄更新日期:2012年6月28日下午12:39
Dickinson D.P.等人Invest.Ophthalmol.Vis.Sci.36(10),2020-2031(1995)
正式符號:PRR4
其他別名:LPRP、PROL4
其他名稱:淚液富脯胺酸蛋白質;鼻咽癌相關富脯胺酸蛋白質4;富脯胺酸多肽4;富脯胺酸蛋白質4
Genbank寄存編號NM_004963
Genbank版本號NM_004963.3 GI:222080082
Genbank記錄更新日期:2012年9月02日下午01:50
Genbank寄存編號NP_004954
Genbank版本號NP_004954.2 GI:222080083
Genbank記錄更新日期:2012年9月02日下午01:50
De Sauvage F.J.等人J.Biol.Chem.266(27),17912-17918(1991);Singh S.等人Biochem.Biophys.Res.Commun.179(3),1455-1463(1991)
正式符號:GUCY2C
其他別名:DIAR6、GUC2C、MUCIL、STAR
其他名稱:GC-C;STA受體;鳥苷酸環化酶C;hSTAR;熱穩定腸毒素受體;腸道鳥苷酸環化酶
Genbank寄存編號U41060
Genbank版本號U41060.2 GI:12711792
Genbank記錄更新日期:2009年11月30日下午04:35
Genbank寄存編號AAA96258
Genbank版本號AAA96258.2 GI:12711793
Genbank記錄更新日期:2009年11月30日下午04:35
Taylor KM.等人Biochim Biophys Acta.2003年4月1日;1611(1-2):16-30
正式符號:SLC39A6
其他別名:LIV-1
其他名稱:LIV-1蛋白質,雌激素調節;ZIP-6;雌激素調節蛋白質LIV-1;溶質載劑家族39(金屬離子轉運體),成員6;溶質載劑家族39成員6;鋅轉運體ZIP6;zrt類及Irt類蛋白質6
Genbank寄存編號AJ012159
Genbank版本號AJ012159.1 GI:3805946
Genbank記錄更新日期:2011年2月01日上午10:27
Genbank寄存編號CAA09930
Genbank版本號CAA09930.1 GI:3805947
Genbank記錄更新日期:2011年2月01日上午10:27
King K.W.等人Biochim.Biophys.Acta 1445(3),257-270(1999)
●正式符號:TPBG
●其他別名:5T4、5T4AG、M6P1
●其他名稱:5T4癌胚抗原;5T4癌胚滋養層醣蛋白;5T4癌滋養
Genbank寄存編號NM_000615
Genbank版本號NM_000615.6 GI:336285433
Genbank記錄更新日期:2012年9月23日下午02:32
Genbank寄存編號NP_000606
Genbank版本號NP_000606.3 GI:94420689
Genbank記錄更新日期:2012年9月23日下午02:32
Dickson,G.等人Cell 50(7),1119-1130(1987)
正式符號:NCAM1
其他別名:CD56、MSK39、NCAM
其他名稱:由單株抗體5.1H11識別之抗原;神經細胞黏附分子,NCAM
Immunogen:HuN901(Smith SV.等人Curr Opin Mol Ther.2005年8
月;7(4):394-401)
舉例而言,參見自鼠類N901抗體人類化。參見Roguska,M.A.等人Proc Natl Sci USA 1994年2月;91:969-973之圖1b及圖1e。
Haglund C.等人Br J Cancer 60:845-851,1989;Baeckstrom D.等人J Biol Chem 266:21537-21547,1991
huC242(Tolcher AW等人,J Clin Oncol.20031月15日;21(2):211-22;Immunogen)
舉例而言,參見US20080138898A1 SEQ ID NO:1及2
Genbank寄存編號J05013
Genbank版本號J05013.1 GI:182417
Genbank記錄更新日期:2010年6月23日上午08:47
Genbank寄存編號AAA35823
Genbank版本號AAA35823.1 GI:182418
Genbank記錄更新日期:2010年6月23日上午08:47
Elwood P.C.等人J.Biol.Chem.264(25),14893-14901(1989)
正式符號:FOLR1
其他別名:FBP、FOLR
其他名稱:FR-α;KB細胞FBP;成年葉酸結合蛋白;葉酸結合
蛋白;葉酸受體α;葉酸受體,成年;卵巢腫瘤相關抗原MOv18
M9346A-Whiteman KR.等人Cancer Res 2012年4月15日;72(增刊8):4628(Immunogen)
Genbank寄存編號X76534
Genbank版本號X76534.1 GI:666042
Genbank記錄更新日期:2011年2月02日上午10:10
Genbank寄存編號CAA54044
Genbank版本號CAA54044.1 GI:666043
Genbank記錄更新日期:2011年2月02日上午10:10
Weterman M.A.等人Int.J.Cancer 60(1),73-81(1995)
正式符號:GPNMB
其他別名:UNQ1725/PRO9925、HGFIN、NMB
其他名稱:醣蛋白NMB;醣蛋白nmb類蛋白質;骨活素(osteoactivin);跨膜醣蛋白HGFIN;跨膜醣蛋白NMB
Celldex Therapeutics:CR011(Tse KF.等人Clin Cancer Res.2006年2月15日;12(4):1373-82)
舉例而言,參見EP1827492B1 SEQ ID NO:22、24、26、31、33及35
Genbank寄存編號AF043724
Genbank版本號AF043724.1 GI:2827453
Genbank記錄更新日期:2010年3月10日下午06:24
Genbank寄存編號AAC39862
Genbank版本號AAC39862.1 GI:2827454
Genbank記錄更新日期:2010年3月10日下午06:24
Feigelstock D.等人J.Virol.72(8),6621-6628(1998)
正式符號:HAVCR1
其他別名:HAVCR、HAVCR-1、KIM-1、KIM1、TIM、TIM-1、TIM1、TIMD-1、TIMD1
其他名稱:T細胞免疫球蛋白域及黏蛋白域蛋白質1;T細胞膜蛋白質1;腎臟損傷分子1
Parry R.等人Cancer Res.2005年9月15日;65(18):8397-405
Genbank寄存編號BX648021
Genbank版本號BX648021.1 GI:34367180
Genbank記錄更新日期:2011年2月02日上午08:40
Sica GL.等人Immunity.2003年6月;18(6):849-61
正式符號:VTCN1
其他別名:RP11-229A19.4、B7-H4、B7H4、B7S1、B7X、B7h.5、PRO1291、VCTN1
其他名稱:B7家族成員,H4;B7超家族成員1;T細胞共刺激分子B7x;T-細胞共刺激分子B7x;含有T細胞活化抑制劑1之V定域;免疫共刺激蛋白質B7-H4
Genbank寄存編號AF447176
Genbank版本號AF447176.1 GI:17432420
Genbank記錄更新日期:2008年11月28日下午01:51
Genbank寄存編號AAL39062
Genbank版本號AAL39062.1 GI:17432421
Genbank記錄更新日期:2008年11月28日下午01:51
Park S.K.等人J.Biochem.119(2),235-239(1996)
正式符號:PTK7
其他別名:CCK-4、CCK4
其他名稱:結腸癌激酶4;非活性的酪胺酸蛋白激酶7;擬酪胺酸激酶受體7;類酪胺酸蛋白激酶7
Genbank寄存編號NM_001040031
Genbank版本號NM_001040031.1 GI:91807109
Genbank記錄更新日期:2012年7月29日下午02:08
Genbank寄存編號NP_001035120
Genbank版本號NP_001035120.1 GI:91807110
Genbank記錄更新日期:2012年7月29日下午02:08
Schwartz-Albiez R.等人J.Immunol.140(3),905-914(1988)
正式符號:CD37
其他別名:GP52-40、TSPAN26
其他名稱:CD37抗原;細胞分化抗原37;白細胞抗原CD37;白細胞表面抗原CD37;四跨膜蛋白26;tspan-26
Boehringer Ingelheim:單株抗體37.1(Heider KH.等人Blood.2011年10月13日;118(15):4159-68)
Trubion:CD37-SMIP(G28-1 scFv-Ig)(Zhao X.等人Blood.2007;110:2569-2577)
舉例而言,參見US20110171208A1 SEQ ID NO:253
Immunogen:K7153A(Deckert J.等人Cancer Res 2012年4月15日;72(增刊8):4625)
Genbank寄存編號AJ551176
Genbank版本號AJ551176.1 GI:29243141
Genbank記錄更新日期:2011年2月01日下午12:09
Genbank寄存編號CAD80245
Genbank版本號CAD80245.1 GI:29243142
Genbank記錄更新日期:2011年2月01日下午12:09
O'Connell FP.等人Am J Clin Pathol.2004年2月;121(2):254-63
正式符號:SDC1
其他別名:CD138、SDC、SYND1、多配體蛋白聚糖
其他名稱:CD138抗原;乙醯肝素硫酸蛋白聚糖纖維母細胞生長因子受體;多配體蛋白聚糖蛋白聚糖1;多配體蛋白聚糖-1
Biotest:嵌合單株抗體(nBT062)-(Jagannath S.等人Poster ASH 3060號,2010;WIPO專利申請案WO/2010/128087)
舉例而言,參見US20090232810 SEQ ID NO:1及2
Immunogen:B-B4(Tassone P.等人Blood 104_3688-3696)
舉例而言,參見US20090175863A1 SEQ ID NO:1及2
Genbank寄存編號NM_004355
Genbank版本號NM_004355.1 GI:343403784
Genbank記錄更新日期:2012年9月23日下午02:30
Genbank寄存編號NP_004346
Genbank版本號NP_004346.1 GI:10835071
Genbank記錄更新日期:2012年9月23日下午02:30
Kudo,J.等人Nucleic Acids Res.13(24),8827-8841(1985)
正式符號:CD74
其他別名:DHLAG、HLADG、II、Ia-GAMMA
其他名稱:CD74抗原(主要組織相容複合體之恆定多肽,第II類抗原相關);HLA第II類組織相容抗原γ鏈;HLA-DR抗原相關恆定鏈;HLA-DR-γ;Ia相關恆定鏈;MHC HLA-DRγ鏈;第II類抗原之γ鏈;p33抗體
Immunomedics:hLL1(米拉珠單抗(Milatuzumab))-Berkova Z.等人Expert Opin Investig Drugs.2010年1月;19(1):141-9)
舉例而言,參見US20040115193 SEQ ID NO:19、20、21、22、23及24
Genmab:HuMax-CD74(參見網站)
Offner S.等人Cancer Immunol Immnnother.2005年5月;54(5):431-45、Suzuki H.等人Ann N Y Acad Sci.2012年7月;1258:65-70)
在人類中,已描述該家族之24個成員-參見參考文獻。
Genbank寄存編號NM_005228
Genbank版本號NM_005228.3 GI:41927737
Genbank記錄更新日期:2012年9月30日下午01:47
Genbank寄存編號NP_005219
Genbank版本號NP_005219.2 GI:29725609
Genbank記錄更新日期:2012年9月30日下午01:47
Dhomen NS.等人Crit Rev Oncog.2012;17(1):31-50
正式符號:EGFR
其他別名:ERBB、ERBB1、HER1、PIG61、mENA
其他名稱:禽類有核紅血球白血病病毒(v-erb-b)致癌基因同源物;細胞生長抑制蛋白質40;細胞增生誘發蛋白質61;原致癌基因c-ErbB-1;受體酪胺酸蛋白激酶erbB-1
BMS:西妥昔單抗(Cetuximab)(愛必妥(Erbitux))-Broadbridge VT.等人Expert Rev Anticancer Ther.2012年5月;12(5):555-65。
舉例而言,參見US6217866-ATTC寄存編號9764。
Amgen:帕尼單抗(Panitumumab)(維克替比(Vectibix))-Argiles G.等人Future Oncol.2012年4月;8(4):373-89
舉例而言,參見US6235883 SEQ ID NO:23-38。
Genmab:紮魯姆單抗(Zalutumumab)-Rivera F.等人Expert Opin Biol Ther.2009年5月;9(5):667-74。
YM Biosciences:尼妥珠單抗(Nimotuzumab)-Ramakrishnan MS.等人MAbs.2009年1月-2月;1(1):41-8。
舉例而言,參見US5891996 SEQ ID NO:27-34。
Genbank寄存編號M34309
Genbank版本號M34309.1 GI:183990
Genbank記錄更新日期:2010年6月23日下午08:47
Genbank寄存編號AAA35979
Genbank版本號AAA35979.1 GI:306841
Genbank記錄更新日期:2010年6月23日下午08:47
Plowman,G.D.等人,Proc.Natl.Acad.Sci.U.S.A.87(13),4905-4909(1990)
正式符號:ERBB3
其他別名:ErbB-3、HER3、LCCS2、MDA-BF-1、c-erbB-3、c-erbB3、erbB3-S、p180-ErbB3、p45-sErbB3、p85-sErbB3
其他名稱:原致癌基因類蛋白質c-ErbB-3;受體酪胺酸-蛋白激酶erbB-3;酪胺酸激酶型細胞表面受體HER3
Merimack Pharma:MM-121(Schoeberl B.等人Cancer Res.2010年3月15日;70(6):2485-2494)
舉例而言,參見US2011028129 SEQ ID NO:1、2、3、4、5、6、7及8。
Genbank寄存編號X70040
Genbank版本號X70040.1 GI:36109
Genbank記錄更新日期:2011年2月02日下午10:17
Genbank寄存編號CCA49634
Genbank版本號CCA49634.1 GI:36110
Genbank記錄更新日期:2011年2月02日下午10:17
Ronsin C.等人Oncogene 8(5),1195-1202(1993)
正式符號:MST1R
其他別名:CD136、CDw136、PTK8、RON
其他名稱:MSP受體;MST1R變異體RON30;MST1R變異體RON62;PTK8蛋白質酪胺酸激酶8;RON變異體E2E3;c-met相關酪胺酸激酶;巨噬細胞刺激蛋白質受體;p185-Ron;可溶性RON變異體1;可溶性RON變異體2;可溶性RON變異體3;可溶性RON變異體4 (79) EPHA2(EPH受體A2)
Genbank寄存編號BC037166
Genbank版本號BC037166.2 GI:33879863
Genbank記錄更新日期:2012年3月06日下午01:59
Genbank寄存編號AAH37166
Genbank版本號AAH37166.1 GI:22713539
Genbank記錄更新日期:2012年3月06日下午01:59
StrausbergR.L.等人Proc.Natl.Acad.Sci.U.S.A.99(26),16899-16903(2002)
正式符號:EPHA2
其他別名:ARCC2、CTPA、CTPP1、ECK
其他名稱:ephrin型-受體A2;上皮細胞受體蛋白質酪胺酸激酶;可溶性EPHA2變異體1;酪胺酸蛋白激酶受體ECK
Medimmune:1C1(Lee JW.等人Clin Cancer Res.2010年5月1日;16(9):2562-2570)
舉例而言,參見US20090304721A1圖7及8。
Genbank寄存編號M27394
Genbank版本號M27394.1 GI:179307
Genbank記錄更新日期:2009年11月30日上午11:16
Genbank寄存編號AAA35581
Genbank版本號AAA35581.1 GI:179308
Genbank記錄更新日期:2009年11月30日上午11:16
Tedder T.F.等人Proc.Natl.Acad.Sci.U.S.A.85(1),208-212(1988)
正式符號:MS4A1
其他別名:B1、Bp35、CD20、CVID5、LEU-16、MS4A2、S7
其他名稱:B淋巴細胞抗原CD20;B淋巴細胞細胞表面抗原B1;CD20抗原;CD20受體;白細胞表面抗原Leu-16
Genentech/Roche:利妥昔單抗(Rituximab)-Abdulla NE.等人BioDrugs.2012年4月1日;26(2):71-82。
舉例而言,參見US5736137,ATCC寄存編號HB-69119。
GSK/Genmab:奧伐組單抗(Ofatumumab)-Nightingale G.等人Ann Pharmacother.2011年10月;45(10):1248-55。
舉例而言,參見US20090169550A1 SEQ ID NO:2、4及5。
Immunomedics:維妥珠單抗(Veltuzumab)-Goldenberg DM.等人Leuk Lymphoma.2010年5月;51(5):747-55。
舉例而言,參見US7919273B2 SEQ ID NO:1、2、3、4、5及6。
Genbank寄存編號NM_002160
Genbank版本號NM_002160.3 GI:340745336
Genbank記錄更新日期:2012年9月23日下午02:33
Genbank寄存編號NP_002151
Genbank版本號NP_002151.2 GI:153946395
Genbank記錄更新日期:2012年9月23日下午02:33
Nies D.E.等人J.Biol.Chem.266(5),2818-2823(1991);Siri A.等人Nucleic Acids Res.19(3),525-531(1991)
正式符號:TNC
其他別名:150-225、GMEM、GP、HXB、JI、TN、TN-C
其他名稱:GP 150-225;肌腱抗原(cytotactin);神經膠瘤相關細胞外基體抗原;腱生蛋白(hexabrachion)(生腱蛋白);肌腱
(myotendinous)抗原;神經黏連蛋白(neuronectin);生腱蛋白;生腱蛋白-C同功異型物14/AD1/16
Philogen:G11(von Lukowicz T.等人J Nucl Med.2007年4月;48(4):582-7)及F16(Pedretti M.等人Lung Cancer.2009年4月;64(1):28-33)
舉例而言,參見US7968685 SEQ ID NO:29、35、45及47。
Genbank寄存編號U09278
Genbank版本號U09278.1 GI:1888315
Genbank記錄更新日期:2010年6月23日上午09:22
Genbank寄存編號AAB49652
Genbank版本號AAB49652.1 GI:1888316
Genbank記錄更新日期:2010年6月23日上午09:22
Scanlan,M.J.等人Proc.Natl.Acad.Sci.U.S.A.91(12),5657-5661(1994)
正式符號:FAP
其他別名:DPPIV、FAPA
其他名稱:170kDa黑素瘤膜結合明膠酶;整體膜絲胺酸蛋白酶;表面表達蛋白酶(seprase)
Genbank寄存編號NM_012242
Genbank版本號NM_012242.2 GI:61676924
Genbank記錄更新日期:2012年9月30日下午01:48
Genbank寄存編號NP_036374
Genbank版本號NP_036374.1 GI:7110719
Genbank記錄更新日期:2012年9月30日下午01:48
Fedi P.等人J.Biol.Chem.274(27),19465-19472(1999)
正式符號:DKK1
其他別名:UNQ492/PRO1008、DKK-1、SK
其他名稱:dickkopf相關蛋白質1;dickkopf-1類;dickkopf類蛋白質1;dickkopf相關蛋白質1;hDkk-1
Novartis:BHQ880(Fulciniti M.等人Blood.20097月9日;114(2):371-379)
舉例而言,參見US20120052070A1 SEQ ID NO:100及108。
Genbank寄存編號NM_001803
Genbank版本號NM_001803.2 GI:68342029
Genbank記錄更新日期:2012年9月30日下午01:48
Genbank寄存編號NP_001794
Genbank版本號NP_001794.2 GI:68342030
Genbank記錄更新日期:2012年9月30日下午01:48
Xia M.Q.等人Eur.J.Immunol.21(7),1677-1684(1991)
正式符號:CD52
其他別名:CDW52
其他名稱:坎帕斯(CAMPATH)-1抗原;CD52抗原(坎帕斯-1抗原);CDW52抗原(坎帕斯-1抗原);劍橋病理學1抗原;附睾分泌蛋白E5;he5;人類附睾特異性蛋白質5
阿侖單抗(Alemtuzumab)(坎帕斯)-Skoetz N.等人Cochrane Database Syst Rev.2012年2月15日;2:CD008078。
舉例而言,參見Drugbank寄存編號DB00087(BIOD00109,BTD00109)
Genbank寄存編號NM_021181
Genbank版本號NM_021181.3 GI:1993571
Genbank記錄更新日期:2012年6月29日上午11:24
Genbank寄存編號NP_067004
Genbank版本號NP_067004.3 GI:19923572
Genbank記錄更新日期:2012年6月29日上午11:24
Boles K.S.等人Immunogenetics 52(3-4),302-307(2001)
正式符號:SLAMF7
其他別名:UNQ576/PRO1138、19A、CD319、CRACC、CS1
其他名稱:19A24蛋白質;CD2子組1;CD2類受體活化細胞毒性細胞;CD2類受體-活化細胞毒性細胞;膜蛋白質FOAP-12;新穎LY9(淋巴細胞抗原9)類蛋白質;蛋白質19A
BMS:elotuzumab/HuLuc63(Benson DM.等人J Clin Oncol.2012年6月1日;30(16):2013-2015)
舉例而言,參見US20110206701 SEQ ID NO:9、10、11、12、13、14、15及16。
Genbank寄存編號AF035753
Genbank版本號AF035753.1 GI:3452260
Genbank記錄更新日期:2010年3月10日下午06:36
Genbank寄存編號AAC32802
Genbank版本號AAC32802.1 GI:3452261
Genbank記錄更新日期:2010年3月10日下午06:36
Rius C.等人Blood 92(12),4677-4690(1998)
正式符號:ENG
其他別名:RP11-228B15.2、CD105、END、HHT1、ORW、ORW1
其他名稱:CD105抗原
Genbank寄存編號X05908
Genbank版本號X05908.1 GI:34387
Genbank記錄更新日期:2011年2月02日上午10:02
Genbank寄存編號CCA29338
Genbank版本號CCA29338.1 GI:34388
Genbank記錄更新日期:2011年2月02日上午10:02
Wa11ner B.P.等人Nature 320(6057),77-81(1986)
正式符號:ANXA1
其他別名:RP11-71A24.1、ANX1、LPC1
其他名稱:膜聯蛋白I(脂皮質素I);膜聯蛋白-1;依鈣蛋白II;依鈣蛋白-2;嗜鉻粒結合蛋白-9;脂皮質素I;p35;磷脂酶A2抑制蛋白質
Genbank寄存編號M60335
Genbank版本號M60335.1 GI:340193
Genbank記錄更新日期:2010年6月23日上午08:56
Genbank寄存編號AAA61269
Genbank版本號AAA61269.1 GI:340194
Genbank記錄更新日期:2010年6月23日上午08:56
Hession C.等人J.Biol.Chem.266(11),6682-6685(1991)
正式符號:VCAM1
其他別名:CD106、INCAM-100
其他名稱:CD106抗原;血管細胞黏附蛋白質1
抗整合素αvβ6
親本抗體亦可為包含白蛋白結合肽(ABP)序列之融合蛋白質(Dennis等人(2002)「Albumin Binding As A General Strategy For Improving The Pharmacokinetics Of Proteins」J Biol Chem.277:35035-35043;WO 01/45746)。本發明抗體包括藉以下各者教示之具有ABP序列之融合蛋白質:(i)Dennis等人(2002)J Biol Chem.277:35035-35043第35038頁表III及表IV處;(ii)US 2004/0001827[0076]處;及(iii)WO 01/45746第12-13頁處,且其全部以引用之方式併入本文中。
在一個實施例中,已培養抗體以靶向特異性腫瘤相關抗原αvβ6。
可標記細胞結合劑(例如)以有助於在併入為結合物或併入為結合物之部分之前偵測或純化試劑。標記可為生物素標記。在另一實施例中,可用放射性同位素標記細胞結合劑。
本發明之實施例包括ConjA,其中細胞結合劑係選自如上文所述之抗原中的任一者之抗體。
本發明之實施例包括ConjB,其中細胞結合劑係選自如上文所述之抗原中的任一者的抗體。
本發明之實施例包括ConjCD,其中細胞結合劑係選自如上文所述之抗原中的任一者之抗體。
本發明之實施例包括ConjA,其中細胞結合劑係選自如上文所述之抗體中之任一者。
本發明之實施例包括ConjB,其中細胞結合劑係選自如上文所述之抗體中之任一者。
本發明之實施例包括ConjCD,其中細胞結合劑係選自如上文所述之抗體中之任一者。
本發明亦可關於結合物,其中細胞結合劑係選自如上文所述之抗原中之任一者的抗體且如上文所述之抗體中之任一者連接至不同藥物。
藥物負載量為PBD藥物/細胞結合劑(例如抗體)之平均數量。其中使本發明之化合物結合至半胱胺酸,藥物負載量可在1至8藥物(D)/細胞結合劑範圍內,亦即其中使1、2、3、4、5、6、7及8個藥物部分共價附著至細胞結合劑。結合物之組合物包括與1至8個一系列藥物結合之細胞結合劑(例如抗體)之集合。其中將本發明之化合物結合至離胺酸,藥物負載量可在1至80藥物(D)/細胞結合劑範圍內,但40、20、10或8之上限可為較佳的。結合物之組合物包括與1至80、1至40、1至20、1至10或1至8個一系列藥物結合之細胞結合劑(例如抗體)之集合。
可藉由諸如UV、逆相HPLC、HIC、質譜、ELISA分析及電泳之習知方式來表徵來自結合反應之ADC製劑中的藥物/抗體之平均數量。亦可測定折合為p之ADC之定量分佈。藉由ELISA可測定ADC之特定製備中之p之平均值(Hamblett等人(2004)Clin.Cancer Res.10:7063-7070;Sanderson等人(2005)Clin.Cancer Res.11:843-852)。然而,p(藥物)值之分佈因抗體-抗原結合及ELISA之偵測限制而不可辯別。此外,用於抗體-藥物結合物之偵測的ELISA分析並不測定藥物部分在何處(諸如重鏈或輕鏈片段或特定胺基酸殘基)附著至抗體。在一些情況下,可藉由諸如逆相HPLC或電泳之方式來實現p為一定值之
均質ADC與具有其他藥物負載的ADC之分離、純化及表徵。此類技術亦適用於其它類型的結合物。
對於一些抗體-藥物結合物,可藉由抗體上之附著位點之數量來限制p。舉例而言,抗體可具有僅僅一個或若干個半胱胺酸巰基或可具有僅僅一個或若干個充分反應性巰基,經由巰基可附著連接子。更高藥物負載量(例如p>5)可導致某些抗體-藥物結合物之聚集、不可溶性、毒性或細胞滲透性之缺失。
通常,在結合反應期間使少於理論最大值之藥物部分結合至抗體。抗體可含有(例如)許多不與藥物-連接子中間產物(D-L)或連接子試劑反應的離胺酸殘基。僅僅最具反應性的離胺酸基團可與胺反應性連接子試劑反應。此外,僅僅最具反應性的半胱胺酸巰基可與巰基反應性連接子試劑反應。一般而言,抗體並不含有許多(若存在)可連接至藥物部分的游離及反應性半胱胺酸巰基。化合物之抗體中的大多數半胱胺酸巰基殘基以二硫橋鍵之形式存在且必須在部分或完全還原條件下使用諸如二硫蘇糖醇(DTT)或TCEP之還原劑來還原。可以若干不同方式控制ADC之負載量(藥物/抗體比率),包括:(i)限制藥物-連接子中間產物(D-L)或連接子試劑相對於抗體之莫耳過量,(ii)限制結合反應時間或溫度,及(iii)半胱胺酸巰基修飾之部分或限制性還原條件。
某些抗體具有可還原鏈間二硫鍵,亦即半胱胺酸橋鍵。藉由使用諸如DTT(二硫蘇糖醇)之還原劑處理可使得抗體變為反應性以與連接子試劑結合。由此,理論上各半胱胺酸橋鍵將形成兩個反應性巰基親核體。可經由離胺酸與2-亞胺基硫雜環戊烷(陶德氏(Traut's)試劑)之反應將額外親核基團引入到抗體中以使得胺轉化成巰基。可藉由工程改造一個、兩個、三個、四個或更多個半胱胺酸殘基(例如製備包含一或多個非原生半胱胺酸胺基酸殘基之突變抗體)來將反應性巰基引
入到抗體(或其片段)中。US 7521541傳授藉由引入反應性半胱胺酸胺基酸來工程改造抗體。
可在抗體中之反應性位點處工程改造半胱胺酸胺基酸且其並不形成鏈內或分子間雙硫鍵(Junutula等人,2008b Nature Biotech.,26(8):925-932;Dornan等人(2009)Blood 114(13):2721-2729;US 7521541;US 7723485;WO2009/052249)。經工程改造之半胱胺酸巰基可與本發明之連接子試劑或藥物-連接子試劑反應以形成具有半胱胺酸經工程改造的抗體及PBD藥物部分之ADC,該等連接子試劑或藥物-連接子試劑具有巰基反應性親電子基團,諸如順丁烯二醯亞胺或α鹵基醯胺。由此可設計、控制且已知藥物部分之位置。由於經工程改造之半胱胺酸巰基通常以高產率與巰基反應性連接子試劑或藥物-連接子試劑反應,故可控制藥物負載量。藉由重鏈或輕鏈上之單個位點處的取代來工程改造IgG抗體以引入半胱胺酸胺基酸獲得對稱抗體上之兩個新型半胱胺酸。使用接近均質性的結合產物ADC可達成接近2之藥物負載量。
其中抗體之一個以上親核或親電子基團與藥物-連接子中間產物或連接子試劑接著藥物部分試劑反應,則所得產物為ADC化合物之混合物,其中藥物部分之分佈(例如1、2、3等)附著至抗體。諸如聚合反相(PLRP)及疏水相互作用(HIC)之液相層析法可依據藥物負載值分離混合物中之化合物。可分離具有單一藥物負載值(p)之ADC製劑,然而此等單一負載值ADC仍可為異質混合物,因為可經由連接子在抗體上之不同位點附著藥物部分。
由此本發明之抗體-藥物結合物組合物包括抗體-藥物結合化合物之混合物,其中抗體具有一或多個PBD藥物部分,且其中可將藥物部分在各個胺基酸殘基處附著至抗體。
在一個實施例中,二聚體吡咯并苯并二氮呯基團/細胞結合劑之
平均數量在1至20範圍內。在一些實施例中,該範圍係選自1至8、2至8、2至6、2至4及4至8。
在一些實施例中,存在一個二聚體吡咯并苯并二氮呯基團/細胞結合劑。
除非另外說明,否則上文所包括的為熟知之離子、鹽、溶劑合物及此等取代物之受保護形式。舉例而言,提及羧酸(-COOH)時亦包括其陰離子(羧酸根)形式(-COO-)、鹽或溶劑合物以及習知的受保護形式。類似地,提及胺基時包括胺基之質子化形式(-N+HR1R2)鹽或溶劑合物(例如鹽酸鹽)以及胺基之習知的受保護形式。類似地,提及羥基時亦包括其陰離子形式(-O-)、鹽或溶劑合物以及習知的受保護形式。
可便利或合乎需要地製備、純化及/或處置活性化合物之對應的鹽,例如醫藥學上可接受之鹽。醫藥上可接受鹽之實例論述於Berge等人,J.Pharm.Sci.,66,1-19(1977)中。
舉例而言,若化合物為陰離子型或具有可為陰離子型之官能團(例如-COOH可為-COO-),則可與適合之陽離子形成鹽。適合之無機陽離子的實例包括(但不限於)鹼金屬離子(諸如Na+及K+)、鹼土金屬陽離子(諸如Ca2+及Mg2+)及其他陽離子(諸如Al3+)。適合之有機陽離子的實例包括(但不限於)銨離子(亦即NH4 +)及經取代之銨離子(例如NH3R+、NH2R2 +、NHR3 +、NR4 +)。一些適合之經取代的銨離子之實例為彼等來源於以下各者之銨離子:乙胺、二乙胺、二環己胺、三乙胺、丁胺、乙二胺、乙醇胺、二乙醇胺、哌嗪、苯甲胺、苯基苯甲胺、膽鹼、葡甲胺及緩血酸胺以及胺基酸(諸如離胺酸及精胺酸)。常見四級銨離子之實例為N(CH3)4 +。
若化合物為陽離子型或具有可為陽離子型之官能團(例如,-NH2
可為-NH3 +),則可與適合之陰離子形成鹽。適合之無機陰離子的實例包括(但不限於)彼等來源於以下無機酸之無機陰離子:氫氯酸、氫溴酸、氫碘酸、硫酸、亞硫酸、硝酸、亞硝酸、磷酸及亞磷酸。
適合之有機陰離子的實例包括(但不限於)彼等來源於以下有機酸之有機陰離子:2-乙醯氧基苯甲酸、乙酸、抗壞血酸、天冬胺酸、苯甲酸、樟腦磺酸、肉桂酸、檸檬酸、依地酸、乙二磺酸、乙磺酸、反丁烯二酸、葡庚糖酸、葡萄糖酸、麩胺酸、乙醇酸、羥基順丁烯二酸、羥基萘羧酸、羥乙基磺酸、乳酸、乳糖酸、月桂酸、順丁烯二酸、蘋果酸、甲磺酸、黏液酸、油酸、草酸、棕櫚酸、雙羥萘酸、泛酸、苯乙酸、苯磺酸、丙酸、丙酮酸、水楊酸、硬脂酸、丁二酸、對胺基苯磺酸、酒石酸、甲苯磺酸、三氟乙酸及戊酸。適合之聚合有機陰離子的實例包括(但不限於)彼等來源於以下聚合酸之聚合有機陰離子:鞣酸、羧甲基纖維素。
可便利或合乎需要地製備、純化及/或處置活性化合物之對應的溶劑合物。本文以習知意義使用術語「溶劑合物」,其係指溶質與溶劑(例如活性化合物、活性化合物之鹽)之複合物。若溶劑為水,則溶劑合物可便利地稱為水合物,例如單水合物、二水合物、三水合物等。
本發明包括其中添加溶劑遍及PBD部分之亞胺鍵的化合物,下文說明該溶劑為水或醇(RAOH,其中RA為C1-4烷基):
可將此等形式稱為PBD之甲醇胺及甲醇胺醚形式(如描述於上文關於R10之部分中)。此等平衡之平衡視存在該等化合物之條件以及部
分自身之性質而定。
可(例如)藉由凍乾以固體形式分離此等特定化合物。
本發明之某些化合物可以一或多種特定幾何、光學、對映異構、非對映異構、差向異構、萎縮性、立體異構、互變異構、構形異構或變旋異構形式存在,包括(但不限於)順式-及反式-形式;E-及Z-形式;c-、t-及r-形式;內-及外-形式;R-、S-及內消旋-形式;D-及L-形式;d-及l-形式;(+)及(-)形式;酮-、烯醇-及烯醇化物-形式;同-及抗-形式;向斜-及背斜-形式;α-及β-形式;軸向及赤道形式;舟-、椅-、扭轉-、包膜-及半椅-形式;及其組合,在下文中共同稱為「異構體」(或「異構形式」)。
術語「對掌性」係指具有與鏡像搭配物不可重疊之特性的分子,而術語「非對掌性」係指與鏡像搭配物可重疊之分子。
術語「立體異構體」係指具有一致的化學構成但在原子或基團在空間中之配置方面不同的化合物。
「非對映異構體」係指具有兩個或兩個以上對掌性中心且其分子並不互為鏡像之立體異構體。非對映異構體具有不同物理特性,例如熔點、沸點、光譜特性及反應性。可在諸如電泳及層析之高解析度分析程序下分離非對映異構體之混合物。
「對映異構體」係指化合物之兩個互為不可重疊鏡像的立體異構體。
本文所用之立體化學定義及約定一般遵循S.P.Parker編,McGraw-Hill Dictionary of Chemical Terms(1984)McGraw-Hill Book Company,New York;及Eliel,E.及Wilen,S.,「Stereochemistry of Organic Compounds」,John Wiley & Sons,Inc.,New York,1994。本發明之化合物可含有不對稱或對掌性中心,且因此以不同立體異構形式
存在。希望本發明之化合物的全部立體異構形式形成本發明之部分,該等立體異構形式包括(但不限於)非對映異構體、對映異構體及滯轉異構體以及其混合物(諸如外消旋混合物)。許多有機化合物以光學活性形式存在,亦即其能夠使平面偏振光之平面旋轉。在描述光學活性化合物時,使用前綴D及L或R及S表示分子圍繞其對掌性中心之絕對組態。前綴d及l或(+)及(-)用於標示由化合物引起之平面偏振光之旋轉跡象,其中(-)或l意謂化合物為左旋的。用(+)或d前綴之化合物為右旋的。對於既定化學結構,此等立體異構體為一致的,例外之處在於其互為鏡像。特定立體異構體亦可稱為對映異構體,且此類異構體之混合物通常稱為對映異構混合物。對映異構體之50:50混合物稱為外消旋混合物或外消旋物,其可在化學反應或製程中還不具有立體選擇或立體特異性時出現。術語「外消旋混合物」及「外消旋物」係指兩種對映異構物質之等莫耳混合物,其缺乏光學活性。
應注意,除如下文對互變異構形式論述之外,自如本文所用之術語「異構體」特定地排除結構(或構造)異構體(亦即原子之間之連接不同而非僅原子在空間中之位置不同的異構體)。舉例而言,提及甲氧基時(-OCH3)不應理解為提及其結構異構體羥甲基(-CH2OH)。類似地,提及鄰氯苯基時不應理解為提及其結構異構體間氯苯基。然而,提及一類結構時可充分包括屬於彼類別內之結構異構形式(例如C1-7烷基包括正丙基及異丙基;丁基包括正丁、異丁、第二丁及第三丁基;甲氧基苯基包括鄰甲氧基苯基、間甲氧基苯基及對甲氧基苯基)。
以上排除並不涉及互變異構形式,例如酮-、烯醇-及烯醇化物-形式,如在(例如)以下互變異構對中:酮/烯醇(下文所說明)、亞胺/烯胺、醯胺/亞胺基醇、脒/脒、亞硝基/肟、硫酮/硫酚、N-亞硝基/羥基偶氮及硝基/異硝基。
術語「互變異構體」或「互變異構形式」係指經由低能量障壁可互相轉化的具有不同能量之結構異構體。舉例而言,質子互變異構體(亦稱為質子轉移互變異構體)包括經由質子之遷移相互轉化,諸如酮-烯醇及亞胺-烯胺異構化。價態互變異構體包括藉由一些鍵結電子之重組相互轉化。
應注意術語「異構體」中特定地包括具有一或多個同位素取代之化合物。舉例而言,H可呈任何同位素形式,包括1H、2H(D)及3H(T);C可呈任何同位素形式,包括12C、13C及14C;O可呈任何同位素形式,包括16O及18O;及其類似物。
可併入本發明之化合物中的同位素之實例包括氫、碳、氮、氧、磷、氟及氯之同位素,諸如(但不限於)2H(氘,D)、3H(氚)、11C、13C、14C、15N、18F、31P、32P、35S、36Cl及125I。本發明之經各種同位素標記的化合物,例如將諸如3H、13C及14C之放射性同位素併入至其中之化合物。此類經同位素標記之化合物可適用於代謝研究、反應動力學研究、偵測或成像技術(諸如正電子發射斷層攝影法(PET)或單光子發射電腦斷層攝影法(SPECT),包括藥物或受質組織分佈分析)或用於患者之放射性治療。本發明之經氘標記或取代之治療性化合物可具有經改良的DMPK(藥物代謝及藥物動力學)特性,該等特性與分佈、代謝及排泄(ADME)相關。用諸如氘之較重同位素取代可得到某些由更大代謝穩定性產生之治療優勢,例如增加之活體內半衰期或降低之劑量需求。經18F標記之化合物可適用於PET或SPECT研究。本發明之經同位素標記之化合物及其前藥一般可藉由進行下文所描述的流程中或實例及製備中所揭示之程序藉由用易於得到的經同位素標
記之試劑取代未經同位素標記之試劑來製備。另外,用較重同位素尤其氘(亦即2H或D)取代可得到某些由更大代謝穩定性產生之治療優勢,例如增加的活體內半衰期或降低的劑量需求或治療指數之改良。
應理解,在此情形下將氘視為取代基。可藉由同位素增濃因素來界定此類較重同位素(尤其氘)之濃度。在本發明化合物中,未特定標示為特定同位素之任何原子意欲代表彼原子之任何穩定同位素。
除非另外說明,否則提及特定化合物時包括全部此類異構形式,包括(完全或部分地)其外消旋混合物及其他混合物。此類異構形式之製備(例如不對稱合成)及分離(例如分步結晶及層析方式)的方法為本領域中已知的或藉由以已知方式調適本文所教示之方法或已知方法可容易地獲得。
一般而言,藉由以下來量測抗體-藥物結合物(ADC)之細胞毒性或細胞生長抑制活性:使具有受體蛋白質(例如HER2)之哺乳細胞在細胞培養基中暴露至ADC之抗體;培養細胞約6小時至約5天之時間段;及量測細胞成活力。將基於細胞之活體外分析用以量測本發明之ADC的成活力(增殖)、細胞毒性及凋亡之誘導(卡斯蛋白酶活性)。
可藉由細胞增殖分析來量測抗體-藥物結合物之活體外效能。CellTiter-Glo®發光細胞成活力分析為市售可得的(Promega Corp.,Madison,WI)、基於鞘翅目(Coleoptera)螢光素酶之重組表現之均質分析方法(美國專利第5583024;5674713及5700670號)。此細胞增殖分析基於所存在之ATP之量(代謝活性細胞之指示)測定培養物中的活細胞之數量(Crouch等人(1993)J.Immunol.Meth.160:81-88;US 6602677)。在96孔格局中進行CellTiter-Glo®分析,使得其經受自動化高處理量篩查(HTS)(Cree等人(1995)AntiCancer Drugs 6:398 404)。均
質分析程序涉及將單一試劑(CellTiter-Glo®試劑)直接添加至在補充有血清之培養基中培養的細胞中。並不要求細胞洗滌、培養基之移除及多個吸液步驟。在添加試劑且混合10分鐘後內系統在384孔格局中偵測到少至15個細胞/孔。可使用ADC連續治療細胞或可治療該等細胞且使其自ADC分離。一般而言,經短暫(亦即3小時)治療之細胞展示與經連續治療之細胞相同的效能效應。
均質「添加-混合-量測」形式引起細胞溶解且產生與所存在之ATP的量成正比之發光訊號。ATP之量與存在於培養物中的細胞之數量成正比。CellTiter-Glo®分析產生由螢光素酶反應產生的「輝光型(glow-type」發光訊號,其半衰期一般大於五小時,視細胞類型及所用培養基而定。以相對發光單位(RLU)反映活細胞。藉由重組螢火蟲螢光素酶使受質甲蟲螢光素氧化去羧基,同時使ATP轉化成AMP且生成光子。
亦可藉由細胞毒性分析來量測抗體-藥物結合物之活體外效能。用PBS洗滌、用胰蛋白酶分離、於完整培養基(含有10%FCS)中稀釋經培養的黏附細胞,離心該等黏附細胞,使其再懸浮於新製培養基中且用血球計計數。直接計數懸浮液培養物。適合於計數之單分散細胞懸浮液可能需要藉由重複抽吸來攪拌懸浮液以打碎細胞凝塊。
將細胞懸浮液稀釋至所需接種密度且分配(100μL/孔)至黑色96孔培養盤中。培育黏附細胞株之培養盤隔夜以得到黏附性。可接種之日使用懸浮液細胞培養物。
在適當的細胞培養基中製得ADC(20μg/mL)之儲備溶液(1mL)。藉由依序轉移100μL至900μL細胞培養基在15mL離心管中製得儲備ADC之連續10倍稀釋液。
將四個重複孔之各ADC稀釋液(100μL)分配於96孔黑色培養盤中,預先用細胞懸浮液(100μL)裝盤,得到200μL之最終體積。對照
孔接受細胞培養基(100μL)。
若細胞株之加倍時間大於30小時,則ADC培育為5天,否則進行四天培育。
在培育期結束時,使用Alamarblue分析來評估細胞成活力。在整個培養盤(20μL/孔)上分配AlamarBlue(Invitrogen)且培育4小時。在Varioskan閃速酶標儀上以激發570nm、發射585nm量測Alamar blue螢光。根據經ADC治療之孔中的平均螢光與對照孔中的平均螢光相比計算百分比細胞存活率。
可藉由腫瘤異種移植研究在小鼠中量測本發明之抗體-藥物結合物(ADC)之活體內功效。舉例而言,可藉由高表現HER2轉基因外植體小鼠模型來量測本發明之抗HER2 ADC之活體內功效。自對赫賽汀®療法不起反應或不充分反應之Fo5 mmtv轉基因小鼠傳播。同種移植使用呈某些劑量含量(mg/kg)及PBD藥物暴露(μg/m2)之ADC及安慰劑緩衝液對照物(媒劑)治療個體一次,且經兩週或更長時間監測該等個體以量測腫瘤加倍之時間、對數細胞致死率及腫瘤收縮率。
本發明之結合物可用以在目標位置處提供PBD化合物。
目標位置較佳為增殖性細胞群體。抗體為存在於增殖性細胞群體上之抗原的抗體。
在一個實施例中,與存在於增殖性細胞群體(例如腫瘤細胞群體)中的抗原之量相比抗原在非增殖性細胞群體中不存在或以降低的量存在。
在目標位置處可使連接子分裂以便釋放化合物RelA或RelB。由此,結合物可用以選擇性地提供化合物RelA或RelB至目標位置。
可藉由目標位置處所存在的酶來使連接子分裂。
目標位置可為活體外、活體內或離體。
本發明之抗體-藥物結合物(ADC)化合物包括具有抗癌活性效用者。特定言之,化合物包括藉由連接子結合(亦即共價附著)至PBD藥物部分(亦即毒素)之抗體。當未使藥物結合至抗體時,PBD藥物具有細胞毒性效應。由此藉由結合至抗體來調變PBD藥物部分之生物活性。本發明之抗體-藥物結合物(ADC)選擇性地將有效劑量之細胞毒性劑傳遞至腫瘤組織,藉此實現更大的選擇性(亦即較低的有效劑量)。
由此,在一個態樣中,本發明提供如本文中所描述之用於治療的結合化合物。
在另一態樣中,亦提供如本文中所描述之結合化合物用於增生性疾病的治療。本發明之第二態樣提供結合化合物在製造用於治療增生性疾病之藥劑中的用途。
一般技術者能夠容易地確定候選結合物是否治療任何特定細胞型之增殖性病況。舉例而言,在下文實例中描述可便利地用於評估由特定化合物提供的活性之分析。
術語「增生性疾病」係關於非所需的過量或異常細胞之非所需或不受控之細胞增殖,諸如活體外或活體內贅生性或增生性生長。
增殖性病況之實例包括(但不限於)良性、前惡性及惡性細胞增殖,其包括(但不限於)贅瘤及腫瘤(例如組織細胞瘤、神經膠瘤、星形細胞瘤、骨瘤);癌症(例如肺癌、小細胞肺癌、胃腸癌、腸癌、結腸癌、乳腺癌、卵巢癌、前列腺癌、睾丸癌、肝癌、腎臟癌、膀胱癌、胰臟癌、腦癌、肉瘤、骨肉瘤、卡波西氏(Kaposi's)肉瘤、黑素瘤);淋巴瘤;白血病牛皮癬;骨骼疾病;增生病症(例如結締組織的)及動脈粥樣硬化。尤其受關注之癌症包括(但不限於)白血病及卵巢癌。
可治療任何類型之細胞,包括(但不限於)肺臟、胃腸(包括例如腸、結腸)、乳腺(乳房)、卵巢、前列腺、肝臟(肝)、腎臟(腎)、膀
胱、胰臟、大腦及皮膚。
在一個實施例中,治療為胰臟癌之治療。
在一個實施例中,治療為細胞表面上具有αvβ6整合素腫瘤的治療。
預期本發明之抗體-藥物結合物(ADC)可用以治療各種疾病或病症,例如其特徵為腫瘤抗原之過度表現。示例性病況或過度增殖性病症包括良性或惡性腫瘤;白血病、血液及淋巴惡性腫瘤。其他疾病包括神經元、神經膠質、星形膠質細胞、下丘腦、腺體、巨噬細胞、上皮、基質、囊胚、發炎、血管生成及免疫(包括自體免疫)病症。
一般而言,待治療之疾病或病症為過度增生性疾病(諸如癌症)。
在本文中待治療之癌症之實例包括(但不限於)癌、淋巴瘤、母細胞瘤、肉瘤及白血病或淋巴惡性腫瘤。此類癌症之更多特定實例包括鱗狀細胞癌(例如上皮鱗狀細胞癌);肺癌,包括小細胞肺癌、非小細胞肺癌;肺腺癌及肺鱗狀癌;腹膜癌;肝細胞癌;胃(gastric)癌或胃(stomach)癌,包括胃腸癌;胰臟癌;神經膠母細胞瘤;子宮頸癌;卵巢癌;肝癌;膀胱癌;肝腫瘤;乳腺癌;結腸癌;直腸癌;結腸直腸癌;子宮內膜癌或子宮癌;唾液腺癌;腎臟(kidney)癌或腎(renal)癌;前列腺癌;外陰癌;甲狀腺癌;肝癌;肛門癌;陰莖癌以及頭頸癌。
在治療中可使用ADC化合物之自體免疫疾病包括風濕病症(諸如類風濕性關節炎、斯耶格倫氏(Sjögren's)症候群、硬皮病、諸如SLE及狼瘡腎炎之狼瘡、多發性肌炎/皮肌炎、冷球蛋白血症、抗磷脂抗體症候群及牛皮癬性關節炎);骨關節炎;自體免疫胃腸及肝臟病症(諸如發炎性腸疾病(例如潰瘍性結腸炎及克羅恩氏病)、自體免疫胃炎及惡性貧血、自體免疫肝炎、原發性膽汁性肝硬化、一級硬化性膽管炎及乳糜瀉);脈管炎(諸如ANCA相關脈管炎,包括徹奇-斯全司
(Churg-Strauss)脈管炎、韋格納氏(Wegener's)肉芽腫病及多動脈炎);自體免疫神經病症(諸如多發性硬化症、斜視眼陣攣肌陣攣症候群、重症肌無力、視神經脊髓炎、帕金森氏(Parkinson's)疾病、阿茲海默氏(Alzheimer's)病及自體免疫多發性神經病);腎病症(諸如絲球體腎炎、古巴士德氏(Goodpasture's)症候群及伯傑氏(Berger's)疾病);自體免疫皮膚病學病症(諸如牛皮癬、風疹、蕁麻疹、尋常天疱瘡、大皰性類天疱瘡及皮膚紅斑狼瘡);血液學病症(諸如血小板減少性紫癜症、血栓性血小板減少性紫癜症、輸液後紫斑病及自體免疫性溶血性貧血);動脈粥樣硬化;葡萄膜炎;自體免疫聽覺疾病(諸如內耳疾病及聽覺缺失);白塞氏(Behcet's)病;雷諾氏(Raynaud's)症候群;器官移植及自體免疫內分泌病症(諸如糖尿病相關自體免疫疾病,諸如胰島素依賴型糖尿病(IDDM)、阿狄森氏(Addison's)疾病及自體免疫甲狀腺疾病(例如葛瑞夫茲氏(Graves')疾病及甲狀腺炎))。更佳的此類疾病包括(例如)類風濕性關節炎、潰瘍性結腸炎、ANCA相關脈管炎、狼瘡、多發性硬化症、斯耶格倫氏症候群、葛瑞夫茲氏疾病、IDDM、惡性貧血、甲狀腺炎及絲球體腎炎。
本發明之結合物可用於一種治療方法中。亦提供一種治療方法,其包含向需要治療之個體投與治療有效量的本發明之結合化合物。術語「治療有效量」為足以向患者展示益處之量。此類益處可為至少改善至少一個症狀。所投與的實際量及投與之速率與時間-時程將視所治療之性質及嚴重性而定。治療之處方(例如劑量之決定)在一般醫師及其他醫療醫生之職責內。
可單獨投與本發明之化合物或與其他治療組合,視待治療之病症而定同時或依序。治療及療法之實例包括(但不限於)化學療法(投與活性劑,包括例如藥物(諸如化學治療劑));手術;及放射療法。
「化學治療劑」為與作用機制無關之適用於癌症之治療的化合物。化學治療劑之類別包括(但不限於):烷基化劑、抗代謝物、紡錘體毒素植物鹼、細胞毒性/抗腫瘤抗生素、拓撲異構酶抑制劑、抗體、光敏劑及激酶抑制劑。化學治療劑包括「靶向療法」及習知化學療法中所使用的化合物。
化學治療劑之實例包括:埃羅替尼(erlotinib)(TARCEVA®,Genentech/OSI Pharm.)、多烯紫杉醇(TAXOTERE®,Sanofi-Aventis)、5-FU(氟尿嘧啶、5-氟尿嘧啶,CAS號51-21-8)、吉西他濱(gemcitabine)(GEMZAR®,Lilly)、PD-0325901(CAS號391210-10-9,Pfizer)、順鉑(cisplatin)(順二胺二氯鉑(II),CAS號15663-27-1)、卡鉑(carboplatin)(CAS號41575-94-4)、太平洋紫杉醇(TAXOL®,Bristol-Myers Squibb Oncology,Princeton,N.J.)、曲妥珠單抗(trastuzumab)(HERCEPTIN®,Genentech)、替莫唑胺(temozolomide)(4-甲基-5-側氧基-2,3,4,6,8-五氮雜雙環[4.3.0]壬-2,7,9-三烯-9-甲醯胺,CAS號85622-93-1,TEMODAR®,TEMODAL®,Schering Plough)、他莫昔芬(tamoxifen)((Z)-2-[4-(1,2-二苯基丁-1-烯基)苯氧基]-N,N-二甲基-乙胺,NOLVADEX®,ISTUBAL®,VALODEX®)及小紅莓(doxorubicin)(ADRIAMYCIN®)、Akti-1/2、HPPD及雷帕黴素(rapamycin)。
化學治療劑之更多實例包括:奧沙利鉑(oxaliplatin)(ELOXATIN®,Sanofi)、硼替佐米(bortezomib)(VELCADE®,Millennium Pharm.)、舒癌特(sutent)(SUNITINIB®,SU11248,Pfizer)、來曲唑(letrozole)(FEMARA®,Novartis)、甲磺酸伊馬替尼(imatinib mesylate)(GLEEVEC®,Novartis)、XL-518(MEK抑制劑,Exelixis,WO 2007/044515)、ARRY-886(Mek抑制劑,AZD6244,Array BioPharma,Astra Zeneca)、SF-1126(PI3K抑制劑,Semafore
Pharmaceuticals)、BEZ-235(PI3K抑制劑,Novartis)、XL-147(PI3K抑制劑,Exelixis)、PTK787/ZK 222584(Novartis)、氟維司群(fulvestrant)(FASLODEX®,AstraZeneca)、甲醯四氫葉酸(leucovorin)(醛葉酸)、雷帕黴素(西羅莫司(sirolimus),RAPAMUNE®,Wyeth)、拉帕替尼(lapatinib)(TYKERB®,GSK572016,Glaxo Smith Kline)、洛那法尼(lonafarnib)(SARASARTM,SCH 66336,Schering Plough)、索拉非尼(sorafenib)(NEXAVAR®,BAY43-9006,Bayer Labs)、吉非替尼(gefitinib)(IRESSA®,AstraZeneca)、伊立替康(irinotecan)(CAMPTOSAR®,CPT-11,Pfizer)、替吡法尼(tipifarnib)(ZARNESTRATM,Johnson & Johnson)、ABRAXANETM(不含十六醇聚氧乙烯醚(Cremophor))、太平洋紫杉醇之經白蛋白工程改造奈米顆粒調配物(American Pharmaceutical Partners,Schaumberg,IL)、凡德他尼(vandetanib)(rINN,ZD6474,ZACTIMA®,AstraZeneca)、氮芥苯丁酸(chlorambucil)、AG1478、AG1571(SU 5271;Sugen)、坦西莫司(temsirolimus)(TORISEL®,Wyeth)、帕唑帕尼(pazopanib)(GlaxoSmithKline)、坎弗醯胺(canfosfamide)(TELCYTA®,Telik)、噻替派(thiotepa)及環磷醯胺(cyclosphosphamide)(CYTOXAN®,NEOSAR®);磺酸烷酯,諸如白消安(busulfan)、英丙舒凡(improsulfan)及哌泊舒凡(piposulfan);氮丙啶,諸如苯唑多巴(benzodopa)、卡波醌(carboquone)、米特多巴(meturedopa)及尤利多巴(uredopa);乙烯亞胺及甲基三聚氰胺,包括六甲蜜胺(altretamine)、三伸乙基蜜胺、三伸乙基磷醯胺、三伸乙基硫代磷醯胺及羥甲基三聚氰胺;多聚乙醯(acetogenin)(尤其布拉他辛(bullatacin)及布拉他辛酮(bullatacinone));喜樹鹼(camptothecin)(包括合成類似物拓朴替康(topotecan));苔蘚蟲素(bryostatin);卡利斯他汀(callystatin);CC-1065(包括其阿多來新(adozelesin)、卡折來新(carzelesin)及比折來新
(bizelesin)合成類似物);念珠藻環肽(cryptophycin)(尤其念珠藻環肽1及念珠藻環肽8);海兔毒素(dolastatin);多卡米辛(duocarmycin)(包括合成類似物KW-2189及CB1-TM1);艾榴塞洛素(eleutherobin);盤克斯塔叮(pancratistatin);沙考地汀(sarcodictyin);海綿抑素(spongistatin);氮芥,諸如氮芥苯丁酸、萘氮芥(chlornaphazine)、氯磷醯胺、雌莫司汀(estramustine)、異環磷醯胺(ifosfamide)、二氯甲基二乙胺(mechlorethamine)、氧化二氯甲基二乙胺鹽酸鹽、美法侖(melphalan)、新恩比興(novembichin)、芬司特瑞(phenesterine)、潑尼莫司汀(prednimustine)、曲洛磷胺(trofosfamide)、尿嘧啶氮芥(uracil mustard);亞硝基脲,諸如卡莫司汀(carmustine)、氯脲菌素(chlorozotocin)、福莫司汀(fotemustine)、洛莫司汀(lomustine)、尼莫司汀(nimustine)及雷莫司汀(ranimnustine);抗生素,諸如烯二炔抗生素(例如卡奇黴素(calicheamicin)、卡奇黴素γ1I、卡奇黴素ωI1(Angew Chem.Intl.Ed.Engl.(1994)33:183-186);達內黴素(dynemicin)、達內黴素A;雙膦酸鹽,諸如氯屈膦酸鹽(clodronate);埃斯培拉黴素(esperamicin);以及新制癌菌素(neocarzinostatin)發色團及相關色蛋白烯二炔抗生素發色團)、阿克拉黴素(aclacinomycin)、放線菌素(actinomycin)、安麯黴素(authramycin)、偶氮絲胺酸(azaserine)、博來黴素(bleomycin)、放線菌素C(cactinomycin)、卡拉比辛(carubicin)、洋紅黴素(carminomycin)、嗜癌菌素(carzinophilin)、色黴素(chromomycinis)、放線菌素D(dactinomycin)、道諾黴素(daunorubicin)、地托比星(detorubicin)、6-重氮-5-側氧基-L-正白胺酸、N-嗎啉基-小紅莓、氰基-N-嗎啉基-小紅莓、2-吡咯啉基-小紅莓及去氧小紅莓、表柔比星(epirubicin)、依索比星(esorubicin)、伊達比星(idarubicin)、奈莫柔比星(nemorubicin)、麻西羅黴素(marcellomycin)、絲裂黴素(mitomycin)(諸如絲裂黴素C)、黴酚酸
(mycophenolic acid)、諾加黴素(nogalamycin)、橄欖黴素(olivomycin)、培洛黴素(peplomycin)、泊非黴素(potfiromycin)、嘌呤黴素(puromycin)、奎那黴素(quelamycin)、羅多比星(rodorubicin)、鏈黑黴素(streptonigrin)、鏈脲黴素(streptozocin)、殺結核菌素(tubercidin)、烏苯美司(ubenimex)、淨司他丁(zinostatin)、左柔比星(zorubicin);抗代謝物,諸如甲胺喋呤(methotrexate)及5-氟尿嘧啶(5-FU);葉酸類似物,諸如迪諾特寧(denopterin)、甲胺喋呤、蝶羅呤(pteropterin)、三甲曲沙(trimetrexate);嘌呤類似物,諸如氟達拉濱(fludarabine)、6-巰基嘌呤、噻咪嘌呤(thiamiprine)、硫鳥嘌呤(thioguanine);嘧啶類似物,諸如安西他濱(ancitabine)、阿紮胞苷(azacitidine)、6-氮雜尿苷(6-azauridine)、卡莫氟(carmofur)、阿糖胞苷(cytarabine)、雙去氧尿苷(dideoxyuridine)、脫氧氟尿苷(doxifluridine)、依諾他濱(enocitabine)、氟尿昔(floxuridine);雄激素,諸如卡普睾酮(calusterone)、丙酸屈他雄酮(dromostanolone propionate)、環硫雄醇(epitiostanol)、美雄烷(mepitiostane)、睾內酯(testolactone);抗腎上腺素,諸如胺格魯米特(aminoglutethimide)、米托坦(mitotane)、曲洛司坦(trilostane);葉酸補充劑,諸如夫羅林酸(frolinic acid);醋葡醛內酯(aceglatone);醛磷醯胺糖苷(aldophosphamide glycoside);胺基乙醯丙酸;恩尿嘧啶(eniluracil);安吖啶(amsacrine);貝斯布西(bestrabucil);比生群(bisantrene);艾達曲克(edatraxate);得弗伐胺(defofamine);秋水仙胺(demecolcine);地吖醌(diaziquone);艾弗鳥胺酸(elfornithine);依利醋銨(elliptinium acetate);埃博黴素(epothilone);依託格魯(etoglucid);硝酸錄;羥基脲(hydroxyurea);香菇多醣(lentinan);氯尼達明(lonidainine);類美登素(maytansinoid),諸如美登素(maytansine)及安絲菌素(ansamitocin);米托胍腙(mitoguazone);米托蒽醌(mitoxantrone);莫
比達摩(mopidamol);二胺硝吖啶(nitracrine);噴司他丁(pentostatin);蛋氨氮芥(phenamet);吡柔比星(pirarubicin);洛索蒽醌(losoxantrone);鬼臼酸(podophyllinic acid);2-乙基醯肼;丙卡巴肼(procarbazine);PSK®多醣複合物(JHS Natural Products,Eugene,OR);雷佐生(razoxane);根瘤菌素(rhizoxin);西佐喃(sizofiran);鍺螺胺(spirogermanium);細交鏈孢菌酮酸(tenuazonic acid);三亞胺醌(triaziquone);2,2',2"-三氯三乙胺;單端孢黴烯族毒素(trichothecene)(尤其T-2毒素、黏液黴素A(verrucarin A)、桿孢菌素A(roridin A)及胺癸叮(anguidine));尿烷(urethan);長春地辛(vindesine);達卡巴嗪(dacarbazine);甘露莫司汀(mannomustine);二溴甘露醇(mitobronitol);二溴衛矛醇(mitolactol);哌泊溴烷(pipobroman);加西托星(gacytosine);阿拉伯糖苷(arabinoside)(「阿糖胞苷(Ara-C)」);環磷醯胺;噻替派;6-硫鳥嘌呤;巰基嘌呤;甲胺喋呤;鉑類似物,諸如順鉑及卡鉑;長春鹼(vinblastine);依託泊苷(etoposide)(VP-16);異環磷醯胺;米托蒽醌;長春新鹼(vincristine);長春瑞賓(vinorelbine)(NAVELBINE®);諾凡特龍(novantrone);替尼泊苷(teniposide);依達曲沙(edatrexate);柔紅黴素(daunomycin);胺基蝶呤(aminopterin);卡培他濱(capecitabine)(XELODA®,Roche);伊班膦酸鹽(ibandronate);CPT-11;拓撲異構酶抑制劑RFS 2000;二氟甲基鳥胺酸(DMFO);類視色素,諸如視黃酸;及以上中之任一者的醫藥學上可接受之鹽、酸及衍生物。
「化學治療劑」之定義中亦包括:「化療劑」定義中亦包括:(i)起調節或抑制腫瘤上之激素作用的抗激素劑,諸如抗雌激素及選擇性雌激素受體調節劑(SERM),包括(例如)他莫昔芬(包括NOLVADEX®;檸檬酸他莫昔芬)、雷洛昔芬(raloxifene)、曲洛昔芬(droloxifene)、4-羥基他莫昔芬、曲沃昔芬(trioxifene)、那洛昔芬
(keoxifene)、LY117018、奧那司酮(onapristone)及FARESTON®(檸檬酸托瑞米芬(toremifine citrate));(ii)調節腎上腺中之雌激素產生、抑制酶芳香酶之芳香酶抑制劑,諸如4(5)-咪唑、胺格魯米特、MEGASE®(乙酸甲地孕酮(megestrol acetate))、AROMASIN®(依西美坦(exemestane),Pfizer)、福美斯坦(formestanie)、法屈唑(fadrozole)、RIVISOR®(伏羅唑(vorozole))、FEMARA®(來曲唑;Novartis)及ARIMIDEX®(阿那曲唑(anastrozole),AstraZeneca);(iii)抗雄激素,諸如氟他胺(flutamide)、尼魯胺(nilutamide)、比卡魯胺(bicalutamide)、亮丙瑞林(leuprolide)及戈舍瑞林(goserelin);以及曲沙他濱(troxacitabine)(1,3-二氧戊環核苷胞嘧啶類似物);(iv)蛋白激酶抑制劑,諸如MEK抑制劑(WO 2007/044515);(v)脂質激酶抑制劑;(vi)反義寡核苷酸,尤其彼等抑制異常細胞增殖中所牽涉之傳訊途徑中之基因表現的反義寡核苷酸,例如PKC-α,Raf及H-Ras,諸如奧利默森(oblimersen)(GENASENSE®,Genta Inc.);(vii)核糖核酸酶,諸如VEGF表現抑制劑(例如ANGIOZYME®)及HER2表現抑制劑;(viii)疫苗,諸如基因療法疫苗,例如ALLOVECTIN®、LEUVECTIN®及VAXID®;PROLEUKIN® rIL-2;拓撲異構酶1抑制劑,諸如LURTOTECAN®;ABARELIX® rmRH;(ix)抗血管生成劑,諸如貝伐單抗(bevacizumab)(AVASTIN®,Genentech);及以上中之任一者的醫藥學上可接受之鹽、酸及衍生物。
「化學治療劑」之定義中亦包括治療性抗體,諸如阿侖單抗(坎帕斯)、貝伐單抗(AVASTIN®,Genentech);西妥昔單抗(ERBITUX®,Imclone);帕尼單抗(VECTIBIX®,Amgen)、利妥昔單抗(RITUXAN®,Genentech/Biogen Idec)、奧伐組單抗(ARZERRA®,GSK)、帕妥珠單抗(PERJETATM,OMNITARGTM,2C4,Genentech)、曲妥珠單抗(HERCEPTIN®,Genentech)、托西莫單抗(tositumomab)
(Bexxar,Corixia)及抗體藥物結合物,吉妥珠單抗奧唑米星(gemtuzumab ozogamicin)(MYLOTARG®,Wyeth)。
具有治療性潛能作為化學治療劑與本發明之結合物組合的人類化單株抗體包括:阿侖單抗、阿泊珠單抗(apolizumab)、阿塞珠單抗(aselizumab)、阿利珠單抗(atlizumab)、貝頻珠單抗(bapineuzumab)、貝伐單抗、比伐珠單抗美坦辛(bivatuzumab mertansine)、坎妥珠單抗美坦辛(cantuzumab mertansine)、西利珠單抗(cedelizumab)、賽妥珠單抗(certolizumab pegol)、西弗絲妥珠單抗(cidfusituzumab)、西地妥珠單抗(cidtuzumab)、達利珠單抗(daclizumab)、艾庫組單抗(eculizumab)、艾法珠單抗(efalizumab)、依帕珠單抗(epratuzumab)、厄利珠單抗(erlizumab)、泛維珠單抗(felvizumab)、芳妥珠單抗(fontolizumab)、吉妥珠單抗奧唑米星、伊諾妥珠單抗奧唑米星(inotuzumab ozogamicin)、伊派利單抗(ipilimumab)、拉貝珠單抗(labetuzumab)、林妥珠單抗(lintuzumab)、馬妥珠單抗(matuzumab)、美泊利珠單抗(mepolizumab)、莫維珠單抗(motavizumab)、莫托珠單抗(motovizumab)、那他珠單抗(natalizumab)、尼妥珠單抗(nimotuzumab)、諾維珠單抗(nolovizumab)、努維珠單抗(numavizumab)、奧克珠單抗(ocrelizumab)、奧馬珠單抗(omalizumab)、帕利珠單抗(palivizumab)、帕考珠單抗(pascolizumab)、派弗西妥珠單抗(pecfusituzumab)、派妥珠單抗(pectuzumab)、帕妥珠單抗、培克珠單抗(pexelizumab)、來利珠單抗(ralivizumab)、蘭比珠單抗(ranibizumab)、瑞利維珠單抗(reslivizumab)、瑞利珠單抗(reslizumab)、來西維珠單抗(resyvizumab)、羅維珠單抗(rovelizumab)、盧利珠單抗(ruplizumab)、西羅珠單抗(sibrotuzumab)、希普利珠單抗(siplizumab)、索土珠單抗(sontuzumab)、他珠單抗四西坦(tacatuzumab tetraxetan)、他西珠單抗
(tadocizumab)、他利珠單抗(talizumab)、特菲巴珠單抗(tefibazumab)、妥珠單抗(tocilizumab)、托利珠單抗(toralizumab)、曲妥珠單抗、土庫珠單抗西莫白介素(tucotuzumab celmoleukin)、土庫西妥珠單抗(tucusituzumab)、恩維珠單抗(umavizumab)、烏珠單抗(urtoxazumab)及維西珠單抗(visilizumab)。
除活性成份(亦即結合化合物)以外,根據本發明且根據本發明使用之醫藥組合物亦可包括醫藥學上可接受之賦形劑、載劑、緩衝液、穩定劑或熟習此項技術者熟知之其他材料。此類材料應為無毒的且不應干擾活性成分之功效。載劑或其他材料之確切性質將視投與之途徑而定,投與途徑可為口服或藉由注射(例如皮膚、皮下或靜脈內)。
用於經口投與之醫藥組合物可為錠劑、膠囊、散劑或液體形式。錠劑可包括固體載劑或佐劑。液體醫藥組合物一般包含液體載劑,諸如水、石油、動物油或植物油、礦物油或合成油。可包括生理鹽水溶液,右旋糖或其他醣溶液或二醇(諸如乙二醇、丙二醇或聚乙二醇)。膠囊可包括固體載劑,諸如明膠。
對於靜脈內、皮膚或皮下注射或在病痛部位處注射,活性成份將呈非經腸可接受之水溶液形式,其不含熱原質且具有適合之pH、等滲性及穩定性。相關熟習此項技術者能夠良好地使用例如等張媒劑(諸如氯化鈉注射液、林格氏注射液(Ringer's Injection)、乳酸林格氏注射液)來製備適合的溶液。視需要可包括防腐劑、穩定劑、緩衝劑、抗氧化劑及/或其他添加劑。
儘管有可能單獨使用(例如投與)結合化合物,往往較佳地使其以組合物或調配物形式存在。
在一個實施例中,組合物為包含如本文所描述之結合化合物及醫藥學上可接受之載劑、稀釋劑或賦形劑的醫藥組合物(例如調配
物、製劑、藥劑)。
在一個實施例中,組合物為包含至少一種如本文所描述之結合化合物以及一或多種熟習此項技術者熟知的其他醫藥學上可接受之成分的醫藥組合物,該等醫藥學上可接受之成分包括(但不限於)醫藥學上可接受之載劑、稀釋劑、賦形劑、佐劑、填充劑、緩衝劑、防腐劑、抗氧化劑、潤滑劑、穩定劑、增溶劑、界面活性劑(例如潤濕劑)、掩蔽劑、著色劑、調味劑及甜味劑。
在一個實施例中,組合物進一步包括其他活性劑,例如其他治療性或預防性試劑。
適合之載劑、稀釋劑、賦形劑等可見於標準醫藥學教科書中。參見例如Handbook of Pharmaceutical Additives,第2版(M.Ash及I.Ash編),2001(Synapse Information Resources,Inc.,Endicott,New York,USA)、Remington's Pharmaceutical Sciences,第20版出版Lippincott,Williams及Wilkins,2000;及Handbook of Pharmaceutical Excipients,第2版,1994。
本發明之另一態樣係關於製得醫藥組合物的方法,該等方法包含摻和至少一種如本文所定義之經[11C]-放射性標記結合物或結合物類化合物以及一或多種熟習此項技術者熟知的其他醫藥學上可接受之成分,醫藥學上可接受之成分為例如,載劑、稀釋劑、賦形劑等。若以各別單位形式(例如錠劑等)調配,則各單位含有預定量(劑量)之活性化合物。
如本文所用,術語「醫藥學上可接受之」係關於化合物、成分、材料、組合物、劑型等,其在合理的醫療判斷之範疇內,適用於與所討論之個體(例如人類)的組織接觸,而不含過量的毒性、刺激、過敏性反應或其他問題或併發症,匹配有合理的益處/風險比率。各載劑、稀釋劑、賦形劑等在與調配物之其他成分相容的意義上必須亦
為「可接受之」。
可藉由任何藥劑學技術中熟知之方法來製備調配物。此類方法包括使活性化合物與構成一或多種附屬成分之載劑締合的步驟。一般而言,藉由使活性化合物與載劑(例如液體載劑、細粉狀固體載劑等)均一地並緊密地締合且隨後使產物成形(若需要)來製備調配物。
可製備調配物以提供迅速或緩慢釋放;即時、延緩、定時或持續釋放;或其組合。
適合於非經腸投與(例如藉由注射)之調配物包括水性或非水性、等張、不含熱原質、無菌液體(例如溶液、懸浮液),其中使活性成份溶解、懸浮或以其他方式提供(例如在脂質體或其他微粒中)。此類液體可額外含有其他醫藥學上可接受之成分,諸如抗氧化劑、緩衝劑、防腐劑、穩定劑、抑菌劑、懸浮劑、增稠劑及使得調配物與預期受者之血液(或其他相關體液)等張的溶質。賦形劑之實例包括(例如)水、醇、多元醇、丙三醇、植物油及類似者。適合之用於此類調配物的等張載劑之實例包括氯化鈉注射液、林格氏溶液或乳酸鹽林格氏注射液。通常,液體中活性成份之濃度為約1ng/mL至約10μg/mL,例如約10ng/mL至約1μg/mL。可使調配物存於單位劑量或多劑量密封容器(例如安瓿及小瓶)中,且可在經冷凍乾燥(凍乾)條件下儲存,僅需要在即將使用之前添加無菌液體載劑(例如水)用於注射。可自無菌散劑、粒劑及錠劑製備即用型注射溶液和懸浮液。
熟習此項技術者應瞭解結合化合物之適當劑量及包含該結合化合物之組合物可隨著患者不同而變化。確定最佳劑量一般將涉及治療益處之程度相對於任何風險或有害副作用之平衡。所選擇的劑量濃度將視各種因素而定,包括(但不限於)特定化合物之活性;投與之途徑;投與之時間;化合物之排泄速率;治療之持續時間;組合使用的
其他藥物、化合物及/或材料;病況之嚴重性及物種、性別、年齡、重量、病況、整體健康狀況及患者之先前病史。化合物之量及投與之途徑將最終由醫師、獸醫或臨床醫師酌情處理,但一般將選擇劑量以在作用位點處獲得局部濃度,該等局部濃度獲得所需效應而不導致實質性有害或有毒副作用。
可在整個治療時程中以一個劑量連續地或間歇地(例如以適當間隔分次給藥)進行投與。確定最有效的投與方式及劑量之方法已為熟習此項技術者所熟知且將隨用於治療之調配物、治療之目的、所治療的目標細胞及所治療的個體而變化。可用由治療醫師、獸醫或臨床醫師所選擇的劑量及模式來進行單次或多次投與。
一般而言,活性化合物之適合之劑量在約100ng至約25mg(更通常地約1μg至約10mg)/個體之公斤體重每日範圍內。在活性化合物為鹽、酯、醯胺、準藥或類似者時,基於母體化合物計算所投與的量且因此所使用的實際重量成比例地增加。
在一個實施例中,根據以下劑量方案向人類患者投與活性化合物:每日約100mg,3次。
在一個實施例中,根據以下劑量方案向人類患者投與活性化合物:每日約150mg,2次。
在一個實施例中,根據以下劑量方案向人類患者投與活性化合物:每日約200mg,2次。
然而在一個實施例中,根據以下劑量方案向人類患者投與結合化合物:每日約50mg或約75mg,3次或4次。
在一個實施例中,根據以下劑量方案向人類患者投與結合化合物:每日約100mg或約125mg,2次。
上文所描述的劑量可應用於結合物(包括PBD部分及抗體之連接子)或應用於所提供的PBD化合物之有效量(例如在連接子分裂之後可
釋放的化合物之量)。
對於疾病之預防或治療,本發明之ADC的適當劑量將視如上文所定義之待治療的疾病之類型、疾病之嚴重性及時程、是否為預防性或治療性目的而投與該分子、預先治療、患者的臨床病史及對抗體之反應及主治醫師的判斷而定。一次性或歷經一系列治療向患者適當地投與該分子。視疾病之類型及嚴重性而定,無論例如藉由一或多次各別投與或藉由連續輸注,約1μg/kg至15mg/kg(例如0.1-20mg/kg)之分子為向患者投與之最初候選劑量。典型的日劑量可在約1μg/kg至100mg/kg或更多範圍內,視上文所提及之因素而定。待向患者投與之ADC的示例性劑量在患者重量之約0.1mg/kg至約10mg/kg範圍內。對於經若干天或更長時間的重複投與而言,視病況而定,持續治療直至出現對疾病症狀之所需抑制為止。示例性給藥方案依序包含投與約4mg/kg之初始起始劑量之時程、每週、每兩週或每三週的ADC之額外劑量。其他劑量方案可為有用的。易於藉由習知技術及分析來監控此療法之進程。
如本文在治療病況之情形下所用之術語「治療」一般係關於治療及療法,無論人類或動物(例如在獸醫學申請案中),其中實現一些所要之治療性效應,例如抑制病況之進展,且包括降低進展速率、中斷進展速率、使病況消退、改善病況及治癒病況。亦包括作為預防性措施之治療(亦即防治、預防)。
如本文所用,術語「治療上有效量」係關於當根據所需治療方案投與時,對於產生一些所需治療性效應、匹配有合理的益處/風險比率而言有效的活性化合物或包含活性化合物之材料、組合物或劑型之量。
類似地,如本文所用,術語「預防上有效量」係關於當根據所
需治療方案投與時,對於產生一些所需預防性效應、匹配有合理的益處/風險比率而言有效的活性化合物或包含活性化合物之材料、組合物或劑型之量。
可藉由若干途徑,採用熟習此項技術者已知之有機化學反應、條件及試劑(包括抗體或細胞結合劑之親核性基團與藥物-連接子試劑的反應)來製備抗體藥物結合物以及具有其他細胞結合劑之結合物。可採用此方法以及各種抗體及細胞結合劑以製備本發明之抗體-藥物結合物。
抗體上之親核基團包括(但不限於)側鏈巰基(例如半胱胺酸)。巰基為親核性的且能夠與連接子部分(諸如本發明之彼等連接子部分)上之親電子基團反應以形成共價鍵。某些抗體具有可還原鏈間二硫鍵,亦即半胱胺酸橋鍵。藉由使用諸如DTT(克萊蘭氏(Cleland's)試劑,二硫蘇糖醇)或TCEP(參(2-羧乙基)膦鹽酸鹽;Getz等人(1999)Anal.Biochem.第273卷:73-80;Soltec Ventures,Beverly,MA)之還原劑處理可使得抗體變為反應性以與連接子試劑結合。由此,理論上各半胱胺酸雙硫橋鍵將形成兩個反應性巰基親核體。可經由離胺酸與2-亞胺基硫雜環戊烷(陶德氏試劑)之反應將額外親核基團引入到抗體中使得胺轉化成巰基。
個體/患者可為動物;哺乳動物;胎盤哺乳動物;有袋動物(例如袋鼠、袋熊);單孔類動物(例如鴨嘴獸);嚙齒動物(例如天竺鼠、倉鼠、大鼠、小鼠);鼠類(例如小鼠);兔類動物(例如兔);禽類(例如鳥);犬科(例如狗);貓科(例如貓);馬科(例如馬);豬科(例如豬);綿羊類(例如綿羊);牛類(例如母牛);靈長類,猿猴(例如猴或猿);猴(例如狨猴、狒狒);猿(例如大猩猩、黑猩猩、猩猩長臂猿)或人
類。
此外,個體/患者可為其發育形式中之任一者,例如胎兒。在一個較佳實施例中,個體/患者為人類。
在一個實施例中,患者為其中各患者患有細胞表面上具有αvβ6整合素之腫瘤的群體。
於ADP 220偏光計(Bellingham Stanley Ltd.)上量測旋光度且以g/100mL提高濃度(c)。使用數位熔點設備(Electrothermal)量測熔點。在Perkin-Elmer Spectrum 1000 FT IR光譜儀上記錄IR光譜。在300K下使用Bruker Avance NMR光譜儀分別以400MHz及100MHz獲取1H及13C NMR光譜。相對於TMS(δ=0.0ppm)報告化學位移,且以s(單峰)、d(雙重峰)、t(三重峰)、dt(雙重三重峰)、dd(雙重峰之雙重峰)、ddd(雙重雙重峰之雙重峰)或m(多重峰)標示訊號,其中以赫茲(Hz)提供耦合常數。使用耦合至具有Waters 2996 PDA之Waters 2695 HPLC的Waters Micromass ZQ儀器收集質譜(MS)數據。所用Waters Micromass ZQ參數為:毛細管(kV),3.38;錐體(V),35;萃取器(V),3.0;源極溫度(℃),100;去溶劑化溫度(℃),200;錐體流動速率(L/h),50;去溶劑化流動速率(L/h),250。在Waters Micromass QTOF Global上以正W模式使用經金屬包覆之硼矽酸酯玻璃端部將樣品引入至儀器中來記錄高解析度質譜(HRMS)數據。在矽膠鋁培養盤(Merck 60,F254)上進行薄層層析法(TLC),且急驟層析法利用矽膠(Merck 60,230-400目數ASTM)。除了HOBt(NovaBiochem)及受固體支撐之試劑(Argonaut)以外,全部其他化學品及溶劑購自Sigma-Aldrich且未經進一步純化按所提供的形式使用。藉由在乾燥氮大氣下在適當的乾燥劑存在下蒸餾來製備無水溶劑,且在4Å分子篩或鈉線
上儲存。石油醚係指在40-60℃下沸騰之餾分。
一般LC/MS條件:使用移動相水(A)(甲酸0.1%)與乙腈(B)(甲酸0.1%)操作HPLC(Waters Alliance 2695)。梯度:初始組成5%B歷經1.0分鐘隨後歷經2.5分鐘5%B至95%B。組成保持在95% B 0.5分鐘,且隨後在0.1分鐘內恢復5% B且保持在此處0.9分鐘。總梯度操作時間等於5分鐘。流動速率3.0mL/min,經由傳送至質譜儀中之零怠體積三通片分離400μL。波長偵測範圍:220nm至400nm。功能類型:二極體陣列(535次掃描)。管柱:Phenomenex® Onyx Monolithic C18 50×4.60mm
將純淨的氯化三異丙基矽烷(56.4mL,262mmol)添加至咪唑(48.7g,715.23mmol)與4-羥基-5-甲氧基-2-硝基苯甲醛1(47g,238mmol)之混合物(一起研磨)。加熱混合物直至酚及咪唑熔化且溶解於溶液中(100℃)。攪拌反應混合物15分鐘且隨後使其冷卻,接著觀察
到在燒瓶之底部形成固體(咪唑氯化物)。用5%EtOAc/己烷稀釋反應混合物且直接負載至矽膠上,並且依序使用5% EtOAc/己烷、10% EtOAc/己烷溶離該板(歸因於較低過量,在產物中發現極少未反應的TIPSCl)。使用含5%乙酸乙酯之己烷溶離所需產物。藉由在減壓下旋轉蒸發移除過量溶離劑,之後在高度真空下乾燥獲得結晶狀感光性固體(74.4g,88%)。藉由LC/MS(4.22min(ES+)m/z(相對強度)353.88([M+H]+,100))所得的純度令人滿意;1H NMR(400MHz,CDCl3)δ 10.43(s,1H),7.60(s,1H),7.40(s,1H),3.96(s,3H),1.35-1.24(m,3H),1.10(m,18H)。
在室溫下將亞氯酸鈉(47.3g,523mmol,80%工業級)與磷酸二氫鈉(35.2g,293mmol)(NaH2PO4)於水(800mL)中之溶液添加至化合物2(74g,209mmol)於四氫呋喃(500mL)中之溶液中。將過氧化氫(60% w/w,140mL,2.93mol)立即添加至劇烈攪拌的兩相混合物中。反應混合物釋出氣體(氧氣),起始材料溶解且反應混合物之溫度上升至45℃。在30分鐘之後LC/MS揭示反應完成。在冰浴中冷卻反應混合物且添加鹽酸(1M)以使pH值降低至3(發現在許多情況下此步驟為不必要的,因為在反應結束時pH已為酸性;請在萃取之前檢驗pH)。隨後用乙酸乙酯(1L)萃取反應混合物且用鹽水(2×100mL)洗滌有機相並經硫酸鎂乾燥。過濾有機相且藉由在減壓下旋轉蒸發移除過量溶劑以獲得定量產率的呈黃色固體之產物6。LC/MS(3.93min(ES-)m/z(相對強度)367.74([M-H]-,100));1H NMR(400MHz,CDCl3)δ 7.36(s,1H),7.24(s,1H),3.93(s,3H),1.34-1.22(m,3H),1.10(m,18H)。
在0℃下將DCC(29.2g,141mmol,1.2當量)添加至酸3(43.5g,117.8mmol,1當量)與羥基苯并三唑水合物(19.8g,129.6mmol,1.1當量)於二氯甲烷(200mL)中之溶液中。移除冷浴且在室溫下使得反應進行30分鐘,此時在-10℃下在氬氣下迅速添加(2S,4R)-2-第三丁基二甲基矽烷基氧甲基-4-羥基吡咯啶4(30g,129.6mmol,1.1當量)與三乙胺(24.66mL,176mmol,1.5當量)於二氯甲烷(100mL)中之溶液(對於大規模,可藉由更進一步冷卻反應混合物來縮短添加時間)。在室溫下攪拌反應混合物40分鐘至1小時且藉由LC/MS與TLC(EtOAc)監控。藉由經矽藻土過濾來移除固體且用冷0.1M HCl水溶液洗滌有機相直至所量測的pH值為4或5。隨後依序用水、飽和碳酸氫鈉水溶液及鹽水洗滌有機相。經硫酸鎂乾燥有機層,過濾且藉由在減壓下旋轉蒸發移除過量溶劑。對殘餘物進行管柱急驟層析法(矽膠;梯度40/60乙酸乙酯/己烷至80/20乙酸乙酯/己烷)。藉由在減壓下旋轉蒸發移除過量溶劑獲得純產物13(45.5g純產物66%及17g略微不純產物,總計90%)。LC/MS 4.43min(ES+)m/z(相對強度)582.92([M+H]+,100);1H NMR(400MHz,CDCl3)δ 7.66(s,1H),6.74(s,1H),4.54(s,1H),4.40(s,1H),4.13(s,1H),3.86(s,3H),3.77(d,J=9.2Hz,1H),3.36(dd,J=11.3,4.5Hz,1H),3.14-3.02(m,1H),2.38-2.28(m,1H),2.10(ddd,J=13.3,8.4,2.2Hz,1H),1.36-1.19(m,3H),1.15-1.05(m,18H),0.91(s,9H),0.17-0.05(m,6H),(存在旋轉異構體)。
在0℃下將TCCA(8.82g,40mmol,0.7當量)添加至5(31.7g,54mmol,1當量)與TEMPO(0.85g,5.4mmol,0.1當量)於無水二氯甲烷(250mL)中之攪拌溶液中。劇烈攪拌反應混合物20分鐘,在該時
刻TLC(50/50乙酸乙酯/己烷)揭示起始材料之完全消耗。經由矽藻土過濾反應混合物且用飽和碳酸氫鈉水溶液(100mL)、硫代硫酸鈉(於300mL中9g)、鹽水(100mL)洗滌濾液且用硫酸鎂乾燥。在減壓下旋轉蒸發獲得定量產率的產物6。LC/MS4.52min(ES+)m/z(相對強度)581.08([M+H]+,100);1H NMR(400MHz,CDCl3)δ 7.78-7.60(m,1H),6.85-6.62(m,1H),4.94(dd,J=30.8,7.8Hz,1H),4.50-4.16(m,1H),3.99-3.82(m,3H),3.80-3.34(m,3H),2.92-2.17(m,2H),1.40-1.18(m,3H),1.11(t,J=6.2Hz,18H),0.97-0.75(m,9H),0.15- -0.06(m,6H),(存在旋轉異構體)。
在2,6-二甲基吡啶(25.6mL,23.5g,220mmol,4當量,用篩乾燥)存在下在-50℃(丙酮/乾冰浴)下將三氟甲磺酸酐(27.7mL,46.4g,165mmol,3當量)注入(控制溫度)至酮6(31.9g,55mmol,1當量)於無水二氯甲烷(900mL)中之劇烈攪拌懸浮液中。當LC/MS揭示反應將完成時在微處理(水/二氯甲烷)之後攪拌反應混合物1.5小時。將水添加至仍較冷的反應混合物中且分離有機層並且用飽和碳酸氫鈉、鹽水及硫酸鎂洗滌。過濾有機相且藉由在減壓下旋轉蒸發移除過量溶劑。對殘餘物進行管柱急驟層析法(矽膠;10/90 v/v乙酸乙酯/己烷),移除過量溶離劑而獲得產物7(37.6g,96%),LC/MS,方法2,4.32min(ES+)m/z(相對強度)712.89([M+H]+,100);1H NMR(400MHz,CDCl3)δ 7.71(s,1H),6.75(s,1H),6.05(d,J=1.8Hz,1H),4.78(dd,J=9.8,5.5Hz,1H),4.15-3.75(m,5H),3.17(ddd,J=16.2,10.4,2.3Hz,1H),2.99(ddd,J=16.3,4.0,1.6Hz,1H),1.45-1.19(m,3H),1.15-1.08(m,18H),1.05(s,6H),0.95
-0.87(m,9H),0.15-0.08(m,6H)。
在氬氣氛圍下將三苯基胂(1.71g,5.60mmol,0.4當量)添加至三氟甲磺酸酯7(10.00g,14mmol,1當量)、甲基酸(2.94g,49.1mmol,3.5當量)、氧化銀(13g,56mmol,4當量)與磷酸三鉀(17.8g,84mmol,6當量)於無水二噁烷(80mL)中之混合物中。使用氬氣沖洗反應物3次且添加氯化雙(苯基腈)鈀(II)(540mg,1.40mmol,0.1當量)。在瞬時升溫至110℃(在添加燒瓶之前預先將drysyn加熱套升溫至110℃)之前再使用氬氣沖洗反應物3次。在10分鐘之後反應物冷卻至室溫且經由板矽藻土過濾。藉由在減壓下旋轉蒸發移除溶劑。對所得殘餘物進行管柱急驟層析法(矽膠;10%乙酸乙酯/己烷)。收集並合併純溶離份,且藉由在減壓下旋轉蒸發移除過量溶離劑獲得產物8(4.5g,55%)。LC/MS,4.27min(ES+)m/z(相對強度)579.18([M+H]+,100);1H NMR(400MHz,CDCl3)δ 7.70(s,1H),6.77(s,1H),5.51(d,J=1.7Hz,1H),4.77-4.59(m,1H),3.89(s,3H),2.92-2.65(m,1H),2.55(d,J=14.8Hz,1H),1.62(d,J=1.1Hz,3H),1.40-1.18(m,3H),1.11(s,9H),1.10(s,9H),0.90(s,9H),0.11(d,J=2.3Hz,6H)。
在大約15℃下將鋅粉末(28g,430mmol,37當量)添加至化合物8(6.7g,11.58mmol)於含5%甲酸之乙醇v/v(70mL)中之溶液中。使用冰浴控制所得放熱以維持反應混合物之溫度低於30℃。在30分鐘之後,經由矽藻土板過濾反應混合物。用乙酸乙酯稀釋濾液且用水、飽和碳酸氫鈉水溶液及鹽水洗滌有機相。用硫酸鎂乾燥有機相,過濾且
藉由在減壓下旋轉蒸發移除過量溶劑。對所得殘餘物進行急驟管柱層析(矽膠;含10%乙酸乙酯之己烷)。收集並合併純溶離份且藉由在減壓下旋轉蒸發移除過量溶劑以獲得產物9(5.1g,80%)。LC/MS,4.23min(ES+)m/z(相對強度)550.21([M+H]+,100);1H NMR(400MHz,CDCl3)δ 7.28(s,1H),6.67(s,1H),6.19(s,1H),4.64-4.53(m,J=4.1Hz,1H),4.17(s,1H),3.87(s,1H),3.77-3.69(m,1H),3.66(s,3H),2.71-2.60(m,1H),2.53-2.43(m,1H),2.04-1.97(m,J=11.9Hz,1H),1.62(s,3H),1.26-1.13(m,3H),1.08-0.99(m,18H),0.82(s,9H),0.03- -0.03(m,J=6.2Hz,6H)。
在-78℃(丙酮/乾冰浴)下在無水吡啶(0.48mL,6.00mmol,2.2當量)存在下將氯甲酸烯丙酯(0.30mL,3.00mmol,1.1當量)添加至胺9(1.5g,2.73mmol)於無水二氯甲烷(20mL)中之溶液中。在30分鐘之後,移除浴且使反應混合物升溫至室溫。用二氯甲烷稀釋反應混合物且添加飽和硫酸銅水溶液。隨後依序使用飽和碳酸氫鈉水溶液及鹽水洗滌有機層。用硫酸鎂乾燥有機相,過濾且藉由在減壓下旋轉蒸發移除過量溶劑以獲得直接用於下一反應之產物10。LC/MS,4.45min(ES+)m/z(相對強度)632.91([M+H]+,100)
將粗10溶解於乙酸/甲醇/四氫呋喃/水(28mL:4mL:4mL:8mL)之7:1:1:2混合物中在室溫下攪拌。在3小時之後,藉由LC/MS觀察到起始材料之完全消失。用乙酸乙酯稀釋反應混合物且依序使用水(2×500mL)、飽和碳酸氫鈉水溶液(200mL)及鹽水洗滌。用硫酸鎂乾燥有機相,過濾且藉由在減壓下旋轉蒸發移除過量乙酸乙酯。對所得殘餘物進行急驟管柱層析法(矽膠,含25%乙酸乙酯之己烷)。收集並合併純溶離份且藉由在減壓下旋轉蒸發移除過量溶離劑以獲得所需產物11(1g,71%)。LC/MS,3.70min(ES+)m/z(相對強度)519.13([M+H]+,95),1H NMR(400MHz,CDCl3)δ 8.34(s,1H),7.69(s,1H),6.78(s,1H),6.15(s,1H),5.95(ddt,J=17.2,10.5,5.7Hz,1H),5.33(dq,J=17.2,1.5Hz,1H),5.23(ddd,J=10.4,2.6,1.3Hz,1H),4.73(tt,J=7.8,4.8Hz,1H),4.63(dt,J=5.7,1.4Hz,2H),4.54(s,1H),3.89-3.70(m,5H),2.87(dd,J=16.5,10.5Hz,1H),2.19(dd,J=16.8,4.6Hz,1H),1.70(d,J=1.3Hz,3H),1.38-1.23(m,3H),1.12(s,10H),1.10(s,8H)。
在-78℃(乾冰/丙酮浴)下在氬氣氛圍下將二甲亞碸(0.35mL,4.83mmol,2.5當量)逐滴添加至乙二醯氯(0.2mL,2.32mmol,1.2當量)於無水二氯甲烷(10mL)中之溶液中。在10分鐘之後在仍為-78℃之溫度下緩慢添加11(1g,1.93mmol)於無水二氯甲烷(8mL)中之溶液。在15分鐘之後逐滴添加三乙胺(1.35mL,用4Å分子篩乾燥,9.65mmol,5當量)且移除乾冰/丙酮浴。使反應混合物達至室溫且用冷鹽酸(0.1M)、飽和碳酸氫鈉水溶液及鹽水萃取。用硫酸鎂乾燥有機相,過濾且藉由在減壓下旋轉蒸發移除過量二氯甲烷以獲得產物12(658mg,66%)。LC/MS,3.52min(ES+)m/z(相對強度)517.14([M+H]+,100);1H NMR(400MHz,CDCl3)δ 7.20(s,1H),6.75-6.63(m,J=8.8,4.0Hz,2H),5.89-5.64(m,J=9.6,4.1Hz,2H),5.23-5.03(m,2H),4.68-4.38(m,2H),3.84(s,3H),3.83-3.77(m,1H),3.40(s,1H),3.05-2.83(m,1H),2.59(d,J=17.1Hz,1H),1.78(d,J=1.3Hz,3H),1.33-1.16(m,3H),1.09(d,J=2.2Hz,9H),1.07(d,J=2.1Hz,9H)。
在0℃下在氬氣下將第三丁基二甲基矽烷基三氟甲烷磺酸酯(0.70mL,3.00mmol,3當量)添加至化合物12(520mg,1.00mmol)與2,6-二甲基吡啶(0.46mL,4.00mmol,4當量)於無水二氯甲烷(40mL)中之溶液中。在10分鐘之後,移除冷浴且在室溫下攪拌反應混合物1小時。用水、飽和碳酸氫鈉水溶液及鹽水萃取反應混合物。用硫酸鎂乾燥有機相,過濾且藉由在減壓下旋轉蒸發移除過量。對所得殘餘物進
行急驟管柱層析法(矽膠;梯度,含10%乙酸乙酯之己烷至含20%乙酸乙酯之己烷)。收集並合併純溶離份且藉由在減壓下旋轉蒸發移除過量溶離劑以得到產物13(540mg,85%)。LC/MS,4.42min(ES+)m/z(相對強度)653.14([M+Na]+,100);1H NMR(400MHz,CDCl3)δ 7.20(s,1H),6.71-6.64(m,J=5.5Hz,2H),5.83(d,J=9.0Hz,1H),5.80-5.68(m,J=5.9Hz,1H),5.14-5.06(m,2H),4.58(dd,J=13.2,5.2Hz,1H),4.36(dd,J=13.3,5.5Hz,1H),3.84(s,3H),3.71(td,J=10.1,3.8Hz,1H),2.91(dd,J=16.9,10.3Hz,1H),2.36(d,J=16.8Hz,1H),1.75(s,3H),1.31-1.16(m,3H),1.12-1.01(m,J=7.4,2.1Hz,18H),0.89-0.81(m,9H),0.25(s,3H),0.19(s,3H)。
將乙酸鋰(87mg,0.85mmol)添加至化合物13(540mg,0.85mmol)於濕潤二甲基甲醯胺(6mL,50:1 DMF/水)中之溶液中。在4小時之後,反應完成且用乙酸乙酯(25mL)稀釋反應混合物並用檸檬酸水溶液(PH約3)、水及鹽水洗滌。用硫酸鎂乾燥有機層,過濾且藉由在減壓下旋轉蒸發移除過量乙酸乙酯。對所得殘餘物進行急驟管柱層析法(矽膠;梯度含25%乙酸乙酯之己烷至含75%乙酸乙酯之己烷)。收集並合併純溶離份且藉由在減壓下旋轉蒸發移除過量溶離劑以得到產物14(400mg,定量)。LC/MS,(3.33min(ES+)m/z(相對強度)475.26([M+H]+,100)。
將二碘代戊烷(0.63mL,4.21mmol,5當量)及碳酸鉀(116mg,0.84mmol,1當量)添加至酚14(400mg,0.84mmol)於丙酮(4mL,用分子篩乾燥)中之溶液中。隨後使反應混合物升溫至60℃且攪拌6小時。藉由在減壓下旋轉蒸發移除丙酮。對所得殘餘物進行急驟管柱層析法(矽膠;50/50,v/v,己烷/乙酸乙酯)。收集並合併純溶離份且移除過量溶離劑以得到90%產率的15。LC/MS,3.90min(ES+)m/z(相對強度)670.91([M]+,100)。1H NMR(400MHz,CDCl3)δ 7.23(s,1H),6.69(s,1H),6.60(s,1H),5.87(d,J=8.8Hz,1H),5.83-5.68(m,J=5.6Hz,1H),5.15-5.01(m,2H),4.67-4.58(m,1H),4.45-4.35(m,1H),4.04-3.93(m,2H),3.91(s,3H),3.73(td,J=10.0,3.8Hz,1H),3.25-3.14(m,J=8.5,7.0Hz,2H),2.92(dd,J=16.8,10.3Hz,1H),2.38(d,J=16.8Hz,1H),1.95-1.81(m,4H),1.77(s,3H),1.64-1.49(m,2H),0.88(s,9H),0.25(s,3H),0.23(s,3H)。
在5℃(冰浴)下將三乙胺(2.23mL,18.04mmol,2.2當量)添加至胺9(4g,8.20mmol)與三光氣(778mg,2.95mmol,0.36當量)於無水四氫呋喃(40mL)中之攪拌溶液中。藉由週期性移除來自反應混合物之等分試樣且使用甲醇淬滅及進行LC/MS分析來監控異氰酸酯反應之進展。在異氰酸酯形成完成後藉由注射至新製異氰酸酯來迅速添加烯丙氧羰基-Val-Ala-PABOH(4.12g,12.30mmol,1.5當量)與三乙胺(1.52mL,12.30mmol,1.5當量)於無水四氫呋喃(40mL)中之溶液。在40℃下攪拌反應混合物4小時。藉由在減壓下旋轉蒸發移除過量溶劑。對所得殘餘物進行急驟管柱層析法(矽膠;梯度,含1%甲醇之二
氯甲烷至含5%甲醇之二氯甲烷)。(使用EtOAc及己烷之替代性層析法條件亦已成功)。收集並合併純溶離份且藉由在減壓下旋轉蒸發移除過量溶離劑以得到產物16(3.9g,50%)。LC/MS,4.23min(ES+)m/z(相對強度)952.36([M+H]+,100);1H NMR(400MHz,CDCl3)δ 8.62(br s,1H),8.46(s,1H),7.77(br s,1H),7.53(d,J=8.4Hz,2H),7.32(d,J=8.5Hz,2H),6.76(s,1H),6.57(d,J=7.6Hz,1H),6.17(s,1H),6.03-5.83(m,1H),5.26(dd,J=33.8,13.5Hz,3H),5.10(s,2H),4.70-4.60(m,2H),4.58(dd,J=5.7,1.3Hz,2H),4.06-3.99(m,1H),3.92(s,1H),3.82-3.71(m,1H),3.75(s,3H),2.79-2.64(m,1H),2.54(d,J=12.9Hz,1H),2.16(dq,J=13.5,6.7Hz,1H),1.67(s,3H),1.46(d,J=7.0Hz,3H),1.35-1.24(m,3H),1.12(s,9H),1.10(s,9H),0.97(d,J=6.8Hz,3H),0.94(d,J=6.8Hz,3H),0.87(s,9H),0.07- -0.02(m,6H)。
使TBS醚16(1.32g,1.38mmol)溶解於乙酸/甲醇/四氫呋喃/水(14mL:2mL:2mL:4mL)之7:1:1:2混合物中且在室溫下攪拌。在3小時之後藉由LC/MS未再觀察到起始材料。用乙酸乙酯(25mL)稀釋反應混合物且依序使用水、飽和碳酸氫鈉水溶液及鹽水洗滌。用硫酸鎂乾燥有機相,過濾且藉由在減壓下旋轉蒸發移除過量乙酸乙酯。對所得殘餘物進行急驟管柱層析法(矽膠,含2%甲醇之二氯甲烷)。收集並合併純溶離份且藉由在減壓下旋轉蒸發移除過量溶離劑以獲得所需產物17(920mg,80%)。LC/MS,3.60min(ES+)m/z(相對強度)838.18([M+H]+,100)。1H NMR(400MHz,CDCl3)δ 8.55(s,1H),8.35
(s,1H),7.68(s,1H),7.52(d,J=8.1Hz,2H),7.31(d,J=8.4Hz,2H),6.77(s,1H),6.71(d,J=7.5Hz,1H),6.13(s,1H),5.97-5.82(m,J=5.7Hz,1H),5.41-5.15(m,3H),5.10(d,J=3.5Hz,2H),4.76-4.42(m,5H),4.03(t,J=6.6Hz,1H),3.77(s,5H),2.84(dd,J=16.7,10.4Hz,1H),2.26-2.08(m,2H),1.68(s,3H),1.44(d,J=7.0Hz,3H),1.30(dt,J=14.7,7.4Hz,3H),1.12(s,9H),1.10(s,9H),0.96(d,J=6.8Hz,3H),0.93(d,J=6.8Hz,3H)。
在-78℃(乾冰/丙酮浴)下在氬氣氛圍下將二甲亞碸(0.2mL,2.75mmol,2.5當量)逐滴添加至乙二醯氯(0.11mL,1.32mmol,1.2當量)於無水二氯甲烷(7mL)中之溶液中。在10分鐘之後在仍為-78℃之溫度下緩慢添加17(920mg,1.10mmol)於無水二氯甲烷(5ml)中之溶液。在15分鐘之後逐滴添加三乙胺(0.77mL,用4Å分子篩乾燥,5.50mmol,5當量)且移除乾冰/丙酮浴。使反應混合物達至室溫且用冷鹽酸(0.1M)、飽和碳酸氫鈉水溶液及鹽水萃取。用硫酸鎂乾燥有機相,過濾且藉由在減壓下旋轉蒸發移除過量二氯甲烷。對所得殘餘物進行管柱急驟層析法(矽膠;梯度,含2%甲醇之二氯甲烷至含5%甲醇之二氯甲烷)。收集並合併純溶離份且藉由在減壓下旋轉蒸發移除過量溶離劑獲得產物18(550mg,60%)。LC/MS,3.43min(ES+)m/z(相對強度)836.01([M]+,100)。1H NMR(400MHz,CDCl3)δ 8.39(s,1H),7.52-7.40(m,2H),7.21-7.08(m,J=11.5Hz,2H),6.67(s,1H),6.60-6.47(m,J=7.4Hz,1H),5.97-5.83(m,1H),
5.79-5.66(m,1H),5.38-4.90(m,6H),4.68-4.52(m,J=18.4,5.5Hz,4H),4.04-3.94(m,J=6.5Hz,1H),3.87-3.76(m,5H),3.00-2.88(m,1H),2.66-2.49(m,2H),2.21-2.08(m,2H),1.76(s,3H),1.45(d,J=7.0Hz,3H),1.09-0.98(m,J=8.9Hz,18H),0.96(d,J=6.7Hz,3H),0.93(d,J=6.9Hz,3H)。
在0℃下在氬氣下將第三丁基二甲基矽烷基三氟甲烷磺酸酯(0.38mL,1.62mmol,3當量)添加至化合物18(450mg,0.54mmol)與2,6-二甲基吡啶(0.25mL,2.16mmol,4當量)於無水二氯甲烷(5ml)中之溶液中。在10分鐘之後,移除冷浴且在室溫下攪拌反應混合物1小時。用水、飽和碳酸氫鈉水溶液及鹽水萃取反應混合物。用硫酸鎂乾燥有機相,過濾且藉由在減壓下旋轉蒸發移除過量溶劑。對所得殘餘物進行管柱急驟層析法(矽膠;50/50 v/v己烷/乙酸乙酯)。收集並合併純溶離份且藉由在減壓下旋轉蒸發移除過量溶離劑以得到產物19(334mg,65%)。LC/MS,4.18min(ES+)m/z(相對強度)950.50([M]+,100)。1H NMR(400MHz,CDCl3)δ 8.53(s,1H),8.02(s,1H),7.44(d,J=7.6Hz,2H),7.21(s,1H),7.08(d,J=8.2Hz,2H),6.72-6.61(m,J=8.9Hz,2H),6.16(s,1H),5.97-5.79(m,J=24.4,7.5Hz,2H),5.41-5.08(m,5H),4.86(d,J=12.5Hz,1H),4.69-4.60(m,1H),4.57(s,1H),4.03(t,J=6.7Hz,1H),3.87(s,3H),3.74(td,J=9.6,3.6Hz,1H),2.43-2.09(m,J=34.8,19.4,11.7Hz,3H),1.76(s,3H),1.43(d,J=6.9Hz,
3H),1.30-1.21(m,3H),0.97(d,J=6.7Hz,3H),0.92(t,J=8.4Hz,3H),0.84(s,9H),0.23(s,3H),0.12(s,3H)。
將乙酸鋰(50mg,0.49mmol)添加至化合物19(470mg,0.49mmol)於濕潤二甲基甲醯胺(4mL,50:1 DMF/水)中之溶液中。在4小時之後,反應完成並用乙酸乙酯稀釋反應混合物且用檸檬酸(pH約3)、水及鹽水洗滌。用硫酸鎂乾燥有機層,過濾且藉由在減壓下旋轉蒸發移除過量乙酸乙酯。對所得殘餘物進行管柱急驟層析法(矽膠;梯度,50/50至25/75 v/v己烷/乙酸乙酯)。收集並合併純溶離份且藉由在減壓下旋轉蒸發移除過量溶離劑以得到產物20(400mg,定量)。LC/MS,3.32min(ES+)m/z(相對強度)794.18([M+H]+,100)。1H NMR(400MHz,CDCl3)δ 8.53(s,1H),8.02(s,1H),7.44(d,J=7.6Hz,2H),7.21(s,1H),7.08(d,J=8.2Hz,2H),6.72-6.61(m,J=8.9Hz,2H),6.16(s,1H),5.97-5.79(m,J=24.4,7.5Hz,2H),5.41-5.08(m,5H),4.86(d,J=12.5Hz,1H),4.69-4.60(m,1H),4.57(s,1H),4.03(t,J=6.7Hz,1H),3.87(s,3H),3.74(td,J=9.6,3.6Hz,1H),2.43-2.09(m,J=34.8,19.4,11.7Hz,3H),1.76(s,3H),1.43(d,J=6.9Hz,3H),1.30-1.21(m,3H),0.97(d,J=6.7Hz,3H),0.92(t,J=8.4Hz,3H),0.84(s,9H),0.23(s,3H),0.12(s,3H)。
將碳酸鉀(70mg,0.504mmol,1當量)添加至15(370mg,0.552mmol,1.2當量)與酚20(400mg,0.504mmol)於無水丙酮(25mL)中之溶液中。在70℃下攪拌反應物8小時。LC/MS展示未耗盡全部起始材料,因此在室溫下攪拌反應物隔夜且第二天攪拌額外的2小時。藉由在減壓下旋轉蒸發移除丙酮。對所得殘餘物進行急驟管柱層析法(矽膠;含80%乙酸乙酯之己烷至100%乙酸乙酯)。收集並合併純溶離份且藉由在減壓下旋轉蒸發移除過量溶離劑以得到產物21(385mg,57%)。LC/MS,4.07min(ES+)m/z(相對強度)1336.55([M+H]+,50)。
將肆正丁基氟化銨(1M,0.34mL,0.34mmol,2當量)添加至21(230mg,0.172mmol)於無水四氫呋喃(3mL)中之溶液中。在10分鐘之後完全耗盡起始材料。用乙酸乙酯(30mL)稀釋反應混合物且依序使用水及鹽水洗滌。用硫酸鎂乾燥有機相,過濾且藉由在減壓下旋轉蒸發移除過量乙酸乙酯。使用所得殘餘物22作為用於下一反應之粗混合物。LC/MS,2.87min(ES+)m/z(相對強度)1108.11([M+H]+,100)。
將肆(三苯基膦)鈀(0)(12mg,0.01mmol,0.06當量)添加至粗22(0.172mmol)與吡咯啶(36μL,0.43mmol,2.5當量)於無水二氯甲烷(10mL)中之溶液中。攪拌反應混合物20分鐘且用二氯甲烷稀釋並依序使用飽和氯化銨水溶液及鹽水洗滌。用硫酸鎂乾燥有機相,過濾且藉由在減壓下旋轉蒸發移除過量二氯甲烷。使用所得殘餘物23作為用於下一反應之粗混合物。LC/MS,2.38min(ES+)m/z(相對強度)922.16([M+H]+,40)。
將碘乙酸酐(0.088g,0.249mmol,1.1當量)於無水DCM(1mL)中之溶液添加至含胺基PEG(8)酸24(0.100g,0.226mmol,1.0當量)之DCM(1mL)中。在暗處在室溫下攪拌混合物4小時。用5%檸檬酸、水洗滌反應混合物,用MgSO4乾燥,過濾且在減壓下濃縮。藉由急驟層析法(矽膠,含3% MeOH與0.1%甲酸之氯仿至含10% MeOH與0.1%甲酸之氯仿)純化殘餘物以獲得呈透明油狀物之產物(0.068g,49%)。LC/MS(1.13min(ES+))(系統1),m/z:610.15[M+H]+。1H NMR(400MHz,CDCl3)δ 7.04(br s,1H),3.78(t,J=6.0Hz,2H,),3.74(s,2H),3.68-3.64(m,28H),3.60-3.56(m,2H),3.46(dd,J=10.2Hz,5.3Hz,2H),2.61(t,J=6.0Hz,2H)。
將溴乙酸酐(0.065g,0.249mmol,1.1當量)於無水DCM(1mL)中之溶液添加至含胺基PEG(8)酸24(0.100g,0.226mmol,1.0當量)之DCM(1mL)中。在暗處在室溫下攪拌混合物4小時。用5%檸檬酸、水洗滌反應混合物,用MgSO4乾燥,過濾且在減壓下濃縮。藉由急驟層析法(矽膠,含3% MeOH與0.1%甲酸之氯仿至含10% MeOH與0.1%甲酸之氯仿)純化殘餘物以獲得呈淡橙色油狀物之產物(0.050g,39%)。LC/MS(1.08min(ES+))(系統1),m/z:562.20[M]+ 564.15[M+2]+。1H
NMR(400MHz,CDCl3)δ 7.28(br s,1H),3.87(s,2H),3.76(t,J=6.1Hz,2H),3.68-3.60(m,28H),3.60-3.56(m,2H),3.47(dd,J=10.3Hz,5.2Hz,2H),2.59(t,J=6.1Hz,2H)。
使用Shimadzu Nexera系列LC/MS用Shimadzu LC/MS-2020四極MS用電噴霧電離獲得LC/MS數據。移動相A為含0.1%甲酸之水。移動相B為含0.1%甲酸之乙腈。流動速率為0.80mL/min。梯度經2.00分鐘自5% B上升直至100% B,保持在100% B 0.50分鐘且隨後經0.05分鐘降回至5% B(保持0.45分鐘)。總操作時間為3分鐘。管柱:Waters,Aquity UPLC BEH Shield RP18 1.7μm,2.1×50mm;(系統1)。
或者,梯度經10.00分鐘自5% B上升直至100% B,保持在100% B2.00分鐘且隨後經0.10分鐘降回至5% B(保持2.90分鐘)。總操作時間為15分鐘。管柱:Phenomenex,Gemini-NX 3u C18 110A,100×2.00mm;(系統2)。
層析圖基於254nm處之紫外偵測。使用MS以正模式獲得質譜。
HPLC分析係在HPLC系統上進行:Shimadzu Prominence系列,具有UV/VIS偵測器(SPD-20A)及溶離份收集器(FRC-10A)。移動相A為含0.1%甲酸之水。移動相B為含0.1%甲酸之乙腈。梯度(適用於分析及製備型系統)經15.00分鐘自0% B上升直至100% B,保持在100% B 2.00分鐘且隨後經1.10分鐘降至13% B。分析型分析,管柱:Phenomenex,Gemini-NX 5μ C18 110A,150×4.60mm且流動速率為1.00mL/min(系統3)。製備型分析,管柱:Phenomenex,Gemini-NX 5μ C18 110A,150×21.20mm且流動速率為20.00mL/min(系統4)。
將N,N'-二異丙基碳化二亞胺(DIC,9.22μL,0.059mmol,1.1當量)添加至胺23(0.054mmol,1.1當量)與碘-(PEG)8-酸25(39.6mg,0.065mmol,1.2當量)於無水二氯甲烷(5ml)中之溶液中。攪拌反應物隔夜直至藉由LC/MS不再觀察到起始材料之存在。用二氯甲烷稀釋反應物且依序使用水及鹽水洗滌。用硫酸鎂乾燥有機相,過濾且藉由在減壓下旋轉蒸發移除過量二氯甲烷。對所得殘餘物進行急驟管柱層析法(矽膠;100%氯仿至含5%甲醇之氯仿)。收集並合併含有產物之溶離份且藉由在減壓下旋轉蒸發移除過量溶離劑,使用反相製備型HPLC(系統4)對其進行進一步純化。使用溶離份收集器收集純溶離份,合併且凍乾所需產物以得到27,A(15.8mg,19%,經3個步驟)。LC-MS,系統1,1.44min(ES+)m/z 1513.60[M+H]+。1H NMR(400MHz,CDCl3)δ 8.82(s,1H),7.92-7.78(m,1H),7.64(d,J
=7.0Hz,2H),7.50(s,1H),7.23-6.98(m,6H),6.81(s,1H),6.75(s,1H),6.69(s,1H),6.46(s,1H),5.76(d,J=8.3Hz,1H),5.32(m,1H),4.73(d,J=11.3Hz,1H),4.67-4.54(m,1H),4.42(br s,1H),4.32-4.19(m,2H),4.18-3.99(m,4H),3.91(s,3H),3.87(s,3H),3.84-3.76(m,3H),3.71(s,2H),3.70-3.58(m,28H),3.56(dd,J=10.1,5.1Hz,2H),3.43(dd,J=10.0,5.1Hz,1H),3.25-3.12(m,1H),3.06-2.87(m,2H),2.73-2.41(m,4H),2.33-1.97(m,3H),1.96-1.71(m,4H),1.84(s,3H),1.78(s,3H),1.71-1.51(m,2H),1.49-1.22(m,3H),1.07-0.85(m,6H)。
將N,N'-二異丙基碳化二亞胺(DIC,9.22μL,0.059mmol,1.1當量)添加至胺23(0.054mmol,1.1當量)與溴-(PEG)8-酸26(36.5mg,0.065mmol,1.2當量)於無水二氯甲烷(5ml)中之溶液中。攪拌反應物隔夜直至藉由LC/MS不再觀察到起始材料之存在。用二氯甲烷稀釋反應物且依序使用水及鹽水洗滌。用硫酸鎂乾燥有機相,過濾且藉由在減壓下旋轉蒸發移除過量二氯甲烷。使用反相製備型HPLC(系統4)純化所得殘餘物。使用溶離份收集器收集純溶離份,合併且凍乾所需產物以得到28,B(26.6mg,33%,經3個步驟)。LC-MS,系統1,1.44min(ES+)m/z 1466.85[M]+。1H NMR(400MHz,CDCl3)δ 8.82(s,1H),7.87(s,1H),7.64(d,J=7.0Hz,2H),7.50(s,1H),7.23-6.98(m,6H),6.81(s,1H),6.74(s,1H),6.69(s,1H),6.45(s,1H),5.75(d,J=9.2Hz,1H),5.32(d,J=11.2Hz,1H),4.72(d,J=11.7Hz,1H),4.68-4.52(m,1H),4.35(br s,1H),4.32-4.17(m,2H),4.17-3.99(m,4H),3.90(s,3H),3.87(s,3H),
3.84-3.74(m,3H),3.72-3.58(m,32H),3.46(dd,J=10.1,5.1Hz,2H),3.25-3.09(m,1H),3.05-2.84(m,2H),2.75-2.40(m,3H),2.34-1.98(m,3H),1.96-1.71(m,4H),1.83(s,3H),1.77(s,3H),1.67-1.52(m,2H),1.48-1.20(m,3H),1.09-0.88(m,6H)。
藉由薄層層析(TLC)使用Merck Kieselgel 60 F254矽膠來監控反應進展,其中鋁培養盤上有螢光指示劑。除非另外陳述,否則使用紫外光或碘蒸氣實現TLC之觀測。使用Merck Kieselgel 60 F254矽膠進行急驟層析法。自Fisher Scientific,U.K.購買萃取及層析溶劑且不經進一步純化即使用。全部化學品係購自Aldrich、Lancaster或BDH。
使用Bruker AV400基於δ尺度以400MHz量測質子NMR化學位移值。已使用以下縮寫:s,單峰;d,雙重峰;t,三重峰;q,四重峰;quin,五重峰;m,多重峰;br,寬峰。以Hz報告耦合常數。除非另外陳述,否則於Merck Kieselgel二氧化矽(Art.9385)上進行管柱層析法(藉由閃速程序)。使用耦合至Waters 2795 HPLC分離模組之Waters Micromass LCT儀器收集質譜(MS)數據。於矽膠鋁培養盤(Merck 60,F254)上進行薄層層析法(TLC)。按所供應的形式未經進一步純化使用全部其他化學品及溶劑。
使用Shimadzu Nexera系列LC/MS用Shimadzu LCMS-2020四極MS、用電噴霧電離獲得LCMS數據。移動相A為含0.1%甲酸之水。移動相B為含0.1%甲酸之乙腈。流動速率為0.80mL/min。梯度經2.00分鐘自5% B上升直至100% B,保持在100% B 0.50分鐘且隨後經0.05分鐘降回至5% B(保持0.45分鐘)。總操作時間為3分鐘。管柱:Waters Aquity UPLC BEH Shield RP18 1.7μm,2.1×50mm;(系統1)。
或者,梯度經10.00分鐘自5% B上升直至100% B,保持在100% B
2.00分鐘且隨後經0.10分鐘降回至5% B(保持2.90分鐘)。總操作時間為15分鐘。管柱:Gemini-NX 3u C18 110A,100×2.00mm;(系統2)。
層析圖基於254nm處之紫外偵測。使用MS以正模式獲得質譜。
將無水DMF(大約0.5mL)逐滴添加至4,4'-(戊烷-1,5-二基雙(氧基))雙(5-甲氧基-2-硝基苯甲酸酸)(29)(36.64g,74.0mmol)與乙二醯氯(18.79mL,0.222莫耳,3.0當量)於無水DCM(450mL)中之攪拌懸浮液中直至出現劇烈發泡且攪拌反應混合物隔夜。蒸發反應混合物至乾燥且用乙醚濕磨。自溶液過濾所得黃色沈澱物,用乙醚(100mL)洗滌且在-40℃下將其立即添加至(3R,5S)-5-((第三丁基二甲基矽烷氧基)甲基)吡咯啶-3-醇(30)(39.40g,0.170莫耳,2.3當量)與無水三乙胺(82.63mL,0.592莫耳,8當量)於無水DCM(400mL)中之溶液中。使反應混合物緩慢升溫至室溫(經2.5小時),在此之後LCMS分析指示反
應完成。添加DCM(250mL)且將混合物轉移至分液漏斗中。依次使用0.1M HCl(2×800mL)、飽和NaHCO3(500mL)及鹽水(300mL)洗滌有機層。在用MgSO4乾燥及過濾、蒸發溶劑之後留下呈黃色發泡體狀之產物(62.8g,92%)。LC/MS,系統1:RT 1.96分鐘;MS(ES+)m/z(相對強度)921.45([M+H]+,100)。
在氬氣氛圍下在0℃下將三氯異三聚氰酸(21.86g,94.07mmol,1.4當量)一次性添加至二醇31(61.90g,67.20mmol)與TEMPO(2.10g,13.44mmol,0.2當量)於無水DCM(500mL)中之溶液中。在0℃下攪拌反應混合物20分鐘,在此之後反應混合物之LCMS分析展示完成反應。用DCM(400mL)稀釋反應混合物且用飽和碳酸氫鈉(500mL)、0.2M硫代硫酸鈉溶液(600mL)、鹽水(400mL)洗滌並乾燥(MgSO4)。蒸發溶劑得到粗產物。急驟層析法[梯度溶離80%正己烷/20%乙酸乙酯至100%乙酸乙酯]得到呈黃色固體狀之純32(49.30g,80%)。LC/MS,系統1:RT 2.03分鐘;MS(ES+)m/z(相對強度)917.55([M+H]+,100)。
在-40℃下將三氟甲磺酸酐(24.19mL,0.144莫耳,6.0當量)逐滴添加至含有2,6-二甲基吡啶(22.33mL,0.192莫耳,8.0當量)之雙-酮32(21.98g,23.96mmol)於無水DCM(400mL)中之劇烈攪拌溶液中。在-40℃下攪拌反應混合物30分鐘,在此之後LCMS分析指示完成反應。迅速地用DCM(500mL)稀釋反應混合物且用冰-冷水(600mL)、冰-冷飽和碳酸氫鈉(400mL)、及鹽水(500mL)洗滌,用MgSO4
乾燥,過濾且蒸發至留下粗棕色油狀物。急驟層析法[梯度溶離80%正己烷/20%乙酸乙酯至66%正己烷/33%乙酸乙酯]得到呈褐色泡沫狀之純33(16.40g,58%)。LC/MS,系統1:RT 2.28min;MS(ES+)m/z(相對強度)無數據。
將三氟甲磺酸酯33(5.06g,4.29mmol)、甲基酸(1.80g,30.00mmol,7當量)及三苯基胂(1.05g,3.43mmol,0.8當量)溶解於無水二噁烷中且在氬氣下攪拌。隨後添加氯化雙苯甲腈鈀(II)且將反應混合物迅速加熱至80℃歷時20分鐘。使反應混合物冷卻,經由矽藻土過濾(用乙酸乙酯洗滌),用水(500mL)、鹽水(500mL)洗滌濾液,用MgSO4乾燥,過濾且蒸發。急驟層析法[梯度溶離50%正己烷/50%乙酸乙酯]得到呈褐色泡沫狀之純34(4.31g,59%)。LC/MS,系統1:RT 2.23min;MS(ES+)m/z(相對強度)913.50([M+H]+,100)。
將鋅粉(26.48g,0.405莫耳,36.0當量)一次性添加至雙-硝基化合物34(10.26g,11.24mmol)於5%甲酸/甲醇(200mL)中之溶液中,該溶液憑藉冷水浴保持在25-30℃之間的溫度。在30℃下攪拌反應物20分鐘,在此之後LCMS展示完成反應。經由矽藻土過濾反應混合物以移除過量鋅,用乙酸乙酯(600mL)洗滌。用水(500mL)、飽和碳酸氫鈉(500mL)及鹽水(400mL)洗滌有機溶離份,用MgSO4乾燥且蒸發。急驟層析法[梯度溶離100%氯仿至99%氯仿/1%甲醇]得到呈橙色發泡體狀之純35(6.22g,65%)。LC/MS,系統1:RT 2.20min;MS
(ES+)m/z(相對強度)853.50([M+H]+,100)。
在-78℃下在氬氣氛圍下將吡啶(1.156mL,14.30mmol,1.5當量)添加至雙-苯胺35(8.14g,9.54mmol)於無水DCM(350mL)中之溶液中。在5分鐘之後,添加氯甲酸烯丙酯(0.911mL,8.58mmol,0.9當量)且使反應混合物升溫至室溫。用DCM(250mL)稀釋反應混合物,用飽和CuSO4溶液(400mL)、飽和碳酸氫鈉(400mL)及鹽水(400mL)洗滌,用MgSO4乾燥。急驟層析法[梯度溶離66%正己烷/33%乙酸乙酯至33%正己烷/66%乙酸乙酯]得到呈橙色發泡體狀之純36(3.88g,43%)。LC/MS,System 1:RT 2.27min;MS(ES+)m/z(相對強度)937.55([M+H]+,100)。
在氬氣下在0℃下三乙胺將(0.854mL,6.14mmol,2.2當量)添加至苯胺36(2.62g,2.79mmol)與三光氣(0.30g,1.00mmol,0.36當量)於無水THF(50mL)中之攪拌溶液中。在室溫下攪拌反應混合物5分鐘。用甲醇淬滅的等分之LCMS分析展示異氰酸酯之形成。一次性添加mPEG2-Val-Ala-PAB-OH(1.54g,3.63mmol,1.3當量)與三乙胺(0.583mL,4.19mmol,1.5當量)於無水THF(50mL)中之溶液且在40℃下攪拌所得混合物隔夜。蒸發反應混合物之溶劑以留下粗產物。急驟層析法[梯度溶離100%氯仿至98%氯仿/2%甲醇]得到呈淺橙色固體狀之純37(2.38g,62%)。LC/MS,系統1:2.29min;MS(ES+)m/z(相對強度)無數據。
在室溫下在氬氣下將肆(三苯基膦)鈀(39mg,0.034mmol,0.02當量)添加至37(2.35g,1.69mmol)與吡咯啶(0.35mL,4.24mmol,2.5當量)於無水DCM(25mL)中之攪拌溶液中。攪拌反應混合物45分鐘隨後用DCM(100mL)稀釋,用飽和氯化銨溶液(100mL)、鹽水(100mL)洗滌,用MgSO4乾燥,過濾且蒸發。急驟層析法[梯度溶離100%氯仿至95%氯仿/5%甲醇]得到呈黃色固體之純38(1.81g,82%)。LC/MS,系統1:RT 2.21min:MS(ES+)m/z(相對強度)1303.65([M+H]+,100)。
在氬氣下在0℃下將三乙胺(0.419mL,3.01mmol,2.2當量)添加至苯胺38(1.78g,1.37mmol)與三光氣(0.15g,0.49mmol,0.36當量)於無水THF(50mL)中之攪拌溶液中。在室溫下攪拌反應混合物5分鐘。用甲醇淬滅的等分之LCMS分析展示異氰酸酯之形成。在40℃下一次性添加Alloc-Val-Ala-PAB-OH(0.67g,1.78mmol,1.3當量)與三乙胺(0.29mL,2.05mmol,1.5當量)於無水THF(45mL)中之溶液且攪拌所得混合物隔夜。蒸發反應混合物之溶劑以留下粗產物。急驟層析法[梯度溶離100%乙酸乙酯至97%乙酸乙酯/3%甲醇]得到呈淺黃色固體狀之純39(1.33g,57%)。LC/MS,系統1:RT 2.21分鐘;MS(ES+)m/z(相對強度)無數據。
將肆正丁基氟化銨(1M,1.52mL,1.52mmol,2.0當量)添加至TBS保護化合物39(1.30g,0.76mmol)於無水THF(15mL)中之溶液中。在室溫下攪拌反應混合物4小時。用氯仿(100mL)稀釋反應混合物且依序使用水(40mL)及鹽水(40mL)洗滌。用MgSO4乾燥有機相且蒸發以留下黃色固體。急驟層析法[梯度溶離95%乙酸乙酯/5%甲醇至90%乙酸乙酯/10%甲醇]得到呈淺黃色固體狀之純40(1.00g,89%)。
LC/MS,系統1:RT 1.60min;MS(ES+)m/z(相對強度)1478.45(100)。
在氬氣下在室溫下將Dess-Martin高碘烷(0.59g,1.38mmol,2.1當量)添加至40(0.97g,0.66mmol)於無水DCM中之攪拌溶液中。攪拌反應混合物4小時。用DCM(100mL)稀釋反應混合物,用飽和碳酸氫鈉溶液(3×100mL)、水(100mL)、鹽水(100mL)洗滌,用MgSO4乾
燥,過濾且蒸發。急驟層析法[梯度溶離100%氯仿至95%氯仿/5%甲醇]得到呈淺黃色固體狀之純41(0.88g,90%)。LC/MS,系統1:RT 1.57min;MS(ES+)m/z(相對強度)1473.35(100)。
將肆(三苯基膦)鈀(5mg,0.004mmol,0.06當量)添加至41(105mg,0.071mmol)與吡咯啶(7μL,0.086mmol,1.2當量)於無水DCM(5ml)中之溶液中。攪拌反應混合物15分鐘,隨後用氯仿(50mL)稀釋且依序使用飽和氯化銨水溶液(30mL)及鹽水(30mL)洗滌。用硫酸鎂乾燥有機相,過濾且蒸發。急驟層析法[梯度溶離100%氯仿至90%氯仿/10%甲醇]得到呈淺黃色固體狀之純42(54mg,55%)。LC/MS,系統1:RT 1.21min;MS(ES+)m/z(相對強度)1389.50(100)。
將N-(3-二甲胺基丙基)-N'-乙基碳化二亞胺(28mg,0.146mmol,1當量)添加至42(203mg,0.146mmol)與順丁烯二醯亞胺-PEG8酸(87
mg,0.146mmol)於氯仿(5ml)中之溶液中。攪拌反應物1.5小時,隨後用氯仿(50mL)稀釋,用水(50mL)、鹽水(30mL)洗滌,用硫酸鎂乾燥,過濾且蒸發。急驟層析法[梯度溶離100%DCM至90%DCM/10%甲醇]得到呈淺黃色固體狀之43(205mg,72%)。LC/MS,系統1:RT 5.75min;MS(ES+)m/z(相對強度)982.90(100),1963.70(5)。
在37℃下在含有5% CO2之潮濕大氣中將K562人類慢性骨髓白血病細胞維持於補充有10%胎牛血清及2mM麩醯胺酸之RPM1 1640培養基中且在37℃下在暗處使用特定劑量的藥物培育1小時或96小時。藉由離心(5min,300g)終止培育且用不含藥物的培養基洗滌細胞一次。適當藥物處理之後,將細胞轉移至96孔微量滴定培養盤(104個細胞/孔,8孔/樣品)。培養盤隨後保持在暗處在37℃下於含有5%CO2之潮濕大氣中。分析係基於活細胞將黃色可溶性四唑鎓鹽3-(4,5-二甲基噻唑-2-基)-2,5-二苯基-2H-四唑鎓溴化物(MTT,Aldrich-Sigma)還原成不可溶的紫色甲沈澱物之能力。培育培養盤4天(使得對照細胞之數量增加大致10倍)之後,將20μL MTT溶液(5mg/mL於磷酸鹽緩衝鹽水中)添加至各孔且再培育培養盤5小時。隨後在300g下離心培養盤5分鐘且大部分培養基自細胞離心塊吸取留下10-20μL/孔。將DMSO(200μL)添加至各孔且攪拌樣品以確保完全混合。隨後在Titertek Multiscan ELISA培養盤讀取器上於波長550nm處讀取光學密度,且構造劑量-反應曲線。對於各曲線而言,將IC50值讀取為使最終光學密度降低至對照值之50%所要求之劑量。
在此分析中化合物RelA具有0.425nM之IC50。
將抗體1(15.0mg,100奈莫耳)稀釋於13mL含有10mM硼酸鈉pH 8.4、2.5mM EDTA的還原緩衝液中,且最終抗體濃度為1.1mg/mL。
添加TCEP之10mM溶液(2莫耳等效物/抗體,200奈莫耳,20.0μL)且在+37℃下於加熱套中加熱還原混合物2小時。在冷卻至室溫之後,以DMSO溶液(15莫耳等效物/抗體,1.5微莫耳,於1.5mL DMSO中)形式添加化合物A。在室溫下混合溶液隔夜(17小時),隨後藉由添加N-乙醯基半胱胺酸(1.5微莫耳,15μL,100mM)淬滅結合,隨後將混合溶液注入至使用封裝有Superdex 200 PG之GE Healthcare XK26/100管柱的AKTATM FPLC中,用4.5mL/min之無菌過濾磷酸鹽緩衝鹽水(PBS)溶離。合併對應於ADC1A單體峰之溶離份,使用15mL Amicon Ultracell 50KDa MWCO自旋過濾器濃縮,分析且無菌過濾。BCA分析得到最終ADC1A之濃度為於8.7mL中1.36mg/mL,所獲得的ADC1A之質量為11.8mg(79%產率)。
對經還原之ADC1A樣品的UHPLC分析在280nm及330nm(化合物A特異性)處展示附著至化合物A之若干分子的輕鏈及重鏈之混合,其與2.6分子化合物A/抗體之藥物/抗體比率(DAR)一致,該UHPLC分析係在Shimadzu Prominence系統上使用Phenomenex Aeris 3.6u XB-C18 150×2.1mm管柱使用水及乙腈之梯度溶離。
對ADC1A樣品之UHPLC分析在280nm處展示98.7%之單體純度,且未偵測到雜質,該UHPLC分析係在Shimadzu Prominence系統上使用Waters Acquity UPLC BEH200 SEC 1.7μm 4.6×150mm管柱用含有5%異丙醇(v/v)之經無菌過濾SEC緩衝液溶離。
將抗體2(5.0mg,33.3奈莫耳)稀釋至4.5mL含有73mM硼酸鈉pH 8.4、1.0mM EDTA之還原緩衝液中,且最終抗體濃度為1.0mg/mL。添加TCEP之10mM溶液(2莫耳等效物/抗體,67奈莫耳,6.6
μL)且在+37℃下於加熱套中加熱還原混合物2.5小時。在冷卻至室溫之後,以DMSO溶液(13.3莫耳等效物/抗體,444奈莫耳,於0.5mL DMSO中)形式添加化合物B。在室溫下混合溶液隔夜(17小時),隨後將混合溶液注入至使用封裝有Superdex 200 PG之GE Healthcare XK26/600管柱的AKTATM FPLC中,用2.5mL/min之經無菌過濾的磷酸鹽緩衝鹽水(PBS)溶離。合併對應於ADC2B單體峰之溶離份,使用15mL Amicon Ultracell 50KDa MWCO自旋過濾器濃縮,分析且無菌過濾。BCA分析得到最終ADC2B之濃度為於3.2mL中0.80mg/mL,所獲得的ADC2B之質量為2.54mg(52%產率)。
對經還原之ADC2B樣品的UHPLC分析在280nm及330nm(化合物B特異性)處展示附著至化合物B之若干分子的輕鏈及重鏈之混合,其與2.3分子化合物B/抗體之藥物/抗體比率(DAR)一致,該UHPLC分析係在Shimadzu Prominence系統上使用Phenomenex Aeris 3.6u XB-C18 150×2.1mm管柱使用水及乙腈之梯度溶離。
對ADC2B樣品之UHPLC分析在280nm處展示99.4%之單體純度,且未偵測到雜質,該UHPLC分析係在Shimadzu Prominence系統上使用Waters Acquity UPLC BEH200 SEC 1.7μm 4.6×150mm管柱用含有5%異丙醇(v/v)之經無菌過濾的磷酸緩衝鹽水(PBS)溶離。
將抗體1(12.0mg,80.0奈莫耳)稀釋於8.5mL含有10mM硼酸鈉pH 8.4、2.5mM EDTA之還原緩衝液中,且最終抗體濃度為1.3mg/mL。添加TCEP之10mM溶液(2莫耳等效物/抗體,160奈莫耳,16.0μL)且於加熱套中在+37℃下加熱還原混合物2.5小時。在冷卻降至室溫之後,以DMSO溶液(10莫耳等效物/抗體,800奈莫耳,於1.0mL DMSO中)形式添加化合物C。在室溫下混合溶液3小時,隨後藉由添加N-乙醯基半胱胺酸(1600奈莫耳,16μL,100mM)淬火結合,隨
後將混合注入至使用封裝有Superdex 200 PG之GE Healthcare XK26/100管柱之AKTATMFPLC中,用4.5mL/min之無菌過濾磷酸鹽緩衝鹽水(PBS)溶離。合併對應於ADC1C單體峰之溶離份,使用15mL Amicon Ultracell 50KDa MWCO自旋過濾器濃縮,分析且無菌過濾。
BCA分析得到最終ADC1C之濃度為於13.4mL中0.61mg/mL,所獲得的ADC1C之質量為8.14mg(68%產率)。
對經還原之ADC1C樣品的UHPLC分析在280nm及330nm(化合物C特異性)處展示附著至化合物C之若干分子的輕鏈及重鏈之混合,其與2.3分子化合物C/抗體之藥物/抗體比率(DAR)一致,該UHPLC分析係在Shimadzu Prominence系統上使用Phenomenex Aeris 3.6u XB-C18 150×2.1mm管柱使用水與乙腈之梯度溶離。
對ADC1C樣品之UHPLC分析在280nm處展示單體純度為97.8%,該UHPLC分析係於Shimadzu Prominence系統上使用Waters Acquity UPLC BEH200 SEC 1.7μm 4.6×150mm管柱用含有5%異丙醇(v/v)之無菌過濾磷酸鹽緩衝鹽水(PBS)溶離。
將抗體1(15.0mg,100奈莫耳)稀釋於13.5mL之10mM硼酸鈉pH 8.4、1mM EDTA的溶液中,最終抗體濃度1.1mg/mL。添加TCEP之2mM溶液(1.6莫耳等效物/抗體,160奈莫耳,80μL)且於保溫箱中在+37℃下加熱還原混合物90分鐘。在冷卻降至室溫之後,以DMSO溶液(10.0莫耳等效物/抗體,10000奈莫耳,於1.5mL DMSO中)形式添加化合物C。在室溫下混合溶液1.5小時,隨後藉由添加N-乙醯基半胱胺酸(400微莫耳,400μL,10mM)淬火結合,隨後將混合溶液注入至使用封裝有Superdex 200 PG之GE Healthcare HiLoadTM 26/600管柱之AKTATM Pure FPLC中,用2.6mL/min之無菌過濾磷酸鹽緩衝鹽水(PBS)溶離。合併對應於ADC1C-2單體峰之溶離份,使用15mL
Amicon Ultracell 50KDa MWCO自旋過濾器濃縮,分析且無菌過濾。
對經還原之ADC1C-2樣品的UHPLC分析在280nm及330nm(化合物C特異性)處展示附著至化合物C之若干分子的輕鏈及重鏈之混合,其與2.39分子化合物C/抗體之藥物/抗體比率(DAR)一致,該UHPLC分析係在Shimadzu Prominence系統上使用Phenomenex Aeris 3.6u XB-C18 150×2.1mm管柱使用水與乙腈之梯度溶離。
對ADC1C-2樣品之UHPLC分析在280nm處展示超過99.8%(具有0.2%二聚體)之單體純度,該UHPLC分析係於Shimadzu Prominence系統上使用Phenomenex Yarra 3u SEC-3000 300×4.60mm用含有200mM磷酸鉀、250mM氯化鉀及10%異丙醇(v/v)pH 6.95之無菌過濾SEC緩衝液溶離。HPLC濃度分析得到最終ADC1C-2之濃度為於7.72mL中0.98mg/mL,所獲得的ADC1C-2之質量為7.5mg(50%產率)。
上述抗體1為赫賽汀。
於如上文所描述之細胞毒性分析中評估ADC1A之細胞毒性,且結果展示於圖1中。實線代表抗原表現細胞株(AECL),且虛線代表抗原非表現細胞株(ANECL),且誤差條指示±標準差。
上述AECL為BT474,且ANECL為MDAMB468。
對年齡為8-12週的CB.17 SCID小鼠在側腹中皮膚注射1mm3腫瘤片段子。當腫瘤達至平均尺寸為100-150mg時開始治療。小鼠每週稱重兩次。腫瘤尺寸每週量測兩次。單獨監控動物。無論哪個首先到達,實驗之終點為腫瘤體積為1000mm3或67天。可追蹤反應者更長時間。
對10個異種移植小鼠之群組靜脈內注射含0.2mL抗體藥物結合物
(ADC)或裸抗體之磷酸鹽緩衝鹽水(媒劑)或者單獨0.2mL媒劑。調節ADC之濃度以得到(例如)於單一劑量中0.3mg ADC/kg體重或1.0mg ADC/kg體重。可以(例如)1週之間隔向各小鼠提供三個一致劑量。
圖2展示與媒劑(點線)對照物相比用0.3mg/kg(實線)或1.0mg/kg(虛線)之ADC1A給藥對10個小鼠之群組的平均腫瘤體積之影響。
圖3展示與媒劑(點線)對照物相比使用0.3mg/kg(實線)或1.0mg/kg(虛線)之ADC1C給藥對10個小鼠之群組的平均腫瘤體積之影響。
圖2及圖3中所報告的研究中之腫瘤為BT474腫瘤。
全部文獻及上文所提及之其他參考文獻以引用之方式併入本文中。
Ac 乙醯基
Acm 乙醯胺基甲基
Alloc 烯丙氧羰基
Boc 二碳酸二第三丁酯
t-Bu 第三丁基
Bzl 苯甲基,其中Bzl-OMe為甲氧基苯甲基且Bzl-Me為甲苯
Cbz或Z 苯甲氧基-羰基,其中Z-Cl及Z-Br分別為氯苯甲氧基羰基及溴苯甲氧基羰基
DMF N,N-二甲基甲醯胺
Dnp 二硝基苯基
DTT 二硫蘇糖醇
Fmoc 9H-茀-9-基甲氧基羰基
imp N-10亞胺保護基:3-(2-甲氧基乙氧基)丙酸酯-Val-
Ala-PAB
MC-OSu 順丁烯二醯亞胺基己醯基-O-N-丁二醯亞胺
Moc 甲氧甲醯基
MP 順丁烯二醯亞胺丙醯胺
Mtr 4-甲氧基-2,3,6-三甲基苯磺醯基
PAB 對胺基苯甲氧基羰基
PEG 伸乙基氧基
PNZ 胺基甲酸對硝基苯甲基酯
Psec 2-(苯磺醯基)乙氧羰基
TBDMS 第三丁基二甲基矽烷基
TBDPS 第三丁基二苯基矽烷基
Teoc 2-(三甲基矽烷基)乙氧羰基
Tos 甲苯磺醯基
Troc 2,2,2-三氯乙氧羰基氯化物
Trt 三苯甲基
Xan 黃嘌呤酸基
Claims (18)
- 一種化合物,其係選自A:
- 一種結合物,其具有式ConjAB:
- 如請求項2之結合物,其中該細胞結合劑為抗體或其活性片段。
- 如請求項3之結合物,其中該抗體或抗體片段為腫瘤相關抗原之抗體或抗體片段。
- 如請求項3之結合物,其中該抗體或抗體片段為結合至一或多個選自(1)-(88)之腫瘤相關抗原或細胞表面受體之抗體:(1)BMPR1B;(2)E16;(3)STEAP1;(4)0772P;(5)MPF;(6)Napi3b;(7)Sema 5b;(8)PSCA hlg;(9)ETBR;(10)MSG783;(11)STEAP2; (12)TrpM4;(13)CRIPTO;(14)CD21;(15)CD79b;(16)FcRH2;(17)HER2;(18)NCA;(19)MDP;(20)IL20R-α;(21)短蛋白聚糖;(22)EphB2R;(23)ASLG659;(24)PSCA;(25)GEDA;(26)BAFF-R;(27)CD22;(28)CD79a;(29)CXCR5;(30)HLA-DOB;(31)P2X5;(32)CD72;(33)LY64;(34)FcRH1;(35)IRTA2;(36)TENB2;(37)PSMA-FOLH1; (38)SST;(38.1)SSTR2;(38.2)SSTR5;(38.3)SSTR1;(38.4)SSTR3;(38.5)SSTR4;(39)ITGAV;(40)ITGB6;(41)CEACAM5;(42)MET;(43)MUC1;(44)CA9;(45)EGFRvIII;(46)CD33;(47)CD19;(48)IL2RA;(49)AXL;(50)CD30-TNFRSF8;(51)BCMA-TNFRSF17;(52)CT Ags-CTA;(53)CD174(Lewis Y)-FUT3;(54)CLEC14A;(55)GRP78-HSPA5;(56)CD70;(57)幹細胞特異性抗原;(58)ASG-5; (59)ENPP3;(60)PRR4;(61)GCC-GUCY2C;(62)Liv-1-SLC39A6;(63)5T4;(64)CD56-NCMA1;(65)CanAg;(66)FOLR1;(67)GPNMB;(68)TIM-1-HAVCR1;(69)RG-1/前列腺腫瘤目標Mindin-Mindin/RG-1;(70)B7-H4-VTCN1;(71)PTK7;(72)CD37;(73)CD138-SDC1;(74)CD74;(75)緊密連接蛋白-CLs;(76)EGFR;(77)Her3;(78)RON-MST1R;(79)EPHA2;(80)CD20-MS4A1;(81)生腱蛋白C-TNC;(82)FAP;(83)DKK-1;(84)CD52; (85)CS1-SLAMF7;(86)內皮因子-ENG;(87)膜聯蛋白A1-ANXA1;(88)V-CAM(CD106)-VCAM1。
- 如請求項2至5中任一項之結合物,其中該抗體或抗體片段為半胱胺酸經工程改造之抗體。
- 如請求項2至6中任一項之結合物,其中藥物(D)比抗體(Ab)之藥物負載量(p)為1至約8的整數。
- 如請求項7之結合物,其中p為1、2、3或4。
- 一種組合物,其包含如請求項2至8中任一項之藥物結合化合物之混合物,其中抗體-藥物結合化合物之混合物中的平均藥物負載量/抗體為約1至約8。
- 如請求項2至8中任一項之結合物或如請求項9之組合物,其用於療法。
- 如請求項2至8中任一項之結合物或如請求項9之組合物,其用於個體之增生性疾病之治療。
- 如請求項11之結合物或組合物,其中該疾病為癌症。
- 一種醫藥組合物,其包含如請求項2至8中任一項之結合物或如請求項9之組合物及醫藥學上可接受之稀釋劑、載劑或賦形劑。
- 如請求項13之醫藥組合物,其進一步包含治療有效量之化學治療劑。
- 一種如請求項2至8中任一項之結合物或如請求項9之組合物的用途,其用於製備用於治療個體之增生性疾病之藥劑。
- 一種治療癌症之方法,其包含向患者投與如請求項14之醫藥組合物。
- 如請求項16之方法,其中向該患者投與化學治療劑與該結合物 之組合。
- 一種製備如請求項2至8中任一項之結合物或如請求項9之組合物的方法,該方法包含使細胞結合劑與如請求項1中所定義之化合物A、B或C反應之步驟。
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EA024118B1 (ru) | 2010-04-15 | 2016-08-31 | Сиэтл Дженетикс, Инк. | Конъюгаты пирролбензодиазепина направленного действия |
AU2012311505B2 (en) | 2011-09-20 | 2016-09-29 | Medimmune Limited | Pyrrolobenzodiazepines as unsymmetrical dimeric PBD compounds for inclusion in targeted conjugates |
EP2751111B1 (en) | 2011-10-14 | 2017-04-26 | MedImmune Limited | Asymmetrical bis-(5H-Pyrrolo[2,1-c][1,4]benzodiazepin-5-one) derivatives for the treatment of proliferative or autoimmune diseases |
EP3309162A1 (en) | 2011-10-14 | 2018-04-18 | Seattle Genetics, Inc. | Targeted conjugates of pyrrolobenzodiazepines |
EA027386B1 (ru) | 2011-10-14 | 2017-07-31 | Медимьюн Лимитед | Пирролобензодиазепины |
CA2850373C (en) | 2011-10-14 | 2019-07-16 | Seattle Genetics, Inc. | Pyrrolobenzodiazepines and targeted conjugates |
TR201902494T4 (tr) | 2012-10-12 | 2019-03-21 | Medimmune Ltd | Pirrolobenzodiazepinler ve onların konjugatları. |
CA2885305C (en) | 2012-10-12 | 2019-11-12 | Spirogen Sarl | Synthesis and intermediates of pyrrolobenzodiazepine derivatives for conjugation |
PT2839860T (pt) | 2012-10-12 | 2019-07-29 | Medimmune Ltd | Pirrolobenzodiazepinas e conjugados das mesmas |
CN105246894A (zh) | 2012-12-21 | 2016-01-13 | 斯皮罗根有限公司 | 用于治疗增殖性和自身免疫疾病的非对称吡咯并苯并二氮杂卓二聚物 |
EA031585B1 (ru) | 2012-12-21 | 2019-01-31 | Медимьюн Лимитед | Пирролобензодиазепины и их конъюгаты |
CN105142674B (zh) | 2013-03-13 | 2018-11-13 | 麦迪穆有限责任公司 | 吡咯并苯并二氮杂卓和其结合物 |
NZ710745A (en) | 2013-03-13 | 2019-03-29 | Genentech Inc | Pyrrolobenzodiazepines and conjugates thereof |
GB201317981D0 (en) | 2013-10-11 | 2013-11-27 | Spirogen Sarl | Pyrrolobenzodiazepines and conjugates thereof |
GB201317982D0 (en) | 2013-10-11 | 2013-11-27 | Spirogen Sarl | Pyrrolobenzodiazepines and conjugates thereof |
US10188746B2 (en) | 2014-09-10 | 2019-01-29 | Medimmune Limited | Pyrrolobenzodiazepines and conjugates thereof |
GB201416112D0 (en) | 2014-09-12 | 2014-10-29 | Medimmune Ltd | Pyrrolobenzodiazepines and conjugates thereof |
CN107124870A (zh) * | 2014-09-17 | 2017-09-01 | 基因泰克公司 | 包含抗her2抗体和吡咯并苯并二氮杂*的免疫缀合物 |
AU2015352545B2 (en) | 2014-11-25 | 2020-10-15 | Adc Therapeutics Sa | Pyrrolobenzodiazepine-antibody conjugates |
HUE050312T2 (hu) | 2015-11-10 | 2020-11-30 | Medimmune Llc | ASCT2-RE specifikus kötõmolekulák és alkalmazásaik |
KR20180078329A (ko) | 2015-11-25 | 2018-07-09 | 주식회사 레고켐 바이오사이언스 | 분지된 링커를 포함하는 항체-약물 접합체 및 이의 제조방법 |
GB201601431D0 (en) | 2016-01-26 | 2016-03-09 | Medimmune Ltd | Pyrrolobenzodiazepines |
GB201602356D0 (en) | 2016-02-10 | 2016-03-23 | Medimmune Ltd | Pyrrolobenzodiazepine Conjugates |
GB201602359D0 (en) | 2016-02-10 | 2016-03-23 | Medimmune Ltd | Pyrrolobenzodiazepine Conjugates |
GB201607478D0 (en) | 2016-04-29 | 2016-06-15 | Medimmune Ltd | Pyrrolobenzodiazepine Conjugates |
WO2017201132A2 (en) | 2016-05-18 | 2017-11-23 | Mersana Therapeutics, Inc. | Pyrrolobenzodiazepines and conjugates thereof |
JP7049276B2 (ja) | 2016-06-24 | 2022-04-06 | メルサナ セラピューティクス インコーポレイテッド | ピロロベンゾジアゼピンおよびその結合体 |
EP3496763A1 (en) * | 2016-08-11 | 2019-06-19 | Genentech, Inc. | Pyrrolobenzodiazepine prodrugs and antibody conjugates thereof |
GB201617466D0 (en) * | 2016-10-14 | 2016-11-30 | Medimmune Ltd | Pyrrolobenzodiazepine conjugates |
GB201702031D0 (en) * | 2017-02-08 | 2017-03-22 | Medlmmune Ltd | Pyrrolobenzodiazepine-antibody conjugates |
RS61795B1 (sr) | 2017-02-08 | 2021-06-30 | Adc Therapeutics Sa | Konjugati pirolobenzodiazepin antitela |
BR112019020136A2 (pt) | 2017-03-29 | 2020-04-22 | Legochem Biosciences Inc | profármaco de dímero de pirrolobenzodiazepina e composto de conjugado ligando-ligante do mesmo |
WO2018192944A1 (en) | 2017-04-18 | 2018-10-25 | Medimmune Limited | Pyrrolobenzodiazepine conjugates |
GB201721337D0 (en) * | 2017-12-19 | 2018-01-31 | Medlmmune Ltd | Pyrrolobenzodiazepine conjugates |
MX2019015042A (es) * | 2017-06-14 | 2020-08-06 | Adc Therapeutics Sa | Regimen de dosificacion. |
IL272304B1 (en) | 2017-08-01 | 2024-06-01 | Medimmune Llc | Conjugation of antibody with monoclonal BCMA drug |
AU2018316532B2 (en) | 2017-08-18 | 2022-11-24 | Medimmune Limited | Pyrrolobenzodiazepine conjugates |
TWI820044B (zh) | 2017-09-29 | 2023-11-01 | 日商第一三共股份有限公司 | 抗體-吡咯并苯二氮呯衍生物複合體 |
US11638760B2 (en) | 2017-11-27 | 2023-05-02 | Mersana Therapeutics, Inc. | Pyrrolobenzodiazepine antibody conjugates |
CN111757757A (zh) | 2017-12-21 | 2020-10-09 | 梅尔莎纳医疗公司 | 吡咯并苯并二氮呯抗体共轭物 |
GB201803342D0 (en) | 2018-03-01 | 2018-04-18 | Medimmune Ltd | Methods |
SG11202009308WA (en) * | 2018-03-28 | 2020-10-29 | Mitsubishi Tanabe Pharma Corp | DRUG CONJUGATES OF cMET MONOCLONAL BINDING AGENTS, AND USES THEREOF |
GB201806022D0 (en) | 2018-04-12 | 2018-05-30 | Medimmune Ltd | Pyrrolobenzodiazepines and conjugates thereof |
US20210283141A1 (en) * | 2018-05-25 | 2021-09-16 | Medimmune Limited | Pyrrolobenzodiazepine conjugates |
CA3112977A1 (en) | 2018-10-19 | 2020-04-23 | Medimmune Limited | Pyrrolobenzodiazepine conjugates |
CA3115136A1 (en) | 2018-10-19 | 2020-04-23 | Medimmune Limited | Pyrrolobenzodiazepine conjugates |
SG11202104993SA (en) | 2018-11-14 | 2021-06-29 | Daiichi Sankyo Co Ltd | Anti-cdh6 antibody-pyrrolobenzodiazepine derivative conjugate |
JP2022524880A (ja) | 2019-03-15 | 2022-05-10 | メドイミューン・リミテッド | がんの治療における使用のための、アゼチドベンゾジアゼピン二量体及びこれを含む複合体 |
EP3949987A4 (en) | 2019-03-25 | 2023-02-22 | Daiichi Sankyo Company, Limited | ANTI-HER2 ANTIBODY PYRROLOBENZODIAZEPINE DERIVATIVE CONJUGATE |
JPWO2020196474A1 (zh) | 2019-03-25 | 2020-10-01 | ||
EP3949988A4 (en) | 2019-03-27 | 2022-11-16 | Daiichi Sankyo Company, Limited | COMBINATION OF AN ANTIBODY-DERIVATIVE CONJUGATE OF PYRROLOBENZODIAZEPINE AND A PARP INHIBITOR |
WO2021030358A1 (en) | 2019-08-12 | 2021-02-18 | Regeneron Pharmaceuticals, Inc. | Macrophage stimulating 1 receptor (mst1r) variants and uses thereof |
KR20210028544A (ko) | 2019-09-04 | 2021-03-12 | 주식회사 레고켐 바이오사이언스 | 인간 ror1에 대한 항체를 포함하는 항체 약물 접합체 및 이의 용도 |
US20240123081A1 (en) | 2019-10-25 | 2024-04-18 | Medimmune, Llc | Branched moiety for use in conjugates |
EP4209506A1 (en) | 2020-09-02 | 2023-07-12 | Daiichi Sankyo Company, Limited | Novel endo-?-n-acetylglucosaminidase |
WO2022053651A2 (en) | 2020-09-10 | 2022-03-17 | Precirix N.V. | Antibody fragment against fap |
JP2024503657A (ja) | 2021-01-13 | 2024-01-26 | メモリアル スローン-ケタリング キャンサー センター | 抗体-ピロロベンゾジアゼピン誘導体コンジュゲート |
GB202105186D0 (en) | 2021-04-12 | 2021-05-26 | Medimmune Ltd | Pyrrolobenzodiazepine conjugates |
TW202334238A (zh) | 2021-11-30 | 2023-09-01 | 日商第一三共股份有限公司 | 蛋白酶分解性遮蔽抗體 |
WO2023203135A1 (en) | 2022-04-22 | 2023-10-26 | Precirix N.V. | Improved radiolabelled antibody |
WO2023213801A1 (en) | 2022-05-02 | 2023-11-09 | Precirix N.V. | Pre-targeting |
Family Cites Families (360)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3361742A (en) | 1964-12-07 | 1968-01-02 | Hoffmann La Roche | 5-oxo-1h-pyrrolo-[2, 1-c][1, 4]-benzodiazepin-2-crylamides |
US3523941A (en) | 1967-03-06 | 1970-08-11 | Hoffmann La Roche | Benzodiazepine compounds and process for their preparation |
US3524849A (en) | 1967-10-27 | 1970-08-18 | Hoffmann La Roche | Process for the preparation of pyrrolo-benzodiazepine acrylamides and intermediates useful therein |
JPS4843755B1 (zh) | 1969-06-26 | 1973-12-20 | ||
FR2027356A1 (en) | 1968-12-30 | 1970-09-25 | Fujisawa Pharmaceutical Co | Benzodiazepinone antibiotics |
JPS6053033B2 (ja) | 1976-12-28 | 1985-11-22 | 財団法人微生物化学研究会 | 新制癌抗生物質マゼスラマイシン及びその製造方法 |
JPS585916B2 (ja) | 1977-12-27 | 1983-02-02 | 株式会社ミドリ十字 | 新規ベンゾジアゼピン系化合物 |
JPS5615289A (en) | 1979-07-17 | 1981-02-14 | Green Cross Corp:The | Novel benzodiazepinnbased compound 3 |
JPS57131791A (en) | 1980-12-31 | 1982-08-14 | Fujisawa Pharmaceut Co Ltd | Benzodiazepine derivative and its preparation |
CA1173441A (en) | 1981-02-27 | 1984-08-28 | Hoffmann-La Roche Limited | Imidazodiazepines |
CA1184175A (en) | 1981-02-27 | 1985-03-19 | Walter Hunkeler | Imidazodiazepines |
CA1185602A (en) | 1981-02-27 | 1985-04-16 | Emilio Kyburz | Imidazodiazepines |
JPS58180487A (ja) | 1982-04-16 | 1983-10-21 | Kyowa Hakko Kogyo Co Ltd | 抗生物質dc−81およびその製造法 |
US4427588A (en) | 1982-11-08 | 1984-01-24 | Bristol-Myers Company | Process for conversion of oxotomaymycin to tomaymycin |
US4427587A (en) | 1982-11-10 | 1984-01-24 | Bristol-Myers Company | Total synthesis of antitumor antibiotics BBM-2040A and BBM-2040B |
JPS59152329A (ja) | 1983-02-17 | 1984-08-31 | Green Cross Corp:The | 局所障害抑制剤 |
US4816567A (en) | 1983-04-08 | 1989-03-28 | Genentech, Inc. | Recombinant immunoglobin preparations |
FR2586683B1 (fr) | 1985-08-29 | 1988-07-01 | Centre Nat Rech Scient | Nouveaux derives de neothramycine, leur procede de preparation et leur application en tant que medicaments |
US5583024A (en) | 1985-12-02 | 1996-12-10 | The Regents Of The University Of California | Recombinant expression of Coleoptera luciferase |
JP2660201B2 (ja) | 1988-08-05 | 1997-10-08 | 塩野義製薬株式会社 | 新規ピロロ[1,4]ベンゾジアゼピン誘導体および老人性痴呆薬 |
AU6355090A (en) | 1989-08-23 | 1991-04-03 | Scripps Clinic And Research Foundation | Compositions and methods for detection and treatment of epstein-barr virus infection and immune disorders |
JPH053790A (ja) | 1990-04-19 | 1993-01-14 | Fujisawa Pharmaceut Co Ltd | デヒドロペプチダーゼ−i |
US5256643A (en) | 1990-05-29 | 1993-10-26 | The Government Of The United States | Human cripto protein |
WO1992007574A1 (en) | 1990-10-25 | 1992-05-14 | Tanox Biosystems, Inc. | Glycoproteins associated with membrane-bound immunoglobulins as antibody targets on b cells |
US5543503A (en) | 1991-03-29 | 1996-08-06 | Genentech Inc. | Antibodies to human IL-8 type A receptor |
US5440021A (en) | 1991-03-29 | 1995-08-08 | Chuntharapai; Anan | Antibodies to human IL-8 type B receptor |
DK0577752T4 (da) | 1991-03-29 | 2007-10-22 | Genentech Inc | Human PF4A receptorer og deres anvendelse |
FR2676230B1 (fr) | 1991-05-07 | 1993-08-27 | Centre Nat Rech Scient | Nouveaux derives de pyrrolo [1,4]-benzodiazepines, leur procede de preparation et medicaments les contenant. |
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 |
US5362852A (en) | 1991-09-27 | 1994-11-08 | Pfizer Inc. | Modified peptide derivatives conjugated at 2-hydroxyethylamine moieties |
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 |
GB9205051D0 (en) | 1992-03-09 | 1992-04-22 | Cancer Res Campaign Tech | Pyrrolobenzodiazepine derivatives,their preparation,and compositions containing them |
FR2696176B1 (fr) | 1992-09-28 | 1994-11-10 | Synthelabo | Dérivés de pipéridine, leur préparation et leur application en thérapeutique. |
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 |
US6214345B1 (en) | 1993-05-14 | 2001-04-10 | Bristol-Myers Squibb Co. | Lysosomal enzyme-cleavable antitumor drug conjugates |
GB9316162D0 (en) | 1993-08-04 | 1993-09-22 | Zeneca Ltd | Fungicides |
US5773223A (en) | 1993-09-02 | 1998-06-30 | Chiron Corporation | Endothelin B1, (ETB1) receptor polypeptide and its encoding nucleic acid methods, and uses thereof |
EP0647450A1 (en) | 1993-09-09 | 1995-04-12 | BEHRINGWERKE Aktiengesellschaft | Improved prodrugs for enzyme mediated activation |
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 |
US6218519B1 (en) | 1996-04-12 | 2001-04-17 | Pro-Neuron, Inc. | Compounds and methods for the selective treatment of cancer and bacterial infections |
AU722499B2 (en) | 1996-05-17 | 2000-08-03 | Schering Corporation | Human B-cell antigens, related reagents |
US6759509B1 (en) | 1996-11-05 | 2004-07-06 | Bristol-Myers Squibb Company | Branched peptide linkers |
US5945511A (en) | 1997-02-20 | 1999-08-31 | Zymogenetics, Inc. | Class II cytokine receptor |
US7033827B2 (en) | 1997-02-25 | 2006-04-25 | Corixa Corporation | Prostate-specific polynucleotide compositions |
US20030185830A1 (en) | 1997-02-25 | 2003-10-02 | Corixa Corporation | Compositions and methods for the therapy and diagnosis of prostate cancer |
US6541212B2 (en) | 1997-03-10 | 2003-04-01 | The Regents Of The University Of California | Methods for detecting prostate stem cell antigen protein |
ES2221982T3 (es) | 1997-03-10 | 2005-01-16 | The Regents Of The University Of California | Antigeno de celulas madre de la prostata (psca). |
US6261791B1 (en) | 1997-03-10 | 2001-07-17 | The Regents Of The University Of California | Method for diagnosing cancer using specific PSCA antibodies |
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) |
WO1998051824A1 (en) | 1997-05-15 | 1998-11-19 | Abbott Laboratories | Reagents and methods useful for detecting disease of the urinary tract |
WO1998051805A1 (en) | 1997-05-15 | 1998-11-19 | Abbott Laboratories | Reagents and methods useful for detecting diseases of the prostate |
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 |
WO2004031238A2 (en) | 2002-10-03 | 2004-04-15 | Mcgill Univeristy | Antibodies and cyclic peptides which bind cea (carcinoembryonic antigen) and their use as cancer therapeutics |
CA2323071C (en) | 1998-03-13 | 2011-06-21 | The Burnham Institute | Molecules that home to various selected organs or tissues |
US6534482B1 (en) | 1998-05-13 | 2003-03-18 | Epimmune, Inc. | Expression vectors for stimulating an immune response and methods of using the same |
US20020187472A1 (en) | 2001-03-09 | 2002-12-12 | Preeti Lal | Steap-related protein |
EA003398B1 (ru) | 1998-05-22 | 2003-04-24 | Дайити Фармасьютикал Ко., Лтд. | Лекарственный комплекс c полимерным носителем |
US20030064397A1 (en) | 1998-05-22 | 2003-04-03 | Incyte Genomics, Inc. | Transmembrane protein differentially expressed in prostate and lung tumors |
WO2002016429A2 (en) | 2000-08-24 | 2002-02-28 | Genentech, Inc. | Compositions and methods for the diagnosis and treatment of tumor |
DE69934618T2 (de) | 1998-07-08 | 2007-05-03 | E-Ink Corp., Cambridge | Verbesserte farbige mikroverkapselte elektrophoretische Anzeige |
GB9818731D0 (en) | 1998-08-27 | 1998-10-21 | Univ Portsmouth | Compounds |
WO2000012508A2 (en) | 1998-08-27 | 2000-03-09 | Spirogen Limited | Pyrrolbenzodiazepines |
GB9818732D0 (en) | 1998-08-27 | 1998-10-21 | Univ Portsmouth | Collection of compounds |
WO2000012130A1 (en) | 1998-08-27 | 2000-03-09 | Smithkline Beecham Corporation | Rp105 agonists and antagonists |
GB9818730D0 (en) | 1998-08-27 | 1998-10-21 | Univ Portsmouth | Collections of compounds |
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 |
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 |
ATE407949T1 (de) | 1998-12-30 | 2008-09-15 | Beth Israel Hospital | Charakterisierung der proteinfamilie von soc/crac kalziumkanälen |
CN1201004C (zh) | 1999-01-29 | 2005-05-11 | 考丽克萨有限公司 | HER-2/neu融合蛋白 |
GB9905124D0 (en) | 1999-03-05 | 1999-04-28 | Smithkline Beecham Biolog | Novel compounds |
US7465785B2 (en) | 1999-03-08 | 2008-12-16 | Genentech, Inc. | Polypeptide encoded by a nucleic acid over-expressed in melanoma |
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 |
US6268488B1 (en) | 1999-05-25 | 2001-07-31 | Barbas, Iii Carlos F. | Prodrug activation using catalytic antibodies |
AU4952600A (en) | 1999-06-03 | 2000-12-28 | Takeda Chemical Industries Ltd. | Screening method with the use of cd100 |
CN100482281C (zh) | 1999-06-25 | 2009-04-29 | 基因技术股份有限公司 | 抗ErbB抗体-类美坦素偶联物在制备药物中的应用 |
US6302318B1 (en) | 1999-06-29 | 2001-10-16 | General Electric Company | Method of providing wear-resistant coatings, and related articles |
US20030119113A1 (en) | 1999-07-20 | 2003-06-26 | Genentech, Inc. | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
US7297770B2 (en) | 1999-08-10 | 2007-11-20 | Genentech, Inc. | PRO6496 polypeptides |
US7294696B2 (en) | 1999-08-17 | 2007-11-13 | Genentech Inc. | PRO7168 polypeptides |
US6909006B1 (en) | 1999-08-27 | 2005-06-21 | Spirogen Limited | Cyclopropylindole derivatives |
EP1208202A2 (en) | 1999-09-01 | 2002-05-29 | Genentech, Inc. | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
US20030206918A1 (en) | 1999-09-10 | 2003-11-06 | Corixa Corporation | Compositions and methods for the therapy and diagnosis of ovarian cancer |
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 |
CN1413220A (zh) | 1999-10-29 | 2003-04-23 | 杰南技术公司 | 抗前列腺干细胞抗原(psca)抗体组合物及其应用方法 |
CA2393126C (en) | 1999-11-29 | 2016-05-24 | 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 |
EP1248800A2 (en) | 1999-11-30 | 2002-10-16 | Corixa Corporation | Compositions and methods for therapy and diagnosis of breast cancer |
EP1239866A4 (en) | 1999-12-10 | 2005-02-09 | Epimmune Inc | INDUCTION OF HER2 / NEU CELLULAR IMMUNE RESPONSES USING PEPTIDE AND NUCLEIC ACID-CONTAINING COMPOSITIONS |
DK1616575T3 (da) | 1999-12-23 | 2012-09-10 | Zymogenetics Inc | Fremgangsmåde til behandling af inflammation |
ATE485306T1 (de) | 1999-12-23 | 2010-11-15 | Zymogenetics Inc | Löslicher interleukin-20-rezeptor |
US6610286B2 (en) | 1999-12-23 | 2003-08-26 | Zymogenetics, Inc. | Method for treating inflammation using soluble receptors to interleukin-20 |
NZ502058A (en) | 1999-12-23 | 2003-11-28 | Ovita Ltd | Isolated mutated nucleic acid molecule for regulation of ovulation rate |
AU784285B2 (en) | 1999-12-24 | 2006-03-02 | Genentech Inc. | Methods and compositions for prolonging elimination half-times of bioactive compounds |
US20040001827A1 (en) | 2002-06-28 | 2004-01-01 | Dennis Mark S. | Serum albumin binding peptides for tumor targeting |
US7297333B2 (en) | 2000-01-20 | 2007-11-20 | Genentech, Inc. | Anti-PRO10268 antibodies |
US20030224379A1 (en) | 2000-01-21 | 2003-12-04 | Tang Y. Tom | Novel nucleic acids and polypeptides |
US20020039573A1 (en) | 2000-01-21 | 2002-04-04 | Cheever Martin A. | Compounds and methods for prevention and treatment of HER-2/neu associated malignancies |
AU2001243142A1 (en) | 2000-02-03 | 2001-08-14 | Hyseq, Inc. | Novel nucleic acids and polypeptides |
US20030104562A1 (en) | 2000-02-11 | 2003-06-05 | Genentech, Inc. | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
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 |
AU2001238596A1 (en) | 2000-02-22 | 2001-09-03 | Millennium Pharmaceuticals, Inc. | 18607, a novel human calcium channel |
US20040052793A1 (en) | 2001-02-22 | 2004-03-18 | Carter Paul J. | Caspase activivated prodrugs therapy |
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 |
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 |
AU2001250412A1 (en) | 2000-03-31 | 2001-10-08 | Ipf Pharmaceuticals Gmbh | Diagnostic and medicament for analysing the cell surface proteome of tumour and inflammatory cells and for treating tumorous and inflammatory diseases, preferably using specific chemokine receptor analysis and the chemokine receptor-ligand interaction |
AU2001253140A1 (en) | 2000-04-03 | 2001-10-15 | The Government Of The United States Of America, As Represented By The Secretary Of The Department Of Health And Human Services | Tumor markers in ovarian cancer |
EP1301594A2 (en) | 2000-04-07 | 2003-04-16 | Arena Pharmaceuticals, Inc. | Non-endogenous, consstitutively activated known g protein-coupled receptors |
WO2001088133A2 (en) | 2000-05-18 | 2001-11-22 | Lexicon Genetics Incorporated | Human semaphorin homologs and polynucleotides encoding the same |
AU2001274888A1 (en) | 2000-05-19 | 2001-12-03 | Human Genome Sciences, Inc. | Nucleic acids, proteins, and antibodies |
WO2001094641A2 (en) | 2000-06-09 | 2001-12-13 | Idec Pharmaceuticals Corporation | Gene targets and ligands that bind thereto for treatment and diagnosis of ovarian carcinomas |
EP1297130A2 (en) | 2000-06-16 | 2003-04-02 | Incyte Genomics, Inc. | G-protein coupled receptors |
MXPA02012749A (es) | 2000-06-30 | 2003-10-06 | Amgen Inc | Moleculas semejantes a b7 y sus usos. |
WO2002002587A1 (en) | 2000-06-30 | 2002-01-10 | Human Genome Sciences, Inc. | B7-like polynucleotides, polypeptides, and antibodies |
EP1383892A2 (en) | 2000-06-30 | 2004-01-28 | Incyte Genomics, Inc. | Human extracellular matrix and cell adhesion polypeptides |
WO2002006339A2 (en) | 2000-07-03 | 2002-01-24 | 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 |
AU2001283507A1 (en) | 2000-07-27 | 2002-02-13 | Mayo Foundation For Medical Education And Research | B7-h3 and b7-h4, novel immunoregulatory molecules |
CA2417671A1 (en) | 2000-07-28 | 2002-02-07 | Ulrich Wissenbach | Trp8, trp9 and trp10, novel markers for cancer |
US7229623B1 (en) | 2000-08-03 | 2007-06-12 | Corixa Corporation | Her-2/neu fusion proteins |
CN1537164A (zh) | 2000-08-14 | 2004-10-13 | 治疗和诊断Her-2/neu相关恶性肿瘤的组合物和方法 | |
WO2002013847A2 (en) | 2000-08-14 | 2002-02-21 | Corixa Corporation | Methods for diagnosis and therapy of hematological and virus-associated malignancies |
GB0020953D0 (en) | 2000-08-24 | 2000-10-11 | Smithkline Beecham Biolog | Vaccine |
AU2001290548A1 (en) | 2000-09-11 | 2002-03-26 | Hyseq, Inc. | Novel nucleic acids and polypeptides |
ES2267814T3 (es) | 2000-09-15 | 2007-03-16 | Zymogenetics, Inc. | Metodo para tratar la inflamacion. |
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 |
NZ525380A (en) | 2000-09-18 | 2008-06-30 | Biogen Idec Inc | Non-fucosylated forms of Cripto and their use as tumor blocking agents |
UA83458C2 (uk) | 2000-09-18 | 2008-07-25 | Байоджен Айдек Ма Інк. | Виділений поліпептид baff-r (рецептор фактора активації в-клітин сімейства tnf) |
DE60115265T2 (de) | 2000-09-19 | 2006-08-10 | Lee, Moses, Holland | Zusammensetzungen und verfahren zur verwendung achiraler analoge von cc-1065 und den duocarmycinen |
EP1474528A4 (en) | 2000-10-13 | 2006-06-14 | Protein Design Labs Inc | METHODS FOR DIAGNOSING PROSTATE CANCER, COMPOSITIONS AND METHODS FOR SCREENING PROSTATE CANCER MODULATORS |
ES2329012T3 (es) | 2000-11-07 | 2009-11-20 | Zymogenetics, Inc. | Receptor del factor de necrosis tumoral humano. |
US20020150573A1 (en) | 2000-11-10 | 2002-10-17 | The Rockefeller University | Anti-Igalpha-Igbeta antibody for lymphoma therapy |
US20040018194A1 (en) | 2000-11-28 | 2004-01-29 | Francisco Joseph A. | Recombinant anti-CD30 antibodies and uses thereof |
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 |
US20030119119A1 (en) | 2001-01-16 | 2003-06-26 | Genentech, Inc. | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
US20030119126A1 (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 |
EP1425302A2 (en) | 2001-01-24 | 2004-06-09 | Protein Design Labs | Methods of diagnosis of breast cancer, compositions and methods of screening for modulators of breast cancer |
AU2002251841A1 (en) | 2001-01-30 | 2002-08-12 | Corixa Corporation | Compositions and methods for the therapy and diagnosis of pancreatic cancer |
US20040170994A1 (en) | 2001-02-12 | 2004-09-02 | Callen David Frederick | DNA sequences for human tumour suppressor genes |
AU2002258518A1 (en) | 2001-03-14 | 2002-09-24 | Millennium Pharmaceuticals, Inc. | Nucleic acid molecules and proteins for the identification, assessment, prevention, and therapy of ovarian cancer |
EP1243276A1 (en) | 2001-03-23 | 2002-09-25 | Franciscus Marinus Hendrikus De Groot | Elongated and multiple spacers containing activatible prodrugs |
WO2002078524A2 (en) | 2001-03-28 | 2002-10-10 | Zycos Inc. | Translational profiling |
US6362331B1 (en) | 2001-03-30 | 2002-03-26 | Council Of Scientific And Industrial Research | Process for the preparation of antitumor agents |
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 |
MXPA03009510A (es) | 2001-04-17 | 2005-04-29 | Univ Arkansas | Secuencias de repeticion del gen ca125 y su uso para intervenciones de diagnosticos y terapeuticas. |
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 |
AU2002334799B2 (en) | 2001-04-26 | 2009-05-07 | Biogen Ma Inc. | Cripto-specific antibodies |
CA2715570A1 (en) | 2001-04-26 | 2002-11-07 | Biogen Idec Ma Inc. | Cripto blocking antibodies and uses thereof |
US6884869B2 (en) | 2001-04-30 | 2005-04-26 | Seattle Genetics, Inc. | Pentapeptide compounds and uses related thereto |
EP1988097A1 (en) | 2001-05-09 | 2008-11-05 | 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 |
DK2116259T3 (da) | 2001-05-24 | 2012-05-21 | Zymogenetics Inc | TACI-immunoglobulinfusionsproteiner |
US7157558B2 (en) | 2001-06-01 | 2007-01-02 | Genentech, Inc. | Polypeptide encoded by a polynucleotide overexpresses in tumors |
WO2003000842A2 (en) | 2001-06-04 | 2003-01-03 | Curagen Corporation | Novel proteins and nucleic acids encoding same |
WO2002098358A2 (en) | 2001-06-04 | 2002-12-12 | Eos Biotechnology, Inc. | Methods of diagnosis and treatment of androgen-dependent prostate cancer, prostate cancer undergoing androgen-withdrawal, and androgen-independent prostate cancer |
AU2002312241A1 (en) | 2001-06-05 | 2002-12-16 | Exelixis, Inc. | B3galts as modifiers of the p53 pathway and methods of use |
WO2002098356A2 (en) | 2001-06-05 | 2002-12-12 | Exelixis Inc. | Ppp2cs as modifiers of the p53 pathway and methods of use |
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 |
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 |
WO2002102235A2 (en) | 2001-06-18 | 2002-12-27 | Eos Biotechnology Inc. | Methods of diagnosis of ovarian cancer, compositions and methods of screening for modulators of ovarian cancer |
WO2003004989A2 (en) | 2001-06-21 | 2003-01-16 | 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 |
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 |
WO2003055439A2 (en) | 2001-07-18 | 2003-07-10 | 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 |
EA007984B1 (ru) | 2001-08-03 | 2007-02-27 | Дженентек, Инк. | ПОЛИПЕПТИДЫ TACIs И BR3 И ИХ ПРИМЕНЕНИЕ |
EP1478772A2 (en) | 2001-08-14 | 2004-11-24 | The General Hospital Corporation | 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 |
WO2003018621A2 (en) | 2001-08-23 | 2003-03-06 | 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 |
JP2005505271A (ja) | 2001-09-06 | 2005-02-24 | 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steap−1と名称が与えられる核酸および対応するタンパク質 |
WO2003025138A2 (en) | 2001-09-17 | 2003-03-27 | Protein Design Labs, Inc. | Methods of diagnosis of cancer compositions and methods of screening for modulators of cancer |
KR101008758B1 (ko) | 2001-09-18 | 2011-01-14 | 제넨테크, 인크. | 종양의 진단 및 치료를 위한 방법 및 이를 위한 조성물 |
WO2003025228A1 (en) | 2001-09-18 | 2003-03-27 | Proteologics, Inc. | Methods and compositions for treating hcap associated diseases |
WO2003025148A2 (en) | 2001-09-19 | 2003-03-27 | Nuvelo, Inc. | Novel nucleic acids and polypeptides |
US7091186B2 (en) | 2001-09-24 | 2006-08-15 | Seattle Genetics, Inc. | p-Amidobenzylethers in drug delivery agents |
WO2003026577A2 (en) | 2001-09-24 | 2003-04-03 | Seattle Genetics, Inc. | P-amidobenzylethers in drug delivery agents |
US20030077644A1 (en) | 2001-09-28 | 2003-04-24 | 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 |
EP1578385A4 (en) | 2001-10-19 | 2011-11-09 | Genentech Inc | COMPOSITIONS AND METHODS FOR THE DIAGNOSIS AND TREATMENT OF INFLAMMATORY INTESTINAL DISEASES |
WO2003035846A2 (en) | 2001-10-24 | 2003-05-01 | National Jewish Medical And Research Center | Structure of tall-1 and its cognate receptor |
ES2278079T3 (es) | 2001-10-31 | 2007-08-01 | Alcon, Inc. | Proteinas morfogenicas oseas (bmp), receptores de bmp y proteinas de union a bmp y su utilizacion en el diagnostico y en el tratamiento del glaucoma. |
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 |
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 |
CA2467242A1 (en) | 2001-11-20 | 2003-05-30 | Seattle Genetics, Inc. | Treatment of immunological disorders using anti-cd30 antibodies |
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 |
US20050041271A1 (en) | 2002-01-16 | 2005-02-24 | Ito Tomoyoshi | Moving image holography reproducing device and color moving image holography reproducing device |
US7452675B2 (en) | 2002-01-25 | 2008-11-18 | The Queen's Medical Center | Methods of screening for TRPM4b modulators |
ATE482719T1 (de) | 2002-02-21 | 2010-10-15 | Univ Duke | Behandlungsverfahren unter verwendung von anti- cd22-antikörpern |
CA2476518A1 (en) | 2002-02-22 | 2003-09-04 | Genentech, Inc. | Compositions and methods for the treatment of immune related diseases |
WO2003074674A2 (en) | 2002-03-01 | 2003-09-12 | Exelixis, Inc. | MSRAs AS MODIFIERS OF THE p53 PATHWAY AND METHODS OF USE |
US20050220798A1 (en) | 2002-06-04 | 2005-10-06 | Reinhard Ebner | Cancer-linked gene as target for chemotherapy |
US6660856B2 (en) | 2002-03-08 | 2003-12-09 | Kaohsiung Medical University | Synthesis of pyrrolo[2,1-c][1,4]benzodiazepine analogues |
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 |
US7317087B2 (en) | 2002-03-25 | 2008-01-08 | The Uab Research Foundation | Members of the FC receptor homolog gene family (FCRH1-3, 6), related reagents, and uses thereof |
WO2003083074A2 (en) | 2002-03-28 | 2003-10-09 | 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 |
MXPA04010092A (es) | 2002-04-16 | 2004-12-13 | Genentech Inc | Composiciones y metodos para el diagnostico y tratamiento de tumores. |
US20030224467A1 (en) | 2002-04-17 | 2003-12-04 | Osborne C. Kent | AIB1 as a prognostic marker and predictor of resistance to endocrine therapy |
AU2003228869A1 (en) | 2002-05-03 | 2003-11-17 | Incyte Corporation | Transporters and ion channels |
EP1572925A4 (en) | 2002-05-15 | 2007-08-15 | Avalon Pharmaceuticals | CANCER-RELATED GENE AS A TARGET FOR CHEMOTHERAPY |
WO2003101388A2 (en) | 2002-05-30 | 2003-12-11 | Bristol-Myers Squibb Company | Human solute carrier family 7 member 11 (hslc7a11) |
WO2003101283A2 (en) | 2002-06-04 | 2003-12-11 | Incyte Corporation | Diagnostics markers for lung cancer |
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 |
EP1513934B1 (en) | 2002-06-06 | 2011-03-02 | Oncotherapy Science, Inc. | Genes and polypeptides relating to human colon cancers |
EP1576111A4 (en) | 2002-06-07 | 2006-10-18 | Avalon Pharmaceuticals | CANCER-ASSOCIATED GENE AS A TARGET FOR CHEMOTHERAPY |
AU2003245441A1 (en) | 2002-06-12 | 2003-12-31 | Avalon Pharmaceuticals, Inc. | Cancer-linked gene as target for chemotherapy |
EP1552002A4 (en) | 2002-06-18 | 2006-02-08 | Archemix Corp | APTAMER TOXIN MOLECULES AND METHOD FOR THEIR USE |
US20040249130A1 (en) | 2002-06-18 | 2004-12-09 | Martin Stanton | Aptamer-toxin molecules and methods for using same |
CA2489803A1 (en) | 2002-06-20 | 2003-12-31 | The Regents Of The University Of California | Compositions and methods for modulating lymphocyte activity |
AU2003278161A1 (en) | 2002-06-21 | 2004-01-06 | Johns Hopkins University School Of Medicine | Membrane associated tumor endothelium markers |
DE10229834A1 (de) | 2002-07-03 | 2004-01-29 | Zinser Textilmaschinen Gmbh | Streckwerk für Spinnmaschinen mit nachgeordneter Verdichtungsvorrichtung |
WO2004009622A2 (en) | 2002-07-19 | 2004-01-29 | 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 |
US20050180972A1 (en) | 2002-07-31 | 2005-08-18 | Wahl Alan F. | Anti-CD20 antibody-drug conjugates for the treatment of cancer and immune disorders |
WO2004015426A1 (en) | 2002-08-06 | 2004-02-19 | 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 |
AU2003259913A1 (en) | 2002-08-19 | 2004-03-03 | Genentech, Inc. | Compositions and methods for the diagnosis and treatment of tumor |
AU2003278725A1 (en) | 2002-08-27 | 2004-03-19 | 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 |
AU2003256038A1 (en) | 2002-08-30 | 2004-03-19 | Ramot At Tel Aviv University Ltd. | Self-immolative dendrimers releasing many active moieties upon a single activating event |
AU2002951346A0 (en) | 2002-09-05 | 2002-09-26 | Garvan Institute Of Medical Research | Diagnosis of ovarian cancer |
EP1545610A4 (en) | 2002-09-06 | 2006-11-08 | Mannkind Corp | EPITOPE SEQUENCES |
CA2498264A1 (en) | 2002-09-09 | 2004-05-13 | Nura, Inc. | 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 |
US20060183120A1 (en) | 2002-10-04 | 2006-08-17 | Teh Bin T | Molecular sub-classification of kidney tumors and the discovery of new diagnostic markers |
US20040138269A1 (en) | 2002-10-11 | 2004-07-15 | Sugen, Inc. | Substituted pyrroles as kinase inhibitors |
EP1581169A4 (en) | 2002-11-08 | 2008-09-17 | Genentech Inc | COMPOSITIONS AND METHODS FOR TREATING DISEASES RELATED TO NATURAL K CELLS |
EP1578940A4 (en) | 2002-11-13 | 2007-12-12 | Genentech Inc | METHOD AND COMPOSITIONS FOR DYSPLASED DIAGNOSIS |
GB0226593D0 (en) * | 2002-11-14 | 2002-12-24 | Consultants Ltd | Compounds |
AU2003282624A1 (en) | 2002-11-14 | 2004-06-03 | Syntarga B.V. | Prodrugs built as multiple self-elimination-release spacers |
EP1578372A4 (en) | 2002-11-15 | 2007-10-17 | Univ Arkansas | CA125 GENE AND ITS USE IN DIAGNOSTIC AND THERAPEUTIC INTERVENTIONS |
JP4915980B2 (ja) | 2002-11-15 | 2012-04-11 | エムユーエスシー ファウンデーション フォー リサーチ デベロップメント | 補体レセプター2標的化補体調節因子 |
AU2003297300A1 (en) | 2002-11-20 | 2004-06-15 | Biogen Idec Inc. | Novel gene targets and ligands that bind thereto for treatment and diagnosis of carcinomas |
ATE542423T1 (de) | 2002-11-21 | 2012-02-15 | Univ Utah Res Found | Purinerge geruchsmodulation |
AU2003298786A1 (en) | 2002-11-26 | 2004-06-18 | 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 |
ES2388280T3 (es) | 2002-12-20 | 2012-10-11 | Abbott Biotherapeutics Corp. | Anticuerpos que reaccionan frente a GPR64 y utilización de los mismos |
US20050249671A9 (en) | 2002-12-23 | 2005-11-10 | David Parmelee | Neutrokine-alpha conjugate, neutrokine-alpha complex, and uses thereof |
CA2512536A1 (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 |
EP1583820A4 (en) | 2003-01-14 | 2007-07-18 | Bristol Myers Squibb Co | ASSOCIATED POLYNUCLEOTIDES AND POLYPEPTIDES ASSOCIATED WITH THE NF-KB WAY |
US7258971B2 (en) | 2003-01-15 | 2007-08-21 | Bayer Healthcare Ag | Methods and compositions for treating urological disorders using carboxypeptidase Z identified as 8263 |
EP2196474A3 (en) | 2003-02-14 | 2010-12-15 | 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 |
AU2003215821B2 (en) | 2003-03-31 | 2009-04-23 | Council Of Scientific And Industrial Research | Non-cross-linking pyrrolo(2,1-c)(1,4)benzodiazepines as potential antitumour agents and process thereof |
GB0321295D0 (en) | 2003-09-11 | 2003-10-15 | Spirogen Ltd | Synthesis of protected pyrrolobenzodiazepines |
EP1675857B1 (en) | 2003-10-22 | 2011-07-13 | THE GOVERNMENT OF THE UNITED STATES OF AMERICA, as represented by THE SECRETARY, DEPARTMENT OF HEALTH AND HUMAN SERVICES | Pyrrolobenzodiazepine derivatives, compositions comprising the same and methods related thereto |
GB0416511D0 (en) | 2003-10-22 | 2004-08-25 | Spirogen Ltd | Pyrrolobenzodiazepines |
EP1720908A2 (en) | 2004-02-17 | 2006-11-15 | Absalus, Inc. | Super-humanized antibodies against respiratory syncytial virus |
EP1718667B1 (en) | 2004-02-23 | 2013-01-09 | Genentech, Inc. | Heterocyclic self-immolative linkers and conjugates |
GB0404577D0 (en) | 2004-03-01 | 2004-04-07 | Spirogen Ltd | Pyrrolobenzodiazepines |
ES2398975T3 (es) | 2004-03-01 | 2013-03-25 | Spirogen Sàrl | Derivados de 11-hidroxi-5H-pirrolo[2,1-c][1,4]benzodiazepin-5-ona como intermedios clave para la preparación de pirrolobenzodiazepinas sustituidas en C2 |
GB0404574D0 (en) | 2004-03-01 | 2004-04-07 | Spirogen Ltd | Amino acids |
GB0404578D0 (en) | 2004-03-01 | 2004-04-07 | Spirogen Ltd | Pyrrolobenzodiazepines |
DE102004010943A1 (de) | 2004-03-03 | 2005-09-29 | Degussa Ag | Verfahren zur Herstellung von N-geschützten 4-Ketprolinderivaten |
JP5166861B2 (ja) | 2004-03-09 | 2013-03-21 | スピロゲン リミティッド | ピロロベンゾジアゼピン |
FR2869231B1 (fr) | 2004-04-27 | 2008-03-14 | Sod Conseils Rech Applic | Composition therapeutique contenant au moins un derive de la pyrrolobenzodiazepine et la fludarabine |
GB0410725D0 (en) | 2004-05-13 | 2004-06-16 | Spirogen Ltd | Pyrrolobenzodiazepine therapeutic agents |
CA2580141C (en) | 2004-09-23 | 2013-12-10 | Genentech, Inc. | Cysteine engineered antibodies and conjugates |
ITRE20040127A1 (it) | 2004-10-12 | 2005-01-12 | Sacmi | Metodo e gruppo per la formatura a compressione di preforme per contenitori in materiale polimerico |
EP1879901B1 (en) | 2005-04-21 | 2009-12-23 | Spirogen Limited | Pyrrolobenzodiazepines |
ATE427949T1 (de) | 2005-10-05 | 2009-04-15 | Spirogen Ltd | 4-a4-(5-oxo-2,3,5,11a-tetrahydro-5h-pyrrolo a2, 1-cua1,4ubenzodiazepin-8-yloxy)-butyrylaminou-1 - pyrrol-2-carbonsaurealkylesterderivate und verwandte verbindung zur behandlung einer proliferativen erkrankung |
US20070154906A1 (en) | 2005-10-05 | 2007-07-05 | Spirogen Ltd. | Methods to identify therapeutic candidates |
EA025871B9 (ru) | 2005-10-07 | 2017-08-31 | Экселиксис, Инк. | Ингибиторы mek и способы их применения |
EP1813614B1 (en) | 2006-01-25 | 2011-10-05 | Sanofi | Cytotoxic agents comprising new tomaymycin derivatives |
MY157757A (en) | 2006-07-18 | 2016-07-15 | Sanofi Aventis | Antagonist antibody against epha2 for the treatment of cancer |
EP1914242A1 (en) | 2006-10-19 | 2008-04-23 | Sanofi-Aventis | Novel anti-CD38 antibodies for the treatment of cancer |
WO2008050140A2 (en) | 2006-10-27 | 2008-05-02 | Spirogen Limited | Compounds for treatment of parasitic infection |
AU2008251608B2 (en) | 2007-05-08 | 2014-03-27 | Genentech, Inc. | Cysteine engineered anti-MUC16 antibodies and antibody drug conjugates |
ES2435779T3 (es) | 2007-07-19 | 2013-12-23 | Sanofi | Agentes citotóxicos que comprenden nuevos derivados de tomaimicina y su uso terapéutico |
NZ584514A (en) | 2007-10-19 | 2012-07-27 | Genentech Inc | Cysteine engineered anti-tenb2 antibodies and antibody drug conjugates |
GB0722088D0 (en) | 2007-11-09 | 2007-12-19 | Spirogen Ltd | Pyrrolobenzodiazepines |
GB0722087D0 (en) | 2007-11-09 | 2007-12-19 | Spirogen Ltd | Polyamides |
GB0813432D0 (en) | 2008-07-22 | 2008-08-27 | Spirogen Ltd | Pyrrolobenzodiazepines |
GB0819097D0 (en) | 2008-10-17 | 2008-11-26 | Spirogen Ltd | Pyrrolobenzodiazepines |
GB0819095D0 (en) | 2008-10-17 | 2008-11-26 | Spirogen Ltd | Pyrrolobenzodiazepines |
EP3100745B1 (en) | 2009-02-05 | 2018-04-18 | Immunogen, Inc. | Novel benzodiazepine derivatives |
EA024118B1 (ru) | 2010-04-15 | 2016-08-31 | Сиэтл Дженетикс, Инк. | Конъюгаты пирролбензодиазепина направленного действия |
BR112012026213B1 (pt) | 2010-04-15 | 2021-12-28 | Medimmune Limited | Compostos de pirrolobenzodiazepinas, conjugado das mesmas, composição farmacêutica compreendendo o conjugado e uso do mesmo para o tratamento de uma doença proliferativa |
AU2011239525B2 (en) | 2010-04-15 | 2015-04-09 | Medimmune Limited | Pyrrolobenzodiazepines used to treat proliferative diseases |
GB201006340D0 (en) | 2010-04-15 | 2010-06-02 | Spirogen Ltd | Synthesis method and intermediates |
AU2012311505B2 (en) | 2011-09-20 | 2016-09-29 | Medimmune Limited | Pyrrolobenzodiazepines as unsymmetrical dimeric PBD compounds for inclusion in targeted conjugates |
EA027386B1 (ru) | 2011-10-14 | 2017-07-31 | Медимьюн Лимитед | Пирролобензодиазепины |
AU2012322933B2 (en) | 2011-10-14 | 2017-02-02 | Medimmune Limited | Synthesis method and intermediates useful in the preparation of pyrrolobenzodiazepines |
EP3309162A1 (en) | 2011-10-14 | 2018-04-18 | Seattle Genetics, Inc. | Targeted conjugates of pyrrolobenzodiazepines |
CA2850373C (en) | 2011-10-14 | 2019-07-16 | Seattle Genetics, Inc. | Pyrrolobenzodiazepines and targeted conjugates |
EP2751111B1 (en) | 2011-10-14 | 2017-04-26 | MedImmune Limited | Asymmetrical bis-(5H-Pyrrolo[2,1-c][1,4]benzodiazepin-5-one) derivatives for the treatment of proliferative or autoimmune diseases |
KR101877598B1 (ko) | 2011-10-14 | 2018-07-11 | 메디뮨 리미티드 | 피롤로벤조디아제핀 및 그의 컨주게이트 |
IN2014MN02092A (zh) | 2012-04-30 | 2015-09-04 | Spirogen Sarl | |
CA2872205C (en) | 2012-04-30 | 2020-07-21 | Ucl Business Plc | Pyrrolobenzodiazepines |
CA2873889A1 (en) | 2012-07-09 | 2014-01-16 | Genentech, Inc. | Anti-cd22 antibodies and immunoconjugates |
MX2015000359A (es) | 2012-07-09 | 2015-04-14 | Genentech Inc | Anticuerpos e inmunoconjugados anti-cd79b. |
CA2879665A1 (en) | 2012-08-02 | 2014-02-06 | Genentech, Inc. | Anti-etbr antibodies and immunoconjugates |
WO2014057118A1 (en) | 2012-10-12 | 2014-04-17 | Adc Therapeutics Sarl | Pyrrolobenzodiazepine-anti-cd22 antibody conjugates |
TR201902494T4 (tr) | 2012-10-12 | 2019-03-21 | Medimmune Ltd | Pirrolobenzodiazepinler ve onların konjugatları. |
SI2906296T1 (en) | 2012-10-12 | 2018-06-29 | Adc Therapeutics Sa | Pyrrolobenzodiazepine-antibody conjugates |
EP2906250B1 (en) | 2012-10-12 | 2018-05-30 | ADC Therapeutics SA | Pyrrolobenzodiazepine-anti-psma antibody conjugates |
ES2660029T3 (es) | 2012-10-12 | 2018-03-20 | Medimmune Limited | Conjugados de anticuerpo-pirrolobenzodiazepinas |
CN104955485B (zh) | 2012-10-12 | 2018-01-30 | Adc疗法责任有限公司 | 吡咯并苯并二氮杂卓‑抗her2抗体结合物 |
HUE035694T2 (en) | 2012-10-12 | 2018-05-28 | Adc Therapeutics Sa | Pirrolobenzodiazepine anti-CD22 antibody conjugates |
ES2703151T3 (es) | 2012-10-12 | 2019-03-07 | Adc Therapeutics Sa | Conjugados de anticuerpos de pirrolobenzodiazepinas |
NZ707486A (en) | 2012-10-12 | 2018-09-28 | Adc Therapeutics Sa | Pyrrolobenzodiazepine - anti-psma antibody conjugates |
CA2885305C (en) | 2012-10-12 | 2019-11-12 | Spirogen Sarl | Synthesis and intermediates of pyrrolobenzodiazepine derivatives for conjugation |
PT2839860T (pt) * | 2012-10-12 | 2019-07-29 | Medimmune Ltd | Pirrolobenzodiazepinas e conjugados das mesmas |
EA031585B1 (ru) | 2012-12-21 | 2019-01-31 | Медимьюн Лимитед | Пирролобензодиазепины и их конъюгаты |
CN105246894A (zh) | 2012-12-21 | 2016-01-13 | 斯皮罗根有限公司 | 用于治疗增殖性和自身免疫疾病的非对称吡咯并苯并二氮杂卓二聚物 |
US9968687B2 (en) | 2013-02-22 | 2018-05-15 | Abbvie Stemcentrx Llc | Anti-DLL3 antibody drug conjugates |
JP6444902B2 (ja) | 2013-03-13 | 2018-12-26 | メドイミューン・リミテッドMedImmune Limited | ピロロベンゾジアゼピン及びその結合体 |
NZ710745A (en) | 2013-03-13 | 2019-03-29 | Genentech Inc | Pyrrolobenzodiazepines and conjugates thereof |
CN105142674B (zh) | 2013-03-13 | 2018-11-13 | 麦迪穆有限责任公司 | 吡咯并苯并二氮杂卓和其结合物 |
US20160106861A1 (en) | 2013-04-26 | 2016-04-21 | Spirogen Sarl | Axl antibody-drug conjugate and its use for the treatment of cancer |
WO2015052535A1 (en) | 2013-10-11 | 2015-04-16 | Spirogen Sàrl | Pyrrolobenzodiazepine-antibody conjugates |
GB201317982D0 (en) | 2013-10-11 | 2013-11-27 | Spirogen Sarl | Pyrrolobenzodiazepines and conjugates thereof |
EP3054983B1 (en) | 2013-10-11 | 2019-03-20 | Medimmune Limited | Pyrrolobenzodiazepine-antibody conjugates |
EP3054984A1 (en) | 2013-10-11 | 2016-08-17 | Medimmune Limited | Pyrrolobenzodiazepine-antibody conjugates |
GB201317981D0 (en) | 2013-10-11 | 2013-11-27 | Spirogen Sarl | Pyrrolobenzodiazepines and conjugates thereof |
EP3054985B1 (en) | 2013-10-11 | 2018-12-26 | Medimmune Limited | Pyrrolobenzodiazepine-antibody conjugates |
NZ720743A (en) | 2013-12-16 | 2021-12-24 | Medimmune Ltd | Peptidomimetic compounds and antibody-drug conjugates thereof |
GB201406767D0 (en) | 2014-04-15 | 2014-05-28 | Cancer Rec Tech Ltd | Humanized anti-Tn-MUC1 antibodies anf their conjugates |
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BR112016008033B1 (pt) | 2022-08-02 |
MX2016004467A (es) | 2016-12-09 |
ZA201602501B (en) | 2017-07-26 |
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US10029018B2 (en) | 2018-07-24 |
KR102052244B1 (ko) | 2019-12-04 |
US20160250345A1 (en) | 2016-09-01 |
CA2926876A1 (en) | 2015-04-16 |
CN105636613A (zh) | 2016-06-01 |
JP6448632B2 (ja) | 2019-01-09 |
NZ718826A (en) | 2019-10-25 |
GB201317982D0 (en) | 2013-11-27 |
EP3054990B1 (en) | 2019-03-27 |
TWI716343B (zh) | 2021-01-21 |
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