TWI765864B - 關於抗-cd19抗體藥物共軛物之組合物及方法 - Google Patents
關於抗-cd19抗體藥物共軛物之組合物及方法 Download PDFInfo
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Abstract
在一些態樣中,本發明係關於抗體-藥物共軛物,其包含抗-CD19抗體、連接體及活性劑。該抗體-藥物共軛物可包含自發分解性基團。該連接體可包含O-經取代之肟,例如,其中該肟之氧原子經將該肟共價連接至該活性劑之基團取代;且該肟之碳原子經將該肟共價連接至該抗體之基團取代。
Description
抗體-藥物共軛物(ADC)技術係容許癌細胞選擇性細胞凋亡之靶標定向技術。通常,ADC藉由使用抗體靶向癌細胞及隨後在細胞中釋放毒性物質(即,藥物)、藉此觸發細胞死亡而起作用。由於ADC技術容許將藥物精確地遞送至靶癌細胞且在特定條件下釋放,同時使對健康細胞之附帶損害最小化,故ADC技術增加治療抗體之效能並減小不良反應之風險。 抗體-藥物共軛物之基本結構係「抗體-連接體-低分子藥物(毒素)」。連接體理想地容許藥物(例如)在自抗體分離(例如,藉由酶介導之水解)後、在藥物到達靶細胞後對靶癌細胞展現效應。連接體亦藉由連接抗體及藥物起功能作用。抗體-藥物共軛物之效能及毒性藉此部分取決於連接體之穩定性,且因此,連接體在藥物安全性中起重要作用。 抗體-藥物共軛物之連接體可大致分類為不可裂解或可裂解之連接體。許多不可裂解之連接體使用硫醚(包含抗體之半胱胺酸)附接至抗體。側接藥物通常不可在活體內自抗體解離。然而,在廣泛使用之硫醇-馬來醯亞胺方法之情形下,抗體-藥物共軛物不穩定,此可導致在其到達靶細胞之前或之後藥物自共軛物解離。 可裂解之連接體可由(例如)胞質酶水解。可裂解之連接體可包含二硫鍵,例如,包括抗體之半胱胺酸。容許經由硫醇交換反應解離之二硫化物連接體部分依賴於抗體-藥物共軛物攝入靶細胞中及二硫化物曝露於為還原環境之胞質液。然而,由於血液中存在多種類型之硫醇(例如,白蛋白及麩胱甘肽),故藥物可在到達其靶標之前自抗體解離。 鑒於上文,期望用於抗體-藥物共軛物之改良之連接體。
在一些態樣中,本發明係關於抗-CD19抗體-藥物共軛物(ADC)。抗體-藥物共軛物可包含(例如)用於分離活性劑與抗體及連接體之自發分解性基團。 在一些實施例中,本發明係關於抗體-藥物共軛物,其包含抗-CD19抗體、連接體及活性劑(例如,藥物)。連接體可包含O-經取代之肟。在較佳實施例中,肟之氧原子經將肟共價連接至活性劑之基團取代,且肟之碳原子經將肟共價連接至抗體之基團取代。在一些實施例中,肟之碳原子經將肟共價連接至活性劑之基團取代,且肟之氧原子經將肟共價連接至抗體之基團取代。在一些實施例中,連接體不包含肟。舉例而言,連接體可包含經取代之三唑代替肟。 在一些實施例中,本發明係關於由式(I)代表之抗體-藥物共軛物,其包含對CD19具有結合特異性之抗體(A)、連接體及具有期望功能或活性之活性劑(B) (例如藥物、毒素、配體、檢測探針或諸如此類)。其中 G係糖或糖酸之殘基,較佳地葡糖醛酸或其衍生物之殘基; A代表抗-CD19抗體; B代表活性劑,例如藥物; W代表拉電子基團、較佳地-C(O)NR’-,其中C(O)鍵結至苯基環且NR’鍵結至L; 每一Z獨立地代表(C1
-C8
)烷基、鹵素、氰基或硝基,較佳地氫; n係0至3之整數; L包含將A共價連接至W之3至100個原子之鏈;且 R1
及R2
各自獨立地係氫、(C1
-C8
)烷基或(C3
-C8
)環烷基、較佳地氫,或R1
及R2
與其附接之碳原子一起形成(C3
-C8
)環烷基環。 在一些態樣中,本發明係關於包含抗體-藥物共軛物之醫藥組合物。在一些態樣中,本發明係關於治療個體之癌症之方法,其包含向個體投與包含抗體-藥物共軛物之醫藥組合物。 在一些態樣中,本發明係關於製造抗體-藥物共軛物之方法。該方法可包含使生物分子與前藥反應。舉例而言,生物分子可包含抗-CD19抗體及酮或醛,前藥可包含烷氧基胺,且反應可產生肟,藉此將抗體共價連接至前藥。該方法可包含異戊二烯化抗體。舉例而言,抗體可為抗-CD19抗體,抗體可包含異戊二烯化序列,異戊二烯化抗體可包含將抗體與類異戊二烯轉移酶及類異戊二烯轉移酶受質一起培育,且受質可包含前藥。因此,抗體與類異戊二烯轉移酶一起培育,且受質可將抗體共價連接至前藥。
在一些態樣中,本發明係關於抗-CD19抗體-藥物共軛物(ADC)。抗體-藥物共軛物可包含(例如)用於自ADC分離活性劑之自發分解性基團。 在一些實施例中,本發明係關於抗體-藥物共軛物,其包含抗-CD19抗體、連接體及活性劑(例如,藥物)。連接體可包含O-經取代之肟。在較佳實施例中,肟之氧原子經將肟共價連接至活性劑之基團取代,且肟之碳原子經將肟共價連接至抗體之基團取代。在一些實施例中,肟之碳原子經將肟共價連接至活性劑之基團取代,且肟之氧原子經將肟共價連接至抗體之基團取代。在一些實施例中,連接體不包含肟。舉例而言,連接體可包含經取代之三唑代替肟。 ADC可由式(I)代表,其包含對CD19具有結合特異性之抗體(A)、連接體及具有期望功能或活性之活性劑(B) (例如藥物、毒素、配體、檢測探針或諸如此類)。其中 G係糖或糖酸之殘基,較佳地葡糖醛酸或其衍生物之殘基; A代表抗-CD19抗體; B代表活性劑,例如藥物; W代表拉電子基團、較佳地-C(O)NR’-,其中C(O)鍵結至苯基環且NR’鍵結至L; 每一Z獨立地代表(C1
-C8
)烷基、鹵素、氰基或硝基,較佳地氫; n係0至3之整數; L包含將A共價連接至W之3至100個原子之鏈;且 R1
及R2
各自獨立地係氫、(C1
-C8
)烷基或(C3
-C8
)環烷基、較佳地氫,或R1
及R2
與其附接之碳原子一起形成(C3
-C8
)環烷基環。 連接A及B之部分體一起(即,自L至OC(=O))形成連接體。 連接體可包含(例如)藉由易於酶裂解之鍵(例如醣苷鍵)偶合之糖或糖酸之殘基。此殘基係由式(I)中之G代表。糖或糖酸可為葡糖醛酸或其衍生物,其能自ADC藉由β-葡萄糖醛酸苷酶裂解。葡糖醛酸或其衍生物之殘基可由式(II)代表:(II) 其中R3
係氫或羧基保護基團、較佳地氫,且每一R4
獨立地係氫或羥基保護基團、較佳地氫。 羧基保護基團可為用於在(例如)有機合成中掩蔽羧酸之任何適宜保護基團,例如甲基、甲氧基甲基、甲硫基甲基、四氫吡喃基、苄基氧基甲基、苯甲醯甲基、N-酞醯亞胺基甲基、2,2,2-三氯乙基、2-鹵代乙基、2-(對-甲苯磺醯基)乙基、第三丁基、桂醯基、苄基、三苯基甲基、雙(鄰-硝基苯基)甲基、9-蒽基甲基、2-(9,10-二側氧基)蒽基甲基、胡椒基、2-三甲基矽基乙基、三甲基矽基或第三丁基二甲基矽基。在一些實施例中,整個部分體R3
-OC(=O)-由羧基-掩蔽部分體(例如2-烷基-1,3-噁唑啉基)置換。 羥基保護基團可為適於在(例如)有機合成中掩蔽羥基之任何適宜保護基團,例如乙醯基、甲基、乙氧基乙基、苯甲醯基、苄基、4-甲氧基苄基、3,4-二甲氧基苄基、四氫吡喃基(THP)、四氫呋喃基(THF)、第三丁基二甲基矽基(TBDMS)、三甲基矽基(TMS)、三乙基矽基(TES)、三異丙基矽基(TIPS)、第三丁基二苯基矽基(TBDPS)、三-異丙基矽基氧基甲基(TOM)、β-甲氧基乙氧基甲基(MEM)、甲氧基甲基(MOM)、烯丙基或三苯甲基。 拉電子基團W可為-C(O)-、-C(O)NR’-、-C(O)O-、-SO2
NR’-、-P(O)R’’NR’-、-SONR’-或-PO2
NR’-、較佳地-C(O)NR’-,且R’及R’’可各自獨立地係氫、(C1
-C8
)烷基、(C3
-C8
)環烷基、(C1
-C8
)烷氧基、(C1
-C8
)烷硫基、單-或二-(C1
-C8
)烷基胺基、(C3
-C20
)雜芳基或(C6
-C20
)芳基。在該等實施例中,W較佳地經定向,使得羰基、磷醯基、磺醯基或亞磺醯基直接結合至苯基環。 連接體可包含選自-C(O)-、-C(O)NR’-、-C(O)O-、-SO2
NR’-、-P(O)R’’NR’-、-SONR’-及-PO2
NR’-、較佳地-C(O)NR’-之拉電子基團,其中R’及R’’可各自獨立地係氫、(C1
-C8
)烷基、(C3
-C8
)環烷基、(C1
-C8
)烷氧基、(C1
-C8
)烷硫基、單-或二-(C1
-C8
)烷基胺基、(C3
-C20
)雜芳基或(C6
-C20
)芳基。 L及/或連接體可包含經取代或未經取代之具有1至50個碳原子之伸烷基且滿足以下(i)至(iv)中之至少一者、較佳地至少兩者: (i) 伸烷基包括至少一個不飽和鍵、較佳地3或4個雙鍵且沒有三鍵, (ii) 伸烷基包括至少一個伸雜芳基, (iii) 伸烷基之至少一個碳原子經一或多個選自氮(N)、氧(O)及硫(S)之雜原子、較佳地至少一個氮及至少一個氧(例如,如在肟中)置換,且 (iv) 伸烷基經一或多個具有1至20個碳原子之烷基、較佳地2或3個甲基取代。 舉例而言,L及/或連接體可包含至少一個異戊二烯基衍生物單元、較佳地兩個異戊二烯基衍生物單元,其各自由式(III)代表,其較佳可由類異戊二烯轉移酶識別為(例如)類異戊二烯轉移酶之產物或受質之一部分。L及/或連接體可包含藉由1,3-偶極環加成反應、雜-迪爾斯-艾爾德反應(hetero-Diels-Alder reaction)、親核取代反應、非醛醇型羰基反應、加成至碳-碳多鍵、氧化反應或點擊反應形成之結合單元。結合單元可藉由乙炔與疊氮化物之間之反應、或醛或酮基團與肼或烷氧基胺之間之反應來形成;該等結合單元可由式(A)、(B)、(C)或(D)代表。L1
係單鍵或具有1至30個碳原子、較佳地12個碳原子之伸烷基; R11
係氫或具有1至10個碳原子之烷基,較佳為甲基;且 L2
係具有1至30個碳原子、較佳地11個碳原子之伸烷基。在一些實施例中,L1
及/或L2
可包含至少一個由式(III)代表之異戊二烯基衍生物單元、較佳地兩個異戊二烯基衍生物單元。L2
可由至少一個由式(III)代表之異戊二烯基衍生物單元、較佳地兩個異戊二烯基衍生物單元組成。 點擊化學反應可在溫和條件下實施,其可在抗體存在下實施而不使抗體變性。點擊化學反應顯示高反應特異性。因此,即使抗體具有各種官能基(例如,胺、羧基、甲醯胺及胍鹽),亦可實施點擊化學而不(例如)影響抗體之胺基酸側鏈。疊氮化物基團與乙炔基團之間之點擊化學反應可(例如)在抗體存在下進行而不修飾抗體之胺基酸側鏈官能基。此外,點擊化學反應可精確地靶向特異性官能基,例如自然中極少發現之官能基,而與反應物之性質無關。在一些情形下,反應物經選擇以改良整體反應效率。舉例而言,疊氮化物-乙炔點擊化學反應可以高產率產生三唑(例如,參見Hia, RK等人,Chem. Rev., 109:5620 (2009);Meldal, M及Tornoe, CW, Chem Rev., 108:2952 (2008);Kolb, HC等人,Angew. Chemie Int. Ed. Engl., 40:2004 (2001),其各自以引用方式併入本文中)。 疊氮化物及乙炔官能基在天然蛋白質中不存在。因此,胺基酸側鏈、N-末端胺或C-末端羧基應皆不受利用該等官能基之點擊化學反應影響。 式I之L部分體及/或連接體可進一步包括由-(CH2
)r
(V(CH2
)p
)q
-或-(CH2
CH2
X)w
-代表之連接單元,其中 V係單鍵、-O-、-S-、-NR21
-、-C(O)NR22
-、-NR23
C(O)-、-NR24
SO2
-或-SO2
NR25
-、較佳地-O-; X係-O-、(C1
-C8
)伸烷基或-NR21
-,較佳為-O-; R21
至R25
各自獨立地係氫、(C1
-C6
)烷基、(C1
-C6
)烷基(C6
-C20
)芳基或(C1
-C6
)烷基(C3
-C20
)雜芳基,較佳為氫; r係1至10、較佳地3之整數; p係0至10、較佳地1之整數; q係1至10、較佳地1之整數;且 w係1至10、較佳地3之整數。 L及/或連接體較佳包含由式(A)、(B)、(C)或(D)代表之結合單元及由-(CH2
)r
(V(CH2
)p
)q
-或-(CH2
CH2
X)w
-代表之連接單元。 舉例而言,L較佳係由以下兩個結構中之一者代表,且因此,連接體可包含以下兩個結構中之一者: L及/或連接體可包含、或,其中 V代表單鍵、-O-、-S-、-NR21
-、-C(O)NR22
-、-NR23
C(O)-、-NR24
SO2
-或-SO2
NR25
-,較佳為-O-; R21
至R25
各自獨立地代表氫、(C1
-C6
)烷基、(C1
-C6
)烷基(C6
-C20
)芳基或(C1
-C6
)烷基(C3
-C20
)雜芳基; r係1至10、較佳地3之整數; p係0至10、較佳地1之整數; q係1至10、較佳地1之整數;且 L1
係單鍵。 在較佳實施例中,抗體包含能由類異戊二烯轉移酶識別之異戊二烯化序列。亦即,抗體之至少一個C-末端可包含能由類異戊二烯轉移酶(例如,作為受質,例如在形成抗體-藥物共軛物之前,或作為類異戊二烯轉移酶之產物,例如在形成抗體-藥物共軛物後)識別之異戊二烯化序列。抗體可進一步包含間隔體,例如將抗體之肽鏈連接至異戊二烯化序列之胺基酸或一段胺基酸。間隔體可由1至20個連續胺基酸組成。甘胺酸及脯胺酸係用於間隔體之較佳胺基酸,且可以任一組合使用。(例如)相對於ADC中不包括之抗體之形式,抗體可包含羧基末端處之添加或缺失。 類異戊二烯轉移酶之實例包括法尼基蛋白轉移酶(FTase)及香葉基香葉基轉移酶(GGTase),其可催化法尼基或香葉基-香葉基轉移至靶蛋白之至少一個C-末端半胱胺酸。GGTase可分類為GGTase I或GGTase II。FTase及GGTase I可識別CAAX基序,且GGTase II可識別XXCC、XCXC或CXX基序,其中C代表半胱胺酸,A代表脂族胺基酸(例如,異白胺酸、纈胺酸、甲硫胺酸、白胺酸),且每一X獨立地代表(例如)麩醯胺酸、麩胺酸鹽、絲胺酸、半胱胺酸、甲硫胺酸、丙胺酸或白胺酸(參見
Nature Rev. Cancer, 5(5):405-12 (2005);Nature Chemical Biology 17:498-506 (2010);Lane KT, Bees LS, J. Lipid Research, 47:681-699 (2006);Kasey PJ, Seabra MC, J. Biological Chemistry, 271(10):5289-5292 (1996),其各自之全文以引用方式併入本文中)。 可使用來自各種來源之類異戊二烯轉移酶。舉例而言,類異戊二烯轉移酶可自人類、動物、植物、細菌、病毒或其他來源獲得。在一些實施例中,使用天然類異戊二烯轉移酶。在一些實施例中,可使用經天然修飾或人工修飾之類異戊二烯轉移酶。舉例而言,類異戊二烯轉移酶可包含一或多個胺基酸取代、添加及/或缺失,及/或類異戊二烯轉移酶可藉由添加組胺酸-tag、GST、GFP、MBP、CBP、Isopeptag、BCCP、Myc-tag、攜鈣蛋白-tag、FLAG-tag、HA-tag、麥芽糖結合蛋白-tag、Nus-tag、麩胱甘肽-S-轉移酶-tag、綠色螢光蛋白-tag、硫氧還蛋白-tag、S-tag、Softag 1、Softag 3、Strep-tag、SBP-tag、Ty-tag及諸如此類中之至少一者經修飾。 類異戊二烯轉移酶識別異受質及/或受質。術語異受質係指包含化學修飾之受質類似物。類異戊二烯轉移酶可烷基化抗體之C-末端處之特定胺基酸基序(例如,CAAX基序) (例如,參見Duckworth, BP等人,ChemBioChem, 8:98 (2007);Uyen TT等人,ChemBioChem, 8:408 (2007);Labadie, GR等人,J. Org. Chem., 72(24):9291 (2007);Wollack, JW等人,ChemBioChem, 10:2934 (2009),其各自以引用方式併入本文中)。官能化抗體可使用可烷基化C-末端半胱胺酸之類異戊二烯轉移酶及異受質產生。 異受質可為(例如)式IV化合物。C-末端CAAX基序之半胱胺酸可使用類異戊二烯轉移酶結合至異受質。在一些實施例中,AAX可隨後藉由蛋白酶移除。半胱胺酸可視情況在羧基末端處藉由(例如)酶甲基化(例如,參見Bell, IM, J. Med. Chem., 47(8):1869 (2004),其以引用方式併入本文中)。 本發明之抗體-藥物共軛物可使用業內已知之任何方法(包括分子生物學及細胞生物學方法)製備。舉例而言,可使用瞬時或穩定轉染方法。可使用標準PCR及/或接合技術將編碼能由類異戊二烯轉移酶識別之特定胺基酸基序之遺傳序列插入已知質體載體中以便表現在其C-末端處具有特定異戊二烯化序列之抗體。因此,可使具有至少一個能由類異戊二烯轉移酶識別之異戊二烯化序列之抗體在適宜宿主(例如CHO細胞)中或在大腸桿菌(E coli
.)中表現。 術語「抗體」係指經由免疫球蛋白分子之可變區內之至少一個抗原識別位點識別並特異性結合至CD19的免疫球蛋白分子。如本文所用術語「抗體」包括完整多株抗體、完整單株抗體、抗體片段(例如,Fab、Fab′、F(ab′)2
、Fd及Fv片段)、單鏈Fv (scFv)突變體、多特異性抗體(例如自兩個或更多個完整抗體生成之雙特異性抗體)、嵌合抗體、人類化抗體、人類抗體、包括抗體之抗原測定部分之融合蛋白及包括抗原識別位點之任何其他經修飾免疫球蛋白分子,只要抗體特異性結合至CD19即可。抗體基於其重鏈恆定結構域之身份(分別稱作α、δ、ε、γ及μ)可為5個主要種類之免疫球蛋白中之任一者:IgA、IgD、IgE、IgG及IgM、或其亞類(同型) (例如,IgG1、IgG2、IgG3、IgG4、IgA1及IgA2)。不同種類之免疫球蛋白具有不同且眾所周知之亞單位結構及三維構形。術語「抗體」並不指不與免疫球蛋白序列共用同源性之分子。舉例而言,如本文所用術語「抗體」不包括「重複體」。 術語「抗體片段」係指完整抗體之一部分且係指完整抗體之抗原測定可變區。抗體片段之實例包括Fab、Fab′、F(ab′)2
、Fd及Fv片段、自抗體片段形成之直鏈抗體、單鏈抗體及多特異性抗體。 術語「單株抗體」係指參與單一抗原決定子或表位之高度特異性識別及結合之均質抗體群體。此與通常包括針對多種不同抗原決定子之不同抗體之多株抗體相對。術語「單株抗體」包括(但不限於)抗體片段(例如Fab、Fab′、F(ab′)2
、Fd、Fv)、單鏈(scFv)突變體、包括抗體部分之融合蛋白、及包括抗原識別位點之任何其他經修飾免疫球蛋白分子以及完整及全長單株抗體。另外,「單株抗體」係指以任何多種方法(包括(但不限於)雜交瘤、噬菌體選擇、重組體表現及轉基因動物)製得之該等抗體。 術語「人類化抗體」係指係含有最少非人類(例如,鼠類)序列之特異性免疫球蛋白鏈、嵌合免疫球蛋白或其片段的非人類(例如,鼠類)抗體之形式。一般而言,人類化抗體係人類免疫球蛋白,其中互補決定區(CDR)經具有期望特異性、親和性及能力之非人類物種(例如,小鼠、大鼠、兔及倉鼠)之CDR之殘基置換(例如,參見Jones等人,Nature, 321:522-525 (1986);Riechmann等人,Nature, 332:323-327 (1988);Verhoeyen等人,Science, 239:1534-1536 (1988))。在一些情況下,人類免疫球蛋白之Fv框架區(FR)殘基經具有期望特異性、親和性及/或結合能力之非人類物種之抗體(即,其靶向CD19)中之相應殘基置換。人類化抗體可藉由取代Fv框架區中及/或經置換非人類殘基內之其他殘基經修飾以精製並最佳化抗體特異性、親和性及/或結合能力。一般而言,人類化抗體包括實質上全部的至少一個、且通常兩個或三個含有全部或實質上全部的對應於非人類免疫球蛋白之CDR的可變結構域,而全部或實質上全部框架區(FR)具有人類免疫球蛋白一致序列之彼等。人類化抗體亦可包括免疫球蛋白恆定區或結構域(Fc) (通常為人類免疫球蛋白之恆定區或結構域)之至少一部分。用於生成人類化抗體之方法之實例闡述於美國專利第5,225,539號中,其以引用方式併入本文中。 如本文所用術語「人類抗體」係指由人類核苷酸序列編碼之抗體或具有對應於藉由使用業內已知之任何技術由人類產生之抗體之胺基酸序列的抗體。人類抗體之此定義包括完整全長抗體及/或其片段。 術語「嵌合抗體」係指其中免疫球蛋白分子之胺基酸序列係源自兩個或更多個物種(其中之一者較佳係人類)之抗體。一般而言,輕鏈及重鏈二者之可變區對應於具有期望特異性、親和性及能力之源自哺乳動物(例如,小鼠、大鼠、兔等)之一個物種之抗體之可變區,而恆定區與源自另一物種(通常人類)之抗體中之序列同源以(例如)避免在該物種中引發免疫反應。 術語「表位」及「抗原決定子」在本文中可互換使用且係指能由特定抗體識別並特異性結合之抗原之該部分。在抗原係或包含多肽或蛋白質時,表位可自鄰接及/或非鄰接胺基酸形成,例如藉由蛋白質之二級、三級及/或四級摺疊併置。自鄰接胺基酸形成之表位在蛋白質變性時通常得以保留,而藉由三級摺疊形成之表位在蛋白質變性時可丟失。在獨特空間構象中,表位通常包括3個或更多個、5個或更多個、或8至10個或更多個胺基酸。在較佳實施例中,表位係CD19之一部分,較佳為CD19、較佳地人類CD19之細胞外部分。 抗體「特異性結合」至表位或抗原性分子,此意指抗體較替代物質(包括無關蛋白質)更頻繁、更快速、以更大持續時間、以更大親和性或以上述之一些組合與表位或抗原性分子相互作用或締合。在具體實施例中,「特異性結合」意指(例如)抗體以約0.1 mM或更小、但更通常小於約1 μM之KD
結合至蛋白質。在具體實施例中,「特異性結合」意指抗體有時以約0.1 μM或更小之KD
且在其他時間以約0.01 μM或更小之KD
結合至蛋白質。由於不同物種中之同源蛋白質之間之序列身份,特異性結合可包括識別一種以上物種中之特定蛋白質之抗體。應理解,特異性結合至第一靶標之抗體或結合殘基可特異性結合至或可不特異性結合至第二靶標。如上文所述,「特異性結合」不必需要(但其可包括)排他性結合,亦即結合至單一靶標。通常但不必,本文所用術語結合意指特異性結合。 抗體(包括其片段/衍生物及單株抗體)可使用業內已知之方法獲得(例如,參見McCafferty等人,Nature 348:552-554 (1990);Clackson等人,Nature 352:624-628;Marks等人,J. Mol. Biol. 222:581-597 (1991);Marks等人,Bio/Technology 10:779-783 (1992);Waterhouse等人,Nucleic Acids Res.21:2265-2266 (1993);Morimoto等人,J Biochemical & Biophysical Methods 24:107-117 (1992);Brennan等人,Science 229:81(1985);Carter等人,Bio/Technology 10:163-167 (1992);Kohler等人,Nature 256:495 (1975);Kilpatrick等人,Hybridoma 16(4):381-389 (1997);Wring等人,J. Pharm. Biomed. Anal. 19(5):695-707 (1999);Bynum等人,Hybridoma 18(5):407-411 (1999), Jakobovits等人,Proc. Natl. Acad. Sci. USA, 90:2551 (1993);Jakobovits等人,Nature, 362:255-258 (1993);Bruggemann等人,Year Immuno.7:33 (1993);Barbas等人,Proc. Nat. Acad. Sci. USA 91:3809-3813 (1994);Schier等人,Gene 169:147-155 (1995);Yelton等人,J. Immunol. 155:1994-2004 (1995);Jackson等人,J. Immunol. 154(7):3310-9 (1995);Hawkins等人,J. Mol. Biol. 226:889-896 (1992)、美國專利第4,816,567號、第5,514,548號、第5,545,806號、第5,569,825號、第5,591,669號、第5,545,807號;PCT專利申請公開案第WO 97/17852號,其各自全文以引用方式併入本文中)。 本發明之較佳抗體可特異性結合至CD19、較佳人類CD19。抗體可較佳選自(但不限於)布利莫單抗(blinatumomab)、MEDI-551、MOR208 (XmAb5574)、XmAb-5871、MDX-1342、MDX-1435、cHD37、AFM-11、AFM-12、GBR401、HD37、DI-B4、huB4、B496及hBU12,其(例如)進一步包含異戊二烯化序列及/或間隔體。抗體可包含布利莫單抗、MEDI-551、MOR208 (XmAb5574)、XmAb-5871、MDX-1342、MDX-1435、cHD37、AFM-11、AFM-12、GBR401、HD37、DI-B4、huB4、B496或hBU12或其中之任一者之互補決定區。在一些實施例中,抗體包含DI-B4或其互補決定區。DI-B4係由Merck KGaA研發之CD19靶向之單株抗體,其係針對患有CD19陽性B細胞惡性病之患者之臨床試驗(Nature Reviews Drug Discovery 13:319-321(2014);亦參見https://clinicaltrials.gov/ct2/show/NCT01805375)。抗體可包含美國專利第8,957,195號中揭示之抗體中之任一者或其中之任一者之互補決定區。 在抗體包含至少一條輕鏈及至少一條重鏈時,抗體之至少一條輕鏈、或抗體之至少一條重鏈或二者可包含具有能由類異戊二烯轉移酶識別之胺基酸基序之胺基酸區。由於抗體可包含四條多肽鏈(例如,兩條重鏈及兩條輕鏈),抗體可包含四個異戊二烯化序列,其各自可用於經由連接體將活性劑偶聯至抗體。因此,抗體-藥物共軛物可包含4個各自偶聯至活性劑之連接體。因此,抗體-藥物共軛物可包含至少一個連接體及至少一種活性劑。抗體-藥物共軛物可包含至少兩個連接體,且抗體-藥物共軛物可包含至少兩種活性劑。抗體-藥物共軛物可包含1、2、3或4個連接體。抗體-藥物共軛物可包含1、2、3或4種活性劑。 本發明之抗體-藥物共軛物可包含異戊二烯化序列,例如CYYX、XXCC、XCXC或CXX、較佳地CYYX (其中,C代表半胱胺酸,Y代表脂族胺基酸,例如白胺酸、異白胺酸、纈胺酸及/或甲硫胺酸,且X代表測定類異戊二烯轉移酶之受質特異性之胺基酸,例如麩醯胺酸、麩胺酸鹽、絲胺酸、半胱胺酸、甲硫胺酸、丙胺酸及/或白胺酸)。 活性劑可為藥物、毒素、親和性配體、檢測探針或上述之任一者之組合。 活性劑可選自厄洛替尼(erlotinib);硼替佐米(bortezomib);氟維司群(fulvestrant);舒癌特(sutent);來曲唑(letrozole);甲磺酸伊馬替尼(imatinib mesylate);PTK787/ZK 222584;奧沙利鉑(oxaliplatin);5-氟尿嘧啶(5-fluorouracil);甲醯四氫葉酸(leucovorin);雷帕黴素(rapamycin) (西羅莫司(Sirolimus));拉帕替尼(lapatinib);洛那法尼(lonafarnib);索拉菲尼(sorafenib);吉非替尼(gefitinib);AG1478;AG1571;烷基化劑(例如,噻替派(thiotepa)或環磷醯胺(cyclophosphamide));磺酸烷基酯(例如,白消安(busulfan)、英丙舒凡(improsulfan)或哌泊舒凡(piposulfan));氮丙啶(例如,苯并多巴(benzodopa)、卡波醌(carboquone)、美妥替派(meturedopa)或烏瑞替派(uredopa));伸乙亞胺、甲基三聚氰胺、六甲蜜胺(altretamine)、三伸乙基三聚氰胺、三伸乙基磷醯胺、三伸乙基硫代磷醯胺、三羥甲基三聚氰胺;番荔枝內酯(acetogenin)(例如,布拉他辛(bullatacin)或布拉他辛酮(bullatacinone));喜樹鹼(camptothecin);托泊替康(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)或比折來新(bizelesin)合成類似物);念珠藻素(cryptophycin) (例如,念珠藻素1或念珠藻素8);多拉斯他汀(dolastatin);多卡米星(duocarmycin) (包括合成類似物,例如KW-2189及CB1-TM1);艾榴塞洛素(eleutherobin);水鬼蕉鹼(pancratistatin);匍枝珊瑚醇(sarcodictyin);海綿抑制素(spongistatin);氮芥(nitrogen mustard) (例如,氮芥苯丁酸(chlorambucil)、萘氮芥(chlornaphazine)、氯磷醯胺、雌氮芥(estramustine)、異環磷醯胺(ifosfamide)、甲基二氯乙基胺(mechlorethamine)、甲基二氯乙基胺氧化物鹽酸鹽、美法侖(melphalan)、新氮芥(novembichin)、苯乙酸氮芥膽甾醇酯(phenesterine)、潑尼莫司汀(prednimustine)、曲磷胺(trofosfamide)或尿嘧啶氮芥);硝基脲(例如,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)或雷莫司汀(ranimnustine));抗生素(例如,烯二炔抗生素,例如選自卡奇黴素(calicheamycin) γ 1I及卡奇黴素ω 1I之卡奇黴素,或達內黴素(dynemicin),包括達內黴素A);雙膦酸鹽(例如,氯膦酸(clodronate);埃斯波黴素(esperamicin)、新製癌菌素髮色團(neocarzinostatin chromophore)或相關色蛋白烯二炔抗生素發色團、阿克拉黴素(aclacinomysin)、放線菌素(actinomycin)、安麯黴素(anthramycin)、氮雜絲胺酸(azaserine)、博來黴素(bleomycin)、放線菌素C (cactinomycin)、卡拉黴素(carabicin)、洋紅黴素(carninomycin)、嗜癌黴素(carzinophilin)、色黴素(chromomycin)、放線菌素(dactinomycin)、道諾黴素(daunorubicin)、地托比星(detorubucin)、6-重氮-5-側氧基-L-正白胺酸、多柔比星(doxorubicin) (例如,嗎啉基-多柔比星、氰基嗎啉基-多柔比星、2-吡咯啉基-多柔比星、脂質體多柔比星或去氧多柔比星)、泛艾黴素(epirubicin)、依索比星(esorubicin)、麻西羅黴素(marcellomycin)、絲裂黴素(mitomycin) (例如,絲裂黴素C、黴酚酸(mycophenolic acid)、諾拉黴素(nogalamycin)、橄欖黴素(olivomycin)、培洛黴素(peplomycin)、泊非黴素(potfiromycin)、嘌呤黴素(puromycin)、三鐵阿黴素(quelamycin)、羅多比星(rodorubicin)、鏈黑黴素(streptomigrin)、鏈脲黴素(streptozocin)、殺結核菌素(tubercidin)、烏苯美司(ubenimex)、淨司他汀(zinostatin)或佐柔比星(zorubicin));抗代謝物(例如,5-氟尿嘧啶);葉酸類似物(例如,二甲葉酸(denopterin)、胺甲喋呤(methotrexate)、蝶羅呤(pteropterin)或三甲曲沙(trimetrexate));嘌呤類似物(例如,氟達拉濱(fludarabine)、6-巰嘌呤、硫咪嘌呤(thiamiprine)或硫鳥嘌呤(thiguanine));嘧啶類似物(例如,安西他濱(ancitabine)、阿紮胞苷(azacitidine)、6-氮雜尿苷、卡莫氟(carmofur)、阿糖胞苷(cytarabine)、二去氧尿苷(dideoxyuridine)、去氧氟尿苷(doxifluridine)、依諾他濱(enocitabine)或氟尿苷(floxuridine));雄激素(例如,卡普睪酮(calusterone)、丙酸屈他雄酮(dromostanolone propionate)、環硫雄醇(epitiostanol)、美雄烷(mepitiostane))或睪內酯);抗腎上腺素(例如,胺魯米特(aminoglutethimide)、米托坦(mitotane)或曲洛司坦(trilostane));葉酸補充劑(例如,醛葉酸);醋葡醛內酯(aceglatone);醛磷醯胺醣苷(aldophosphamide glycoside);胺基乙醯丙酸(aminolevulinic acid);恩尿嘧啶(eniluracil);安吖啶(amsacrine);雌二醇-瘤克寧錠複合物(bestrabucil);比生群(bisantrene);依達曲沙(edatraxate);地磷醯胺(defofamine);秋水仙胺(demecolcine);地吖醌(diaziquone);依氟鳥胺酸(elfornithine);依利醋銨(elliptinium acetate);埃博黴素(epothilone);依託格魯(etoglucid);硝酸鎵;羥基脲;香菇多醣(lentinan);氯尼達明(lonidainine);類美登素(maytansinoid) (例如,美登素或安絲菌素(ansamitocin));單端孢黴烯(trichothecene) (尤其T-2毒素、疣皰菌素A (verracurin A)、桿孢菌素A (roridin A)或蛇形菌素(anguidine));米托胍腙(mitoguazone);米托蒽醌(mitoxantrone);莫哌達醇(mopidanmol);硝胺丙吖啶(nitraerine);噴司他汀(pentostatin);蛋胺氮芥(phenamet);吡柔比星(pirarubicin);洛索蒽醌(losoxantrone);2-乙基醯肼;丙卡巴肼(procarbazine);多醣K複合物;雷佐生(razoxane);利索新(rhizoxin);西左非蘭(sizofiran);鍺螺胺(spirogermanium);替奴佐酸(tenuazonic acid);三亞胺醌(triaziquone);2,2’,2’’-三氯三乙胺;單端孢黴烯(尤其T-2毒素、疣皰菌素A、桿孢菌素A及蛇形菌素);胺基甲酸酯;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);噶薩托辛(gacytosine);阿糖胞苷(arabinoside);環磷醯胺;噻替派;類紫杉醇(taxoid) (例如,太平洋紫杉醇(paclitaxel))、無克列莫佛(cremophor)之ABRAXANETM
、太平洋紫杉醇之經白蛋白改造之奈米粒子調配物、多西他賽(doxetaxel);氮芥苯丁酸(chlorambucil);吉西他濱(gemcitabine);6-硫鳥嘌呤;巰嘌呤;鉑類似物(例如,順鉑(cisplatin)或卡鉑(carboplatin));長春鹼(vinblastine);鉑;依託泊苷(etoposide)、異環磷醯胺;米托蒽醌;長春新鹼(vincristine);長春瑞濱(vinorelbine);能滅瘤(novantrone);替尼泊苷(teniposide);依達曲沙;道諾黴素;胺喋呤(aminopterin);截瘤達(xeloda);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(difluoromethylornithine);類視色素(retinoid) (例如,視黃酸);卡培他濱(capecitabine)、及其醫藥上可接受之鹽、溶劑合物、酸或衍生物,但不必限於其。 活性劑可選自(i) 用於調控或抑制對腫瘤之激素作用之抗激素藥劑,例如抗雌激素劑及選擇性雌激素受體調節劑,包括(例如)他莫昔芬(tamoxifen)、雷洛昔芬(raloxifene)、屈洛昔芬(droloxifene)、4-羥基他莫昔芬、曲沃昔芬(trioxifene)、可莫昔芬(keoxifene)、LY117018、奧那司酮(onapristone)及托瑞米芬(toremifene);(ii) 抑制芳香酶之芳香酶抑制劑,其調控腎上腺中之雌激素產生,例如,4(5)-咪唑、胺魯米特、乙酸甲地孕酮(megestrol acetate)、依西美坦(exemestane)、來曲唑(letrozole)及阿那曲唑(anastrozole);(iii) 抗雄激素劑,例如氟他胺(flutamide)、尼魯米特(nilutamide)、比卡魯胺(bicalutamide)、柳培林(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) 芳香酶抑制劑;(v) 蛋白激酶抑制劑;(vi) 脂質激酶抑制劑;(vii) 反義寡核苷酸,尤其為抑制信號傳導路徑中與黏附細胞有關之基因表現之彼等,例如PKC-α、Raf、H-Ras;(viii) 核酶,例如VEGF抑制劑,例如核酶及HER2表現抑制劑;(ix) 疫苗,例如基因療法疫苗;ALLOVECTIN®疫苗、LEUVECTIN疫苗、VAXID疫苗;PROLEUKIN®rlL-2;LURTOTECAN®拓撲異構酶1抑制劑;ABARELIX® rmRH;(x) 抗血管生成劑,例如貝伐珠單抗(Bevacizumab);及(xi) 其醫藥上可接受之鹽、溶劑合物、酸或衍生物。 另外,可使用細胞介素作為活性劑。細胞介素係小的細胞信號傳導蛋白質分子,其由眾多細胞分泌且係一類廣泛用於細胞間通訊之信號傳導分子。細胞介素包括單核因子(monokine)、淋巴因子(lymphokine)、傳統多肽激素及諸如此類。細胞介素之實例包括(但不限於)生長激素(例如,人類生長激素、N-甲二磺醯基人類生長激素或牛生長激素);副甲狀腺激素;甲狀腺素;胰島素;胰島素原;鬆弛素;鬆弛素原;醣蛋白激素(例如,激濾泡素(FSH)、甲狀腺刺激激素(TSH)或黃體促素(LH));肝生長因子;纖維母細胞生長因子;泌乳素;胎盤生乳素;腫瘤壞死因子-α、腫瘤壞死因子-β;穆勒氏(mullerian)抑制物質;小鼠促性腺激素相關肽;抑制素;活化素;血管內皮生長因子;整聯蛋白、促血小板生成素(TPO);神經生長因子(例如,NGF-β);血小板生長因子;轉換生長因子(TGF) (例如,TGF-α或TGF-β);胰島素樣生長因子-I、胰島素樣生長因子-II;促紅血球生成素(EPO);骨誘導因子;干擾素(例如,干擾素-α、干擾素-β或干擾素-γ);群落刺激因子(CSF) (例如,巨噬細胞-CSF (M-CSF)、顆粒球-巨噬細胞-CSF (GM-CSF)或顆粒球-CSF (G-CSF));介白素(IL) (例如,IL-1、IL-1α、IL-2、IL-3、IL-4、IL-5、IL-6、IL-7、IL-8、IL-9、IL-10、IL-11或IL-12);腫瘤壞死因子(TNF) (例如,TNF-α或TNF-β);及多肽因子(例如,LIF或kit配體)。此外,術語「細胞介素」亦包括來自天然來源或重組體細胞培養物之細胞介素及天然序列細胞介素之生物活性等效物。 術語「毒素」係指對活細胞或生物體有毒之物質。毒素可為在接觸身體組織或由身體組織吸收後能經由(例如)與一或多種生物大分子(例如酶或細胞受體)相互作用引起細胞功能障礙或細胞死亡的小分子、肽或蛋白質。毒素包括植物毒素及動物毒素。動物毒素之實例包括(但不限於)白喉毒素、肉毒菌毒素、破傷風毒素、痢疾毒素、霍亂毒素、河豚毒素、雙鞭甲藻毒素及雪卡藻毒素。植物毒素之實例包括(但不限於)蓖麻毒蛋白及AM-毒素。 小分子毒素之實例包括(但不限於)奧裡斯他汀(auristatin)、微管溶素(tubulysin)、格爾德黴素(geldanamycin) (Kerr等人,1997, Bioconjugate Chem.8(6):781-784)、類美登素(EP 1391213, ACR 2008, 41, 98-107)、卡奇黴素(美國專利公開案第2009/0105461號, Cancer Res.1993, 53, 3336-3342)、道諾黴素、多柔比星、胺甲喋呤、長春地辛、SG2285 (Cancer Res.2010, 70(17), 6849-6858)、多拉斯他汀、多拉斯他汀類似物奧裡斯他汀(美國專利第5,635,483)、念珠藻素、喜樹鹼、利索新衍生物、CC-1065類似物或衍生物、多卡米星、烯二炔抗生素、埃斯波黴素、埃博黴素、吡咯并苯并二氮呯(PBD)衍生物、α-瓢菌素及類毒素。毒素可藉由微管蛋白結合、DNA結合、拓撲異構酶抑制及諸如此類展現細胞毒性及細胞生長抑制活性。 術語「配體」係指能與靶生物分子形成複合物之分子。配體之實例係結合至靶蛋白之預定位置以傳遞信號之分子。配體可為受質、抑制劑、刺激劑、神經傳遞質或放射性同位素。 「可檢測部分體」或「標記」係指可藉由光譜、光化學、生物化學、免疫化學、放射性或化學方式檢測之組合物。舉例而言,有用之標記包括32
P、35
S、螢光染料、電子緻密試劑、酶(例如,通常用於ELISA中之酶)、生物素-鏈黴抗生物素蛋白、地高辛(digoxigenin)、半抗原、及抗血清或單株抗體可用之蛋白質、或具有與靶標互補之序列之核酸分子。可檢測部分體通常生成可量測信號,例如可用於對試樣中之結合可檢測部分體之量定量之放射性、色素原性或螢光信號。信號之定量可藉由(例如)完整或隨後消解肽之閃爍計數、密度測定、流式細胞術、ELISA或藉由質譜之直接分析來達成(可評價一或多種肽)。 如本文所用術語「探針」係指如下物質:(i) 提供可檢測信號,(ii) 使第一探針或第二探針相互作用以改質由第一或第二探針提供之可檢測信號,例如螢光共振能量轉移(FRET),(iii) 穩定與抗原或配體之相互作用或增加結合親和性;(iv) 藉由物理參數(例如電荷、疏水性等)影響電泳遷移或細胞突入活性,或(v) 控制配體親和性、抗原-抗體結合或離子複合物形成。 活性劑可為免疫調節化合物、抗癌劑、抗病毒劑、抗細菌劑、抗真菌劑、抗寄生蟲劑或其組合。 免疫調節化合物可選自胺基己酸、硫唑嘌呤、溴隱亭(bromocriptine)、氮芥苯丁酸、氯喹(chloroquine)、環磷醯胺、環孢素(cyclosporine)、環孢素A、達那唑(danazol)、脫氫表雄酮(dehydroepiandrosterone)、地塞米松(dexamethasone)、依那西普(etanercept)、氫化可體松(hydrocortisone)、羥基氯喹(hydroxychloroquine)、英利昔單抗(infliximab)、美洛西卡(meloxicam)、胺甲喋呤、麥考酚酸嗎乙酯(mycophenylate mofetil)、普賴松(prednisone)、西羅莫司(sirolimus)及他克莫司(tacrolimus)。抗癌劑可選自1-甲基-4-苯基吡啶鎓離子、5-乙炔基-1-β-D-呋核亞硝脲咪唑-4-甲醯胺(EICAR)、5-氟尿嘧啶、9-胺基喜樹鹼、放線菌素D、天冬醯胺酶、比卡魯胺、雙-氯乙基亞硝基脲(BCNU)、博來黴素、博來黴素A2、博來黴素B2、白消安、喜樹鹼、卡鉑、卡莫司汀、CB1093、氮芥苯丁酸、順鉑、克立那托(crisnatol)、環磷醯胺、阿糖胞苷、胞嘧啶阿拉伯糖苷、癌得星(cytoxan)、達卡巴嗪、放線菌素、道諾黴素、胺烯咪胺(decarbazine)、去鐵胺(deferoxamine)、去甲氧基-竹紅菌素A (hypocrellin A)、多西他賽、去氧氟尿苷、多柔比星、EB1089、泛艾黴素、依託泊苷、氟尿苷、氟達拉濱、氟他胺、吉西他濱、戈舍瑞林、羥基脲、伊達比星(idarubicin)、異環磷醯胺、干擾素-α、干擾素-γ、伊立替康(irinotecan)、KH1060、乙酸柳培林、洛莫司汀、洛伐他汀(lovastatin)、甲地孕酮、美法侖、巰嘌呤、胺甲喋呤、絲裂黴素、絲裂黴素C、米托蒽醌、黴酚酸、氮芥、亞硝基脲、太平洋紫杉醇、培洛黴素、光敏劑Pe4、酞青素(phthalocyanine)、吡柔比星、普卡黴素(plicamycin)、丙卡巴肼、雷洛昔芬、雷替曲塞(raltitrexed)、瑞複美(revlimid)、利巴韋林(ribavirin)、星狀孢菌素(staurosporine)、他莫昔芬、替尼泊苷、沙利度胺(thalomid)、毒胡蘿蔔內酯(thapsigargin)、硫鳥嘌呤、噻唑羧胺核苷(tiazofurin)、托泊替康、曲奧舒凡(treosulfan)、三甲曲沙、腫瘤壞死因子、萬科(velcade)、維拉帕米(verapamil)、維替泊芬(verteporfin)、長春鹼、長春新鹼、長春瑞濱及佐柔比星。抗病毒劑可選自噴昔洛韋(pencicyclovir)、伐昔洛韋(valacyclovir)、更昔洛韋(gancicyclovir)、膦甲酸(foscarnet)、利巴韋林、碘苷(idoxuridine)、阿糖腺苷(vidarabine)、曲氟尿苷(trifluridine)、阿昔洛韋(acyclovir)、泛昔洛韋(famcicyclovir)、金剛烷胺(amantadine)、金剛乙胺(rimantadine)、西多福韋(cidofovir)、反義寡核苷酸、免疫球蛋白及干擾素。抗細菌劑可選自氯黴素(chloramphenicol)、萬古黴素(vancomycin)、甲硝唑(metronidazole)、三甲氧苄二胺嘧啶(trimethoprin)、磺胺二甲噁唑(sulfamethazole)、奎奴普汀(quinupristin)、達福普汀(dalfopristin)、雷發平(rifampin)、大觀黴素(spectinomycin)、及呋喃妥因(nitrofurantoin)。抗真菌劑可選自兩性黴素B、殺念珠菌素(candicidin)、非律平(filipin)、哈黴素(hamycin)、納他黴素(natamycin)、制黴素(nystatin)、龜裂殺菌素(rimocidin)、聯苯苄唑(bifonazole)、布康唑(butoconazole)、克黴唑(clotrimazole)、益康唑(econazole)、芬替康唑(fenticonazole)、異康唑(isoconazole)、酮康唑(ketoconazole)、魯利康唑(luliconazole)、咪康唑(miconazole)、奧莫康唑(omoconazole)、奧昔康唑(oxiconazole)、舍他康唑(sertaconazole)、硫康唑(sulconazole)、噻康唑(tioconazole)、阿巴康唑(albaconazole)、氟康唑(fluconazole)、艾沙康唑(isavuconazole)、伊曲康唑(itraconazole)、泊沙康唑(posaconazole)、雷夫康唑(ravuconazole)、特康唑(terconazole)、伏立康唑(voriconazole)、阿巴芬淨(abafungin)、阿莫羅芬(amorolfin)、布替萘芬(butenafine)、萘替芬(naftifine)、特比萘芬(terbinafine)、阿尼芬淨(anidulafungin)、卡泊芬淨(caspofungin)、米卡芬淨(micafungin)、苯甲酸、環吡酮(ciclopirox)、氟胞嘧啶(flucytosine)、灰黃黴素(griseofulvin)、鹵普羅近(haloprogin)、托萘酯(tolnaftate)、十一烯酸、結晶紫、秘魯香脂(balsam of peru)、環吡酮胺(ciclopirox olamine)、吡羅克酮乙醇胺(piroctone olamine)、吡硫鋅(zinc pyrithione)及二硫化硒。抗寄生蟲劑可選自甲苯達唑(mebendazole)、雙羥萘酸噻嘧啶(pyrantel pamoate)、噻苯咪唑(thiabendazole)、二乙基乙胺嗪(diethylcarbamazine)、伊維菌素(ivermectin)、氯硝柳胺(niclosamide)、吡喹酮(praziquantel)、阿苯達唑(albendazole)、雷發平、兩性黴素B、美拉胂醇(melarsoprol)、依氟鳥胺酸(eflornithine)、甲硝唑、替硝唑(tinidazole)及米替福新(miltefosine)。 抗體可包含選自Ab-HC-(G)z
CVIM、Ab-HC-(G)z
CVLL、Ab-LC-(G)z
CVIM及Ab-LC-(G)z
CVLL之胺基酸基序,其中Ab代表抗體,-HC-代表重鏈,-LC-代表輕鏈,G代表甘胺酸,C代表半胱胺酸,V代表纈胺酸,I代表異白胺酸,M代表甲硫胺酸,L代表白胺酸,且z係0至20之整數。 抗體-藥物共軛物可具有式(V)或(VI)之結構。Z係氫、(C1
-C8
)烷基、鹵素、氰基或硝基,較佳為氫; X係-O-、(C1
-C8
)伸烷基或-NR21
-,較佳為-O-; R21
係氫、(C1
-C6
)烷基、(C1
-C6
)烷基(C6
-C20
)芳基或(C1
-C6
)烷基(C3
-C20
)雜芳基; n係1至3、較佳地3之整數,且在n係2或更大之整數時,Z各自彼此相同或不同,較佳地相同; r係1至10、較佳地3之整數; q係1至10、較佳地1之整數; w係1至10、較佳地3之整數。 x係0至10、較佳地0之整數; g係1至10、較佳地1之整數; -S-mAb係抗體;且 B係活性劑。 B可選自以下結構中之任一者: 其中y係1至10之整數。 抗體-藥物共軛物可用於將活性劑轉移至個體之靶細胞以使用熟習此項技術者已知之製備組合物之方法治療個體。在一些態樣中,本發明係關於包含如本文中所述抗體-藥物共軛物之組合物(例如,醫藥組合物)。 組合物可以可注射形式、以液體溶液形式或以懸浮液形式製備。適於注射之固體形式亦可製備為(例如)乳液或利用囊封於脂質體中之抗體-藥物共軛物製備。抗體-藥物共軛物可與醫藥上可接受之載劑組合,該載劑包括不誘導產生對接受載劑之個體有害之抗體之任何載劑。適宜載劑通常包含緩慢代謝之大的大分子,例如蛋白質、多醣、聚乳酸、聚乙醇酸、聚合胺基酸、胺基酸共聚物、脂質聚集物及諸如此類。 組合物亦可含有稀釋劑,例如,水、鹽水、甘油及乙醇。其中亦可存在輔助物質(例如潤濕劑或乳化劑)、pH緩衝物質及諸如此類。組合物可藉由注射非經腸投與,其中該注射可為皮下或肌內注射。在一些實施例中,組合物可投與至腫瘤中。組合物可插入(例如,注射至)腫瘤中。其他調配物適於其他投與形式,例如栓劑或經口投與。經口組合物可以溶液、懸浮液、錠劑、丸劑、膠囊或持續釋放調配物形式投與。 組合物可以與劑量及調配物相容之方式投與。組合物較佳包含治療有效量之抗體-藥物共軛物。術語「治療有效量」意指以有效治療或預防疾病或病症之多個劑量時間表投與之單一劑量或組合物。劑量可端視欲治療之個體、個體之健康及身體狀況、欲期望之保護程度及其他相關因子而變。活性成份(例如,抗體-藥物共軛物)之精確量可端視醫生之判斷而定。舉例而言,可向患有癌症或腫瘤之患者投與治療有效量之抗體-藥物共軛物或含有其之組合物以治療癌症或腫瘤。 本發明之抗體-藥物共軛物或含有其之組合物可以其醫藥上可接受之鹽或溶劑合物之形式投與。在一些實施例中,本發明之抗體-藥物共軛物或含有其之組合物可與醫藥上可接受之載劑、醫藥上可接受之賦形劑及/或醫藥上可接受之添加劑一起投與。醫藥上可接受之鹽或溶劑合物、賦形劑及添加劑之有效量及類型可使用標準方法進行量測(例如,參見Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, PA, 第18版, 1990)。 關於癌症或腫瘤之術語「治療有效量」意指如下量:可減少癌細胞之數目;減小癌細胞之大小;抑制癌細胞突入周圍系統中或減少突入;抑制癌細胞擴散至其他系統或減少擴散;抑制癌細胞生長;及/或改善至少一種關於癌症之症狀。在癌症之治療中,可藉由至腫瘤進展之時間(TTP)及/或反應率(RR)評價藥物之有效性。 本文所用術語「醫藥上可接受之鹽」包括有機鹽及無機鹽。其實例包括鹽酸鹽、氫溴酸鹽、氫碘酸鹽、硫酸鹽、檸檬酸鹽、乙酸鹽、草酸鹽、氯化物、溴化物、碘化物、硝酸鹽、硫酸氫鹽、磷酸鹽、酸式磷酸鹽、異菸酸鹽、乳酸鹽、柳酸鹽、酸式檸檬酸鹽、酒石酸鹽、油酸鹽、鞣酸鹽、泛酸鹽、酒石酸氫鹽、抗壞血酸鹽、琥珀酸鹽、馬來酸鹽、龍膽酸鹽、富馬酸鹽、葡萄糖酸鹽、葡糖醛酸鹽、糖二酸鹽、甲酸鹽、苯甲酸鹽、麩胺酸鹽、甲烷磺酸鹽、乙烷磺酸鹽、苯磺酸鹽、對甲苯磺酸鹽及雙羥萘酸鹽(即1,1′-亞甲基雙-(2-羥基-3-萘酸鹽))。醫藥上可接受之鹽可包括另一分子(例如,乙酸根離子、琥珀酸根離子及/或其他相對離子)。 可用於本文所述抗體-藥物共軛物之醫藥上可接受之溶劑合物的實例性溶劑合物包括水、異丙醇、乙醇、甲醇、二甲亞碸、乙酸乙酯、乙酸及乙醇胺。 在一些實施例中,本發明係關於治療個體之癌症之方法,其包含向個體投與包含如本文所述抗體-藥物共軛物之醫藥組合物。癌症優先係與CD19相關之癌症,即,其中至少一些癌細胞表現CD19。癌症可為B細胞惡性病。癌症可為淋巴瘤或白血病。在較佳實施例中,個體係哺乳動物。舉例而言,個體可選自齧齒類動物、兔類動物、貓、犬、豬、羊、牛、馬及靈長類動物。在某些較佳實施例中,個體係人類。 下文將經由實例詳細闡述本發明之構形,但以下實例僅輔助理解本發明。本發明之範疇並不限於此。 例示實例 1. 化合物 1k 之製備 化合物 A 之製備
於室溫下在氮氣氛下將D-葡萄糖醛酸基-6,3-內酯(19g, 107.88mmol)溶解於甲醇(250mL)中,向其中緩慢添加NaOH (100mg)於甲醇(100mL)中之溶液並攪拌2小時,且隨後向混合物中添加NaOH (200mL)於甲醇(15mL)中之溶液並攪拌3小時。在反應完成後,在減壓下移除混合物之甲醇溶劑,並於10℃或更低下向其中添加吡啶(50mL)及乙酸酐(54mL)並於室溫下攪拌4小時。在反應完成後,在減壓下濃縮所得產物。使殘餘物經過管柱層析,藉此獲得化合物A (20g, 50%)。1
H NMR (600MHz, CDCl3
) δ 5.77 (d, J= 7.8Hz, 1H), 5.31 (t, J= 9.6Hz, 1H), 5.24 (t, J= 9.6Hz, 1H), 5.14 (m, 1H), 4.17 (d, J= 9Hz, 1H), 3.74 (s, 3H), 2.12 (s, 3H), 2.04 (m, 9H)化合物 B 之製備
於0℃下在氮氣氛下將化合物A (5g, 13.28mmol)溶解於AcOH (20mL)中之33% HBr中,且隨後於室溫下攪拌2小時。在反應完成後,向其中添加甲苯(50 mL),並在減壓下濃縮混合物。其後,向其中添加乙酸乙酯(100mL)及NaHCO3
溶液(100mL)以萃取有機層,且將所得有機層經無水硫酸鈉乾燥,之後在減壓下濃縮。使殘餘物經過管柱層析,藉此獲得化合物B (5.27g, 100%)。1
H NMR (600MHz, CDCl3
) δ 6.64 (d, J= 3.6Hz, 1H), 5.61 (t, J= 3.6Hz, 1H), 5.24 (t, J= 3.6Hz, 1H), 4.85 (m, 1H), 4.58 (d, d, J= 10.2Hz, 1H), 3.76 (s, 3H), 2.10 (s, 3H), 2.06 (s, 3H), 2.05 (s, 3H)化合物 1a 之製備 ( 參見 美國專利第 6,414,148 號 , 其以引用方式併入本文中 )
於0℃下在氮氣氛下將3-胺基-1-丙醇(3.0g, 66.569mmol)溶解於二氯甲烷(150mL)中,並向其中添加二碳酸二-第三丁基酯(16g, 73.226mmol)。於室溫下將所得混合物攪拌12小時。在反應完成後,在減壓下濃縮溶劑。使殘餘物經過管柱層析,藉此獲得化合物1a
(6.4g, 92%)。1
H NMR (400MHz, CDCl3
) δ 4.78 (s, 1H), 3.65 (m, 2H), 3.30 (m, 2H), 2.90 (s, 1H), 1.68 (m, 2H), 1.48 (s, 9H);EI-MS m/z: 176(M+)化合物 1b 之製備 ( 參見 美國專利第 7,816,344 號 , 其以引用方式併入本文中 )
於0℃下在氮氣氛下將化合物1a
(6.04g, 34.469mmol)及三乙胺(TEA, 14.4mL, 103.407mmol)溶解於四氫呋喃中,且隨後用甲烷磺酸酐(7.21g, 41.363mmol)緩慢處理。於室溫下在氮氣氛下將所得混合物攪拌12小時。在反應完成後,在減壓下濃縮溶劑。使殘餘物經過管柱層析,藉此獲得化合物1b
(9.01g, 98%)。1
H NMR (400MHz, CDCl3
) δ 4.73 (s, 1H), 4.30 (t, J = 5.9Hz, 2H), 3.31-3.24 (m, 2H), 3.04 (s, 3H), 1.94 (t, J= 6.1Hz, 2H), 1.44 (s, 9H)。EI-MS m/z: 254(M+
)化合物 1c 之製備 ( 參見 PCT 專利申請公開案第 WO 2013/166319 號 , 其以引用方式併入本文中 )
於室溫下在氮氣氛下將化合物1b
(3.0g, 11.842mol)溶解於二甲基甲醯胺(40mL)中,且隨後用疊氮化鈉(924mg, 14.211mmol)處理,且將所得混合物於60℃下攪拌12小時。在反應完成後,向其中添加乙酸乙酯(50mL)、蒸餾水(50mL)及1N HCl (5mL)。將如上文所述獲得之有機層經無水硫酸鈉乾燥並在減壓下濃縮。使殘餘物經過管柱層析,藉此獲得化合物1c
(2.3g, 99%)。1
H NMR (600MHz, CDCl3
) δ 4.63 (s, 1H), 3.36 (t, J = 6.6Hz, 2H), 3.24-3.18 (m, 2H), 1.80-1.75 (m, 2H), 1.45 (s, 9H)。EI-MS m/z: 201(M+
)化合物 1d 之製備
於0℃下在氮氣氛下將化合物1c
(3.8g, 18.977mmol)溶解於二氯甲烷(10mL)中,且隨後向其中緩慢添加二噁烷(10mL)中之4M-HCl。將所得混合物攪拌12小時。在反應完成後,在減壓下濃縮所得物,藉此獲得化合物1d
(2.5g, 99%)。1
H NMR (600MHz, DMSO-d6
) δ 8.06 (s, 3H), 3.47 (t, J = 6.6Hz, 2H), 2.82 (t, J = 7.2Hz, 2H), 1.84-1.79 (m, 2H)。EI-MS m/z: 101(M+
)化合物 1e 之製備
於0℃下在氮氣氛下將化合物1d
(58mg, 0.420mmol)及5-甲醯基柳酸(100mg, 0.601mmol)溶解於二甲基甲醯胺(DMF, 2mL)中,且隨後向混合溶液中添加二異丙基乙胺(DIPEA, 0.2mL, 1.202mmol)及PyBop (375mg, 0.721mmol)。於室溫下將所得混合物攪拌3小時。在反應完成後,向其中添加乙酸乙酯(30mL)及蒸餾水(10mL)。將如上文所述獲得之有機層經無水硫酸鈉乾燥並在減壓下濃縮。使殘餘物經過管柱層析,藉此獲得化合物1e
(82mg, 79%)。1
H NMR (400MHz, CDCl3
) δ 13.39 (s, 1H), 9.87 (s, 1H), 8.29 (s, 1H), 7.89 (dd, J = 1.6, 7.2Hz.1H), 7.60 (s, 1H), 7.10 (d, J = 8.8Hz), 3.63-3.57 (m, 2H), 3.48 (t, J = 6.4Hz, 2H), 1.99-1.92 (m, 2H)。EI-MS m/z: 249(M+
)化合物 1f 之製備
於室溫下在氮氣氛下將化合物1e
(78mg, 0.314mmol)及化合物B
(125mg, 0.314mmol)溶解於乙腈(3mL)中,且隨後向其中添加氧化銀(291mg, 1.256mmol)及分子篩(125mg)。於室溫下將所得混合物攪拌3小時。在反應完成後,將混合物經矽藻土過濾,並在減壓下濃縮濾液。使殘餘物經過管柱層析,藉此獲得化合物1f
(160mg, 90%)。1
H NMR (400MHz, CDCl3
) δ 10.00 (s, 1H), 8.66 (d, J= 2.4Hz, 1H), 8.02 (dd, J= 2.0, 6.4Hz, 1H), 7.46 (t, J = 6.4Hz, 1H), 7.14 (d, J = 8.4Hz, 1H), 5.48-5.33 (m, 4H), 4.28 (d, J = 8.8Hz, 1H), 3.74 (s, 3H), 3.73-3.64 (m, 1H), 3.50-3.42 (m, 3H), 2.09-2.07 (m, 9H), 2.00-1.92(m, 2H)。EI-MS m/z: 565(M+
)化合物 1g 之製備
於0℃下在氮氣氛下將化合物1f
(160mg, 1.510mmol)溶解於2-丙醇(0.4mL)及氯仿(2mL)中,且隨後向其中添加矽膠(2g)及硼氫化鈉(27mg, 0.708mmol)。在將所得混合物於0℃下攪拌2小時後,將反應物經矽藻土過濾,並在減壓下濃縮濾液。使殘餘物經過管柱層析,藉此獲得化合物1g
(115mg, 71%)。1
H NMR (600MHz, CDCl3
) δ 8.06 (d, J= 2.4Hz, 1H), 7.50-7.44 (m, 2H), 7.01 (d, J = 90Hz, 1H), 5.45-5.31 (m, 4H), 4.38 (s, 2H), 4.22 (d, J = 9.0Hz, 1H), 3.74 (s, 3H), 3.67-3.61 (m, 1H), 3.46-3.41 (m, 3H), 2.07-2.04 (m, 9H), 1.97-1.91 (m, 2H)。EI-MS m/z: 567(M+
)化合物 1h 之製備
於0℃下在氮氣氛下將化合物1g
(100mg, 0.177mmol)溶解於DMF (1mL)中,且隨後向其中添加碳酸雙(4-硝基苯基)酯(110mg, 0.353mmol)及DIPEA (50uL, 0.265mmol)。於室溫下將所得混合物攪拌2小時。在反應完成後,向其中添加乙酸乙酯(30mL)及蒸餾水(10mL)。將如上文所述獲得之有機層經無水硫酸鈉乾燥並在減壓下濃縮。使殘餘物經過管柱層析,藉此獲得化合物1h
(75mg, 58%)。1
H NMR (600MHz, CDCl3
) δ 8.29-8.27 (m, 2H), 8.23 (d, J= 2.4Hz, 1H), 7.54 (dd, J = 2.4, 6.6Hz, 1H), 7.49 (t, J = 6.4Hz, 1H), 7.39-7.37 (m, 2H), 7.04 (d, J= 8.4Hz, 1H), 5.45-5.29 (m, 4H), 5.28 (s, 2H), 4.23 (d, J = 9.0Hz, 1H), 3.75 (s, 3H), 3.68-3.64 (m, 1H), 3.46-3.42 (m, 3H), 2.08-2.05 (m, 9H), 1.98-1.93 (m, 2H)。EI-MS m/z: 732(M+
)化合物 1i 之製備
於室溫下在氮氣氛下將化合物1h
(50mg, 0.068mmol)溶解於DMF (0.8mL)中,且隨後向其中添加MMAF-OMe (51mg, 0.068mmol)。將所得產物用無水1-羥基苯并三唑(HOBT, 2mg, 0.013mmol)、吡啶(0.24mL)及DIPEA (12uL, 0.068mmol)處理。於室溫下將所得混合物攪拌18小時。在反應完成後,向其中添加乙酸乙酯(20mL)及蒸餾水(10mL)。將如上文所述獲得之有機層經無水硫酸鈉乾燥並在減壓下濃縮。使殘餘物經過管柱層析,藉此獲得化合物1i
(71mg, 78%)。 EI-MS m/z: 1339(M+
)化合物 1j 之製備
於室溫下在氮氣氛下將化合物1i
(30mg, 0.022mmol)及苯基乙炔(3.7uL, 0.033mmol)溶解於乙醇(0.2mL)及水(30ul)中,且隨後向其中添加0.1M CuSO4
水溶液(30ul)及1.0M抗壞血酸鈉水溶液(30ul)。將所得產物用HOBT (2mg, 0.013mmol)、吡啶(0.24mL)及DIPEA (12uL, 0.068mmol)處理。於室溫下將所得混合物攪拌5小時。在反應完成後,向其中添加乙酸乙酯(20mL)及蒸餾水(5mL)。將如上文所述獲得之有機層經無水硫酸鈉乾燥並在減壓下濃縮。使殘餘物經過管柱層析,藉此獲得化合物1j
(26mg, 81%)。 EI-MS m/z: 1441(M+
)化合物 1k 之製備
於0℃下在氮氣氛下將化合物1j
(20mg, 0.013mmol)溶解於甲醇(0.2mL)中,且隨後向其中添加含於水(0.2mL)中之LiOH∙H2
O (6mg, 0.138mmol)。於室溫下將所得混合物攪拌1小時。在反應完成後,向其中添加氯仿(10mL)、甲醇(1mL)、蒸餾水(10mL)及0.5N HCl (1mL)。將如上文所述獲得之有機層經無水硫酸鈉乾燥並在減壓下濃縮。使殘餘物經過管柱層析,藉此獲得化合物1k
(17mg, 87%)。 EI-MS m/z: 1286(M+
)實例 2 及 3. 化合物 2i 及 3i 之製備 化合物 2a 之製備
於0℃下在氮氣氛下將5-甲醯基柳酸(2g, 12.038mmol)溶解於DMF中,且隨後向其中添加2-(三甲基矽基)乙醇(1.72mL, 12.038mmol)及二甲基胺基吡啶(DMAP, 147mg, 1.204mmol)及二環己基碳二亞胺(DCC, 2.5g, 12.038mmol)。將混合物於室溫下攪拌12小時。在反應完成後,向其中添加乙酸乙酯(100mL)及蒸餾水(100mL)。將如上文所述獲得之有機層經無水硫酸鈉乾燥並在減壓下濃縮。使殘餘物經過管柱層析,藉此獲得化合物2a
(1.6g, 50%)。1
H NMR (400MHz, CDCl3
) δ 11.38 (s, 1H), 9.77 (s, 1H), 7.48 (d, J= 8.4Hz, 1H), 6.61 (dd, J= 8.4, 2.0Hz, 1H), 6.53 (d, J= 2.0Hz, 1H), 5.36~5.25 (m, 4H), 4.23 (m, 1H), 3.73 (s, 1H), 2.06 (s, 9H)化合物 2b 之製備
於室溫下在氮氣氛下將化合物2a
(60mg, 0.225mmol)溶解於乙腈(2mL)中,且隨後向其中添加化合物C
(90mg, 0.225mmol)、氧化銀(209mg, 0.900mmol)及分子篩(90mg)。將混合物於室溫下攪拌2小時。在反應完成後,向其中添加乙酸乙酯(50mL)及蒸餾水(30mL)。將如上文所述獲得之有機層經無水硫酸鈉乾燥並在減壓下濃縮。使殘餘物經過管柱層析,藉此獲得化合物2b
(103mg, 79%)。1
H NMR (400MHz, CDCl3
) δ 9.93 (s, 1H), 8.22 (d, J= 2.0Hz, 1H), 7.97 (dd, J= 6.4, 2.0Hz, 1H), 7.26 (d, J= 9.2Hz, 1H), 5.42-5.27 (m, 4H), 4.42-4.30 (m, 2H), 4.24 (d, J = 9.2Hz, 1H), 3.70 (s, 3H), 2.06-2.04 (m, 9H), 1.14-1.08 (m, 2H), 0.07 (s, 9H)化合物 2c 之製備
於0℃下在氮氣氛下將化合物2b
(100mg, 0.171mmol)溶解於2-丙醇(0.3mL)及氯仿(1.5mL)中,且隨後向其中添加矽膠(720mg)及硼氫化鈉(16mg, 0.427mmol)。將混合物攪拌3小時。在反應完成後,向其中添加乙酸乙酯(50mL)及蒸餾水(20mL)。將如上文所述獲得之有機層經無水硫酸鈉乾燥並在減壓下濃縮。使殘餘物經過管柱層析,藉此獲得化合物2c
(94mg, 94%)。1
H NMR (400MHz, CDCl3
) δ 7.71 (d, J= 2.0Hz, 1H), 7.45 (dd, J= 6.4, 2.0Hz, 1H), 7.17 (d, J= 8.4Hz, 1H), 5.40-5.30 (m, 3H), 5.16-5.14 (m, 1H), 4.67 (s, 2H), 4.40-4.29 (m, 2H), 4.18 (d, J = 8.8Hz, 1H), 3.74 (s, 3H), 2.08-2.04 (m, 9H), 1.14-1.09 (m, 2H), 0.08 (s, 9H)化合物 2d 之製備
於0℃下在氮氣氛下將化合物2c
(90mg, 0.154mmol)溶解於DMF (1.0mL)中,且隨後向其中添加碳酸雙(4-硝基苯基)酯(94mg, 0.308mmol)及DIPEA (40uL, 0.231mmol)。將混合物於室溫下攪拌3小時。在反應完成後,向其中添加乙酸乙酯(50mL)及蒸餾水(20mL)。將如上文所述獲得之有機層經無水硫酸鈉乾燥並在減壓下濃縮。使殘餘物經過管柱層析,藉此獲得化合物2d
(104mg, 90%)。1
H NMR (400MHz, CDCl3
) δ 8.28 (m, 2H), 7.80 (d, J = 2.4Hz, 1H), 7.53 (dd, J= 6.4, 2.0Hz, 1H), 7.37 (m, 2H), 7.20 (d, J= 8.8Hz, 1H), 5.41-5.33 (m, 3H), 5.25 (s, 2H), 5.20-5.18(m, 1H), 4.41-4.30 (m, 2H), 4.20 (d, J = 8.8Hz, 1H), 3.74 (s, 3H), 2.08-2.05 (m, 9H), 1.18-1.06 (m, 2H), 0.08 (s, 9H)化合物 2e 之製備
於室溫下在氮氣氛下將化合物2d
(1.5g, 2.00mmol)溶解於DMF (8mL)中,且隨後向其中添加MMAF-OMe (1.34g, 1.80mmol)。將所得組合物用HOBT (54mg, 0.4mmol)、吡啶(5.4mL)及DIPEA (0.383mL, 2.2mmol)處理。將混合物於室溫下攪拌12小時。在反應完成後,向其中添加乙酸乙酯(200mL)及蒸餾水(300mL)。將如上文所述獲得之有機層經無水硫酸鈉乾燥並在減壓下濃縮。使殘餘物經過管柱層析,藉此獲得化合物2e
(1.7g, 70%)。 EI-MS m/z: 1357(M+
)化合物 2f 之製備
於0℃下在氮氣氛下將化合物2e
(1.7g, 1.253mmol)溶解於THF (15mL)中,且隨後向其中添加四丁基氟化銨(1M於THF中) (2.5mL, 2.506mmol)並於室溫下攪拌4小時。在反應完成後,向其中添加乙酸乙酯(200mL)及蒸餾水(300mL)。將如上文所述獲得之有機層經無水硫酸鈉乾燥並在減壓下濃縮。使殘餘物經過管柱層析,藉此獲得化合物2f
(1.34g, 85%)。 EI-MS m/z: 1257(M+
)化合物 2k 之製備
於室溫下在氮氣氛下將化合物2j
(10g, 59.3mmol)溶解於DMF (90mL)中,且隨後向其中添加疊氮化鈉(5.78g, 88.9mmol),並將混合物於100℃下攪拌13小時。在反應完成後,向其中添加氯仿(200mL)及蒸餾水(300mL)以萃取有機層,並將經萃取之有機層經無水硫酸鈉乾燥並在減壓下濃縮。使殘餘物經過管柱層析,藉此獲得化合物2k
(10.3g, 99%)。1
H NMR (600MHz, CDCl3
) δ 3.75-3.73 (m, 2H), 3.70-3.68 (m, 6H), 3.63-3.61 (m, 2H), 3.40 (t, J = 5.4Hz, 2H), 2.20 (t, J = 6.0Hz, 1H)化合物 2l 之製備
於0℃下在氮氣氛下將CBr4
(21.4g, 64.6mmol)溶解於二氯甲烷(MC, 100mL)中,且隨後向其中添加二氯甲烷(100ml)中之三苯基膦(16.9g, 64.6mmol)及化合物2k
(10.3g, 58.7mmol),並將混合物於室溫下攪拌13小時。在反應完成後,向其中添加二氯甲烷(300mL)及蒸餾水(300mL)以萃取有機層,並將經萃取之有機層經無水硫酸鈉乾燥並在減壓下濃縮。使殘餘物經過管柱層析,藉此獲得化合物2l
(12g, 85%)。1
H NMR (400MHz, CDCl3
) δ 3.83 (t, J = 6.4Hz, 2H), 3.72-3.67 (m, 6H), 3.48 (t, J = 6.0Hz, 2H), 3.40 (t, J = 4.8Hz, 2H)化合物 2m 之製備
於室溫下在氮氣氛下將化合物2l
(1g, 4.20mmol)溶解於乙腈中,且隨後向其中添加N-Boc-羥基胺(643mg, 4.82mmol)及DBU (0.659mL, 4.41mmol),並將混合物於60℃下攪拌13小時。在反應完成後,向其中添加二氯甲烷(300mL)及蒸餾水(300mL)以萃取有機層,並將經萃取之有機層經無水硫酸鈉乾燥並在減壓下濃縮。使殘餘物經過管柱層析,藉此獲得化合物2m
(748mg, 70%)。1
H NMR (400MHz, CDCl3
) δ 7.55 (s, 1H), 4.05-4.03 (m, 2H), 3.76-3.74 (m, 2H), 3.74-3.69 (m, 6H), 3.42 (t, J = 4.8Hz, 2H), 1.49 (s, 9H)。EI-MS m/z: 291(M+
)化合物 2n 之製備
將化合物2m
(200mg, 0.688mmol)溶解於甲醇(5mL)中,且隨後向其中添加Pd/C(10%) (70mg)並在氫氣氛下攪拌3小時。在反應完成後,將混合物經矽藻土過濾並在減壓下濃縮,藉此獲得化合物2n
(180mg, 98%)。1
H NMR (400MHz, CDCl3
) δ 4.04-4.01 (m, 2H), 3.74-3.62 (m, 7H), 3.55 (t, J = 5.2Hz, 1H), 2.88 (t, J = 5.2Hz, 1H), 2.81 (t, J = 5.2Hz, 1H), 1.64 (s, 2H), 1.48 (s, 9H)。EI-MS m/z: 265(M+
)化合物 2g 之製備
於0℃下在氮氣氛下將化合物2f
(1.34g, 1.066mmol)及化合物2n
(384mg, 1.28mmol)溶解於DMF (10mL)中,且隨後向其中添加DIPEA (464uL, 2.665mmol)及PyBOP (832mg, 1.599mmol)並於室溫下攪拌4小時。在反應完成後,向其中添加乙酸乙酯(200mL)及蒸餾水(300mL)。將如上文所述獲得之有機層經無水硫酸鈉乾燥並在減壓下濃縮。使殘餘物經過管柱層析,藉此獲得化合物2g
(1.2g, 75%)。EI-MS m/z: 1503(M+
)化合物 2h 之製備
於-10℃下在氮氣氛下將化合物2g
(530mg, 0.352mmol)溶解於甲醇(10mL)中,且隨後向其中緩慢添加水(8mL)中之LiOH (147mg, 7.98mmol)並攪拌1小時。在反應完成後,向其中添加氯仿(200mL)及蒸餾水(30mL, pH 2)。將如上文所述獲得之有機層經無水硫酸鈉乾燥並在減壓下濃縮。使殘餘物經過管柱層析,藉此獲得化合物2h
(260mg, 45%)。EI-MS m/z: 1349(M+
)化合物 2i 之製備
於0℃下在氮氣氛下將化合物2h
(260mg, 0.192mmol)溶解於二氯甲烷(4mL)及水(2mL)中,且隨後向其中添加4M-HCl (於二噁烷中,4mL),並於0℃下攪拌1小時。在反應完成後,在減壓下濃縮所得物,藉此獲得化合物2i
(210mg, 85%)。EI-MS m/z: 1249(M+
)化合物 3k 之製備
於室溫下在氮氣氛下將2-溴乙醇(1.92mL, 27.037mmol)溶解於乙腈(15mL)中,且隨後向其中添加Boc-羥基胺(3.0g, 22.531mmol)及DBU (3.7mL, 24.8mmol),並將混合物於40℃下攪拌24小時。在反應完成後,向其中添加乙酸乙酯(100mL)及蒸餾水(100mL)以萃取有機層,並將經萃取之有機層經無水硫酸鈉乾燥並在減壓下濃縮。使殘餘物經過管柱層析,藉此獲得化合物3k
(2.75g, 69%)。1
H NMR (400MHz, CDCl3
) δ 7.28 (s, 1H), 3.93-3.91 (m, 2H), 3.76-3.74 (m, 2H), 1.50 (s, 9H)。化合物 3l 之製備
於0℃下在氮氣氛下將化合物3k
(2.75g, 15.697mmol)溶解於THF (30mL)中,且隨後向其中添加TEA (3.3mL, 23.518mmol)及Ms2
O (3.28g, 18.814mmol),並將混合物於室溫下攪拌4小時。在反應完成後,向其中添加乙酸乙酯(200mL)及蒸餾水(100mL)以萃取有機層,並將經萃取之有機層經無水硫酸鈉乾燥並在減壓下濃縮,藉此獲得化合物3l
(3.83g, 96%)。1
H NMR (400MHz, CDCl3
) δ 7.37 (s, 1H), 4.48-4.46 (m, 2H), 4.13-4.09 (m, 2H), 3.11 (s, 3H), 1.50(s, 9H)。化合物 3m 之製備
於室溫下在氮氣氛下將化合物3l
(3.83g, 15.00mmol)溶解於DMF (20mL)中,且隨後向其中添加NaN3
(1.95g, 30.00mmol),並將混合物於60℃下攪拌13小時。在反應完成後,向其中添加乙酸乙酯(300mL)及蒸餾水(300mL)以萃取有機層,並將經萃取之有機層經無水硫酸鈉乾燥並在減壓下濃縮。使殘餘物經過管柱層析,藉此獲得化合物3m
(2.02g, 67%)。1
H NMR (400MHz, CDCl3
) δ 7.22-7.20 (m, 1H), 4.05-4.02 (m, 2H), 3.51-3.48 (m, 2H), 1.50(s, 9H)。化合物 3n 之製備
將化合物3m
(2.02g, 9.98mmol)溶解於甲醇(30mL)中,且隨後向其中添加Pd/C (10%) (1.0g)及二噁烷(2.5mL)中之4M HCl並在氫氣氛下攪拌3小時。在反應完成後,將混合物經矽藻土過濾並在減壓下濃縮,藉此獲得化合物3n
(1.98g, 93%)。1
H NMR (400MHz, CDCl3
) δ 10.26 (s, 1H), 8.05 (s, 3H), 3.91-3.88 (m, 2H), 3.1-2.98 (m, 2H), 1.44(s, 9H)。化合物 3g 之製備
於0℃下在氮氣氛下將化合物2f
(280mg, 0.222mmol)及化合物3n
(56mg, 0.266mmol)溶解於DMF (5mL)中,且隨後向其中添加DIPEA (58uL, 0.334mmol)及PyBOP (174mg, 0.334mmol)並於室溫下攪拌4小時。在反應完成後,向其中添加乙酸乙酯(100mL)及蒸餾水(150mL)。將如上文所述獲得之有機層經無水硫酸鈉乾燥並在減壓下濃縮。使殘餘物經過管柱層析,藉此獲得化合物3g
(221mg, 69%)。EI-MS m/z: 1415(M+
)化合物 3h 之製備
於-10℃下在氮氣氛下將化合物3g
(150mg, 0.106mmol)溶解於甲醇(2mL)中,且隨後向其中緩慢添加水(2mL)中之LiOH (40mg, 0.954mmol)並攪拌1小時。在反應完成後,向其中添加氯仿(150mL)及蒸餾水(30mL, pH 2)。將如上文所述獲得之有機層經無水硫酸鈉乾燥並在減壓下濃縮。使殘餘物經過管柱層析,藉此獲得化合物3h
(94mg, 71%)。EI-MS m/z: 1261(M+
)化合物 3i 之製備
於0℃下在氮氣氛下將化合物3h
(90mg, 0.071mmol)溶解於二氯甲烷(1mL)中,且隨後向其中添加三氟乙酸(TFA, 0.2mL)並於0℃下攪拌3小時。在反應完成後,使用Prep HPLC純化所得物,藉此獲得化合物3i
(47mg, 52%)。 EI-MS m/z: 1161(M+
)實例 4. 化合物 4i 之製備 3- 溴 -5- 甲醯基柳酸 ( 化合物 4a) 之製備
於0℃下在氮氣氛下將5-甲醯基柳酸(1g, 6.019mmol)溶解於DMF中,且隨後向其中添加N-溴琥珀醯亞胺(1.07g, 6.109mmol)並將混合物於70℃下攪拌3小時。在反應完成後,向其中添加乙酸乙酯(100mL)、2N-HCl水溶液(2mL)及蒸餾水(100mL)。將如上文所述獲得之有機層經無水硫酸鈉乾燥並在減壓下濃縮。使殘餘物經過管柱層析,藉此獲得化合物4a
(1.2g, 84%)。1
H NMR (400MHz, DMSO-d6
) δ 9.64 (s, 1H), 8.19 (d, J= 2.4Hz, 1H), 8.00 (d, J= 2.0Hz, 1H), 3.16 (s, 1H) 化合物4i
係使用所製備之3-溴-5-甲醯基柳酸(化合物4a
)藉由類似於製備實例2及3之化合物2i
及3i
之方法的方法來製備。 EI-MS m/z: 1328(M+
)實例 5 至 7. LCB14-0648 、 LCB14-0664 及 LCB14-0663 之製備 化合物C
係藉由韓國專利特許公開案第10-2014-0035393號中揭示之方法來製備。實例 5. LCB14-0648 之製備
於室溫下在氮氣氛下將化合物2i
(20mg, 0.014mmol)溶解於乙醇(0.7mL)中,且隨後向其中添加化合物C
(3.7mg, 0.017mmol),並將混合物於45℃下攪拌2小時。在反應完成後,使用Prep HPLC獲得LCB14-0648 (10.2mg, 49%)。 EI-MS m/z: 1441(M+
) LCB14-0663 (實例6)及LCB14-0664 (實例7)係藉由類似於製備LCB14-0648 (實例5)之方法之方法來製備。 LCB14-0663之EI-MS:m/z: 1520(M+
) LCB14-0664之EI-MS:m/z: 1353(M+
)比較實例 1. 化合物 5k 之製備 化合物 5a 之製備
於室溫下在氮氣氛下將4-溴丁酸乙酯(5.0mL, 34.604mmol)溶解於MeOH (75mL)中,且隨後向其中添加水(25mL)中之疊氮化鈉(4.5g, 69.209mmol)並於85℃下攪拌8小時。在反應完成後,在減壓下濃縮溶劑,且向其中添加氯仿(300mL)及蒸餾水(200mL)。將如上文所述獲得之有機層經無水硫酸鈉乾燥並在減壓下濃縮。使殘餘物經過管柱層析,藉此獲得化合物5a
(5.1g, 94%)。1
H NMR (600MHz, CDCl3
) δ 4.15 (q, J = 7.2Hz, 2H), 3.36 (t, J = 7.2Hz, 2H), 2.41 (t, J = 7.2Hz, 2H), 1.94-1.89 (m, 2H), 1.28 (t, J = 8.4Hz, 3H)。化合物 5b 之製備
於0℃下在氮氣氛下將化合物5a
(2.0g, 12.725mmol)溶解於MeOH (32mL)中,且隨後向其中緩慢添加水(26mL)中之KOH (3.56g, 63.625mmol)並於室溫下攪拌6小時。在反應完成後,在減壓下濃縮溶劑,並向其中添加氯仿(300mL)、1N HCl (100mL)及蒸餾水(100mL)。將如上文所述獲得之有機層經無水硫酸鈉乾燥並在減壓下濃縮。使殘餘物經過管柱層析,藉此獲得化合物5b
(1.28g, 78%)。1
H NMR (600MHz, CDCl3
) δ 3.38 (t, J = 7.2Hz, 2H), 2.48 (t, J = 7.2Hz, 2H), 1.95-1.90 (m, 2H)。化合物 5c 之製備
於0℃下在氮氣氛下將化合物5b
(850mg, 6.580mmol)溶解於MeOH (10mL)中,且隨後向其中添加草醯氯(1.1mL, 13.160mmol)及DMF (1滴)並於室溫下攪拌6小時。在反應完成後,在減壓下濃縮溶劑,使得獲得對應於粗產物之化合物5c
(965mg, Qu)且其未經純化即用於下一反應。化合物 5d 之製備
於0℃下在氮氣氛下將4-羥基-3-硝基苯甲酸(5g, 27.304mmol)溶解於THF (120mL)中,且隨後向其中添加1M BH3-THF複合物(54.6mL, 54.6mmol)並於室溫下攪拌20小時。在反應完成後,向其中添加乙酸乙酯(200mL)、0.5N HCl (20mL)及蒸餾水(100mL)。將如上文所述獲得之有機層經無水硫酸鈉乾燥並在減壓下濃縮。使殘餘物經過管柱層析,藉此獲得化合物5d
(4.20g, 91%)。1
H NMR (600MHz, CD3OD) δ 8.06 (d, J = 1.2Hz, 1H), 7.59 (dd, J= 1.2, 7.8Hz, 1H), 7.12 (d, J= 8.4Hz, 1H), 4.83 (s, 2H)化合物 5e 之製備
於室溫下在氮氣氛下將化合物5d
(937mg, 5.539mmol)溶解於乙腈(15mL)中,並向其中添加化合物5c
(2.0g, 5.035mmol)、氧化銀(4.66g, 20.108mmol)及分子篩(2.0g),並於室溫下攪拌14小時。在反應完成後,將混合物經矽藻土過濾,並在減壓下濃縮濾液。使殘餘物經過管柱層析,藉此獲得化合物5e
(1.0g, 40%)。1
H NMR (600MHz, CDCl3
) δ 7.81 (d, J = 1.8Hz, 1H), 7.54 (dd, J= 1.8, 6.6Hz, 1H), 7.37 (d, J= 8.4Hz, 1H), 5.37-5.27 (m, 3H), 5.20 (d, J= 6.6Hz, 1H), 4.72 (d, J = 6.0Hz, 2H), 4.21 (d, J = 9.0Hz, 1H), 3.75 (s, 3H), 2.12 (s, 3H), 2.06 (s, 3H), 2.05 (s, 3H), 2.04-2.02 (m, 1H)。化合物 5f 之製備
將化合物5e
(900mg, 6.35 mmol)溶解於乙酸乙酯(100mL)中,且隨後向其中添加氧化鉑(IV) (84.2mg, 0.370mmol)並於室溫下在氫氣氛下攪拌3小時。在反應完成後,將混合物經矽藻土過濾,並在減壓下濃縮濾液,使得獲得對應於粗產物之化合物5f
(700mg, 83%)且其未經純化即用於下一反應。化合物 5g 之製備
於0℃下在氮氣氛下將化合物5f
(350mg, 0.768mmol)溶解於MC (10mL)中,且隨後向其中添加化合物5c
(136mg, 0.921mmol)及DIPEA (268uL, 1.536mmol)並於室溫下攪拌20分鐘。在反應完成後,向其中添加乙酸乙酯(50mL)及蒸餾水(50mL)。將如上文所述獲得之有機層經無水硫酸鈉乾燥並在減壓下濃縮。使殘餘物經過管柱層析,藉此獲得化合物5g
(280mg, 65%)。1
H NMR (600MHz, CDCl3
) δ 8.37 (d, J = 1.2Hz, 1H), 8.00 (s, 1H), 7.07 (dd, J= 1.8, 6.6Hz, 1H), 6.93 (d, J= 8.4Hz, 1H), 5.43-5.28 (m, 3H), 5.06 (d, J= 7.8Hz, 1H), 4.63 (s, 2H), 4.19 (d, J = 9.6Hz, 1H), 3.76 (s, 3H), 3.44-3.41 (m, 2H), 2.56 (t, J = 7.8Hz, 2H), 2.17-2.00 (m, 12H)。EI-MS m/z: 567(M+
)化合物 5h 之製備
於0℃下在氮氣氛下將化合物5g
(250mg, 0.441mmol)溶解於DMF (4mL)中,且隨後向其中添加碳酸雙(4-硝基苯基)酯(270mg, 0.882mmol)及DIPEA (115uL, 0.661mmol),並於室溫下攪拌1小時。在反應完成後,向其中添加乙酸乙酯(50mL)及蒸餾水(50mL)。將如上文所述獲得之有機層經無水硫酸鈉乾燥並在減壓下濃縮。使殘餘物經過管柱層析,藉此獲得化合物5h
(290mg, 90%)。1
H NMR (600MHz, CDCl3
) δ 8.54 (d, J = 1.8Hz, 1H), 8.28-8.25 (m, 2H), 8.02 (s, 1H), 7.40-7.36 (m, 2H), 7.11 (dd, J= 1.8, 6.6Hz, 1H), 6.96 (d, J= 8.4Hz, 1H), 5.44-5.29 (m, 3H), 5.23 (s, 2H), 5.10 (d, J= 7.8Hz, 1H), 4.21 (d, J = 9.6Hz, 1H), 3.76 (s, 3H), 3.45-3.42 (m, 2H), 2.58 (t, J = 7.2Hz, 2H), 2.11-2.00 (m, 12H)。EI-MS m/z: 732(M+
)化合物 5i 之製備
於室溫下在氮氣氛下將化合物5h
(250mg, 0.341mmol)溶解於DMF (4mL)中,且隨後向其中添加MMAF-OMe (255mg, 0.341mmol)。將所得組合物用HOBT (9mg, 0.068mmol)、吡啶(1.2mL)及DIPEA (60uL, 0.341mmol)處理。將所得混合物於室溫下攪拌2天。在反應完成後,向其中添加乙酸乙酯(50mL)、2N HCl (5mL)及蒸餾水(50mL)。將如上文所述獲得之有機層經無水硫酸鈉乾燥並在減壓下濃縮。使殘餘物經過管柱層析,藉此獲得化合物5i
(340mg, 74%)。 EI-MS m/z: 1339(M+
)化合物 5j 之製備
於0℃下在氮氣氛下將化合物5i
(210mg, 0.156mmol)溶解於甲醇(2mL)中,且隨後向其中添加水(2mL)中之LiOH∙H2
O (66mg, 1.560mmol)。於室溫下將所得混合物攪拌1.5小時。在反應完成後,向其中添加氯仿(50mL)、甲醇(5mL)、蒸餾水(50mL)及0.5N HCl (5mL)。將如上文所述獲得之有機層經無水硫酸鈉乾燥並在減壓下濃縮。使殘餘物經過管柱層析,藉此獲得化合物5j
(107mg, 57%)。 EI-MS m/z: 1184(M+
)化合物 5k 之製備
於室溫下在氮氣氛下將化合物5j
(10mg, 0.008mmol)及苯基乙炔(0.92uL, 0.008mmol)溶解於乙醇(150ul)及水(10ul)中,且隨後向其中添加0.1M CuSO4
水溶液(10ul)及1.0M抗壞血酸鈉水溶液(10ul)。於室溫下將所得混合物攪拌5小時。在反應完成後,向其中添加乙酸乙酯(10mL)及蒸餾水(5mL)。將如上文所述獲得之有機層經無水硫酸鈉乾燥並在減壓下濃縮。使殘餘物經過管柱層析,藉此獲得化合物5k
(5mg, 46%)。 EI-MS m/z: 1286(M+
)實例 8. 化合物 6e 之製備 化合物 6a 之製備
於室溫下在氮氣氛下將化合物2d
(229mg, 0.30mmol)溶解於DMF (2mL)中,且隨後向其中添加MMAE (1.34g, 1.80mmol)。將所得組合物用HOBT (8.2mg, 0.06mmol)、吡啶(0.8mL)及DIPEA (56uL, 0.29mmol)處理。將混合物於室溫下攪拌12小時。在反應完成後,向其中添加乙酸乙酯(100mL)及蒸餾水(100mL)。將如上文所述獲得之有機層經無水硫酸鈉乾燥並在減壓下濃縮。使殘餘物經過管柱層析,藉此獲得化合物6a
(239mg, 65%)。 EI-MS m/z: 1328(M+
)化合物 6b 之製備
於0℃下在氮氣氛下將化合物6a
(239mg, 0.18mmol)溶解於THF (5mL)中,且隨後向其中添加四丁基氟化銨(1M於THF中) (540uL, 2.50.58mol)並於室溫下攪拌3小時。在反應完成後,向其中添加二氯甲烷(100mL)及蒸餾水(100mL)。將如上文所述獲得之有機層經無水硫酸鈉乾燥並在減壓下濃縮。使殘餘物經過管柱層析,藉此獲得化合物6b
(212mg, 95%)。 EI-MS m/z: 1228(M+
)化合物 6c 之製備
於0℃下在氮氣氛下將化合物6b
(200mg, 0.16mmol)及化合物2n (51mg, 0.19mmol)溶解於DMF (4mL)中,且隨後向其中添加DIPEA (42uL, 0.32mmol)及PyBOP (126mg, 0.24mmol)並於室溫下攪拌4小時。在反應完成後,向其中添加乙酸乙酯(100mL)及蒸餾水(100mL)。將如上文所述獲得之有機層經無水硫酸鈉乾燥並在減壓下濃縮。使殘餘物經過管柱層析,藉此獲得化合物6c
(142mg, 60%)。 EI-MS m/z: 1474(M+
)化合物 6d 之製備
於-20℃下在氮氣氛下將化合物6c
(142mg, 0.09mmol)溶解於甲醇(2mL)中,且隨後向其中緩慢添加水(2mL)中之LiOH (36mg, 0.86mmol)並於0℃下攪拌1小時。在反應完成後,向其中添加氯仿(100mL)、蒸餾水(50mL)及2N-HCl水溶液(2mL)。將如上文所述獲得之有機層經無水硫酸鈉乾燥並在減壓下濃縮。殘餘物(6d
, 128mg, 99%)未經純化即用於下一反應。 EI-MS m/z: 1334(M+
)化合物 6e 之製備
於-20℃下在氮氣氛下將化合物6d
(105mg, 0.08mmol)溶解於二氯甲烷(3mL)中,且隨後向其中添加4M-HCl (於二噁烷中,1mL)並於0℃下攪拌1小時。在反應完成後,在減壓下濃縮所得物。使用製備型HPLC純化殘餘物,藉此獲得化合物6e
(47mg, 46%)。 EI-MS m/z: 1234(M+
)實驗實例 1. 關於 β - 葡萄糖醛酸苷酶之反應比較測試 為對實例 1 之化合物 1k 及比較實例 1 之化合物 5k 對 β - 葡萄糖醛酸苷酶之反應彼此進行比較 , 如下實施比較測試。
實例1之化合物1k及比較實例1之化合物5k各自製備為500μM及50μM DMSO原液。分別製備其中880 μL磷酸鹽緩衝液鹽水(PBS)溶液及100 μL化合物1k及化合物5k原液彼此混合之反應溶液(其最終濃度分別係50μM及5μM)。在向反應溶液中添加20μL大腸桿菌β-葡萄糖醛酸苷酶(1mg/ml,Sigma: E.C.3.2.1.31型IX-A;1mg/mL,於PBS中;3.6μg,13μmol)後,於37℃下在恆定溫度之水中起始反應。分別在0 min、25 min、60min及90 min時分配100 μL混合溶液,並向其中添加200 μL乙腈。使用LC-MS/MS定量分析自藉由對混合物試樣實施離心(4℃,15 min,14000 rpm)獲得之上清液中之每一者釋放之MMAF (該實驗係藉由類似於美國專利第8,568,728號中揭示之方法之方法實施,該案件以引用方式併入本文中)。 測試結果圖解說明於圖2中,且自圖2確認,在藉由β-葡萄糖醛酸苷酶進行酶反應後,經由1,6-消除反應自實例1之化合物1k及比較實例1之化合物5k中之每一者顯著快速釋放MMAF (美國專利第8,568,728號,其以引用方式併入本文中)。實驗實例 2. 血漿穩定性比較測試
對實例1之化合物1k及比較實例1之化合物5k之血漿穩定性進行比較。 將10μL化合物1k或5k以5mM溶解於DMSO中,且將每一組合物與990μL小鼠血漿混合,藉此製備50μM試樣,用於評價血漿穩定性。將血漿/化合物溶液於37℃下培育6天。在6天培育期間,在0、1、2、3及6天時取100μL等份試樣並將其與含有200μL乙腈之內標準品混合用於監測血漿蛋白質沈澱。藉由離心乙腈/血漿試樣(4℃,15 min,14000 rpm)獲得上清液,且藉由對上清液實施LC-MS/MS對每一化合物及產物之量進行定量。(該實驗係使用類似於J. Chromatography B, 780:451-457 (2002)中揭示之彼等來實施)。 針對實例1之化合物1k及比較實例1之化合物5k使用LS-MS/MS獲得之結果闡釋於圖3及表1中。比較實例1之化合物5k之穩定性及實例1之化合物1k之穩定性於第1天時分別係14%及80%。因此,實例1之化合物1k於小鼠血漿中之穩定性優於比較實例1之化合物5k。 表1. 化合物1k及化合物5k於小鼠血漿中之穩定性 實驗實例 3. 血漿穩定性測試
為確認使用LCB14-0648 (實例5)、LCB14-0664 (實例6)及LCB14-0663 (實例7) (其係實例5至7中製備之化合物)之各種血漿中之穩定性,藉由與實驗實例2中相同之方法實施血漿穩定性測試,且結果圖解說明於圖4至6中。 確認LCB14-0648 (實例5)、LCB14-0664 (實例6)及LCB14-0663 (實例7) (其係實例5至7中製備之化合物)在小鼠、大鼠、狗及人類血漿中皆穩定高達7天。實例 9 至 11 : 抗體 - 藥物共軛物 (ADC) 之製備 實例 9. DI-B4 (LC)- 葡萄糖醛酸苷連接體 -MMAF ( 下文稱作 「 ADC14-0610 」 ) 之製備 ( 圖 7) 步驟 1 ( 戊二烯化抗體 , D) 美國專利申請公開案第 2012/0308584 號中揭示之受質 (D) 之製備
製備抗體之戊二烯化反應混合物並使其於30℃下反應12小時。使用包含添加至每一輕鏈之c-末端之GGGGGGGCVIM序列(「G7CVIM」)的DI-B4抗體(本文中稱作「DI-B4-(LC)-GGGGGGG-CVIM」及「抗-CD19(LC)-G7CVIM」)。反應混合物由含有24 μM抗體、600nM FTase (Calbiochem編號344145)及1mM LCB14-0606 (根據美國專利申請公開案第2012/0308584號之方法室內製備,該案件以引用方式併入本文中)之緩衝溶液(50 mM Tris-HCl (pH7.4)、5 mM MgCl2
、10 μM ZnCl2
、5 mM DTT)構成。在反應完成後,藉由FPLC純化戊二烯化抗體。於30℃下將戊二烯化抗體在1mM CuSO4
中培育3小時以再氧化任何經還原硫醇。隨後向混合物中添加EDTA至2 mM,且將混合物於30℃下輕柔攪拌30分鐘。藉由FPLC純化所得產物。步驟 2 ( 製備 ADC14-0610 之方法 )
藉由混合100mM乙酸Na緩衝液(pH 4.5, 10% DMSO)、12μM抗體及360μM LCB14-0645 (室內)製備戊二烯化抗體(A)與毒素(3l)之間之肟鍵形成反應混合物並於30℃下輕柔攪拌。在將反應物培育24小時後,經由FPLC及疏水性相互作用層析藉由去鹽純化抗體-藥物共軛物。實例 10. DI-B4 (LC)- 葡萄糖醛酸苷連接體 -MMAE 之製備 DI-B4 (LC)-葡萄糖醛酸苷連接體-MMAE抗體-藥物共軛物係使用所製備之化合物6e
藉由類似於實例10之製備方法之方法來製備。實例 11. DI-B4 (LC)- 葡萄糖醛酸苷連接體 - 瓢菌素之製備 DI-B4 (LC)-葡萄糖醛酸苷連接體-瓢菌素抗體-藥物共軛物係藉由類似於實例10之製備方法之方法來製備。實例 12. ADC14-0610 結合親和性 (ELISA)
將抗-CD19抗體DI-B4、DI-B4-(LC)-GGGGGGG-CVIM及ADC14-0610平鋪,將板與CD19-Fc-His一起培育,且使用偶聯至辣根過氧化酶之抗-His抗體測定抗體之結合親和性。ADC14-0610 (包含DI-B4、GGGGGGG連接體、CVIM異戊二烯化序列、肟連接體、葡糖醛酸及MMAF)之KD
經計算為3.3 nM,其類似於僅DI-B4及具有GGGGGGG連接體及CVIM異戊二烯化序列之DI-B4之KD
(圖8)。實例 13. ADC14-0610 結合親和性 ( 流式細胞術 )
藉由流式細胞術使用抗-CD19抗體DI-B4、DI-B4-(LC)-GGGGGGG- CVIM及ADC14-0610作為一級抗體分析Ramos細胞(其係人類伯基特氏淋巴瘤(Burkitt’s lymphoma) B淋巴球) (圖9)。簡言之,利用解離緩衝液(Gibco編號13151-014)收穫Ramos細胞。將200,000個細胞/試樣在冰上在磷酸鹽緩衝鹽水(PBS)中用4%正常山羊血清封阻30分鐘。將細胞製成丸以移除封阻緩衝液。隨後在冰上將細胞與0.5 μg/mL或2 μg/mL每一抗體在100 μL含有2%胎牛血清(FBS)之PBS中一起培育60分鐘。平行製備2 μg/mL之人類IgG1作為陰性對照。藉由以2000 rpm離心5分鐘將細胞用冷的PBS中之2% FBS洗滌三次。接下來,向細胞中添加PBS中之2% FBS中之100 μL 2 μg/mL藻紅素偶聯之二級抗體(抗人類IgG1-PE;BD 555787),且將混合物在冰上培育30分鐘。藉由以2000 rpm離心5分鐘將細胞用冷的PBS中之2% FBS洗滌三次。在BD FACSCanto II上分析標記之細胞,且藉由FACS Express 3.0軟體分析所得數據。 ADC14-0610抗體結合至Ramos細胞,但經ADC14-0610標記之細胞之螢光強度稍微低於經DI-B4或DI-B4-(LC)-GGGGGGG-CVIM標記之細胞(圖9)。實例 14. ADC14-0610 細胞毒性
將Raji細胞(其係人類伯基特氏淋巴瘤細胞)以200,000個細胞/孔接種於100 μL生長培養基中之96孔板中。將細胞於37℃下在5% CO2
中培育1天。向每一孔中添加100 μL培養基中之4.0 μg/mL至1.5625 ng/mL之抗-CD19抗體DI-B4-(LC)-GGGGGGG-CVIM及ADC14-0610,且將細胞與抗體一起培育72小時。藉由細胞計數評定細胞存活力。 Raji細胞中之實驗係與對於K562細胞(即不表現CD19之人類骨髓性白血病細胞)作為陰性對照以評定任何非特異性細胞毒性之實驗平行實施。 ADC14-0610展示針對Raji細胞之110 ng/mL之IC50
,其優於未偶聯之DI-B4 (圖10)。抗體針對K562對照細胞皆不展示低於10 μg/mL之細胞毒性。實例 15. ADC14-0610 活體內效能
向6週齡雌性經輻照Balb/c裸小鼠皮下注射5×106
個Ramos細胞。兩週後,腫瘤體積達到約130 mm3
,且將小鼠隨機分成10組。隨後向小鼠靜脈內注射2 mg/kg、5 mg/kg或10 mg/kg之ADC14-0610或未偶聯之抗體或媒劑(PBS)。利用卡尺每週兩次量測腫瘤以計算腫瘤體積。ADC14-0610之每一劑量傾向於較10 mg/kg劑量之未偶聯之抗體更佳地抑制腫瘤生長(圖11)。 以引用方式併入 本文所引用之專利、已公開專利申請案及非專利參考文獻中之每一者之全文皆以引用方式併入本文中。 等效內容 熟習此項技術者僅使用常規實驗即可識別或能夠確定本文所述本發明之具體實施例的許多等效內容。此等等效內容皆意欲涵蓋在下文申請專利範圍內。
圖 1
圖解說明自基於β-葡萄糖醛酸苷之連接體之活性藥物釋放機制。圖 2
係繪示來自實驗實例1之連接體由β-葡萄糖醛酸苷酶水解的圖。圖 3
係繪示來自實驗實例2之兩種藥物-連接體共軛物之血漿穩定性的圖。圖 4
係繪示實例5中製備之LCB14-0648之血漿穩定性的圖。圖 5
係繪示實例6中製備之LCB14-0663之血漿穩定性的圖。圖 6
係繪示實例7中製備之LCB14-0664之血漿穩定性的圖。圖 7
展示用於藥物偶聯至抗體之策略。圖 8
含有使用各種DI-B4抗體衍生物作為ELISA之抗體以計算每一抗體之KD
的ELISA結果。DI-B4衍生物係DI-B4、DI-B4-(LC)-GGGGGGG- CVIM及ADC14-0610。結果顯示ADC14-0610具有3.3 nM之KD
,其類似於未經修飾之抗體之KD
。圖 9
顯示使用抗-CD19抗體DI-B4、DI-B4-(LC)-GGGGGGG-CVIM及ADC14-0610作為一級抗體標記之Ramos細胞(其係人類伯基特氏淋巴瘤(Burkitt’s lymphoma) B淋巴球)的流式細胞術結果。ADC14-0610抗體-藥物共軛物結合至Ramos細胞,但經ADC14-0610標記之細胞之螢光強度稍微低於經DI-B4或DI-B4-(LC)-GGGGGGG-CVIM標記之細胞。圖 10
顯示抗-CD19抗體DI-B4-(LC)-GGGGGGG-CVIM (a-CD19 mAb)及ADC14-0610 (a-CD19 ADC B)及MMAF針對Raji細胞之細胞毒性。ADC14-0610展示0.11 μg/mL之IC50
。圖 11
顯示在經輻照Balb/c小鼠模型中,偶聯至MMAF之抗-CD19抗體DI-B4 (「CD19 ADC」;ADC14-0610)較未偶聯之DI-B4抗體或PBS媒劑更大地減小Ramos腫瘤體積(左)。向動物投與單一劑量之10 mg/kg之DI-B4抗體(CD19 (10MPK))或單一劑量之2 mg/kg、5 mg/kg或10 mg/kg (分別2MPK、5 MPK或10 MPK)之偶聯之DI-B4抗體ADC14-0610 (CD19 ADC)。小鼠體重在DI-B4小鼠與接受偶聯至MMAF之DI-B4之小鼠之間無變化(右)。
Claims (46)
- 一種抗體-藥物共軛物,其具有由式I代表之結構:
- 如請求項1之抗體-藥物共軛物,其中R3係氫。
- 如請求項1之抗體-藥物共軛物,其中每一R4皆係氫。
- 如請求項3之抗體-藥物共軛物,其中R3係氫且每一R4皆係氫。
- 如請求項1之抗體-藥物共軛物,其中W代表-C(O)NR’-,其中C(O)鍵結至該苯基環且NR’鍵結至L。
- 如請求項1之抗體-藥物共軛物,其中Z代表氫。
- 如請求項1之抗體-藥物共軛物,其中R1及R2各自代表氫。
- 如請求項1之抗體-藥物共軛物,其中該伸烷基之碳原子經一或多個選自氮(N)、氧(O)及硫(S)之雜原子置換。
- 如請求項9之抗體-藥物共軛物,其中L包含肟,且該至少一個異戊二烯基單元將該肟共價連接至該抗體。
- 如請求項12之抗體-藥物共軛物,其中L包含兩個聚乙二醇單元。
- 如請求項12之抗體-藥物共軛物,其中L包含肟,且該至少一個聚乙二醇單元將該肟共價連接至該藥物。
- 如請求項1之抗體-藥物共軛物,其中L包含由-(CH2)r(V(CH2)p)q-代表之連接單元,其中:r係1至10之整數;p係0至10之整數;q係1至10之整數;V係單鍵、-O-、-S-、-NR21-、-C(O)NR22-、-NR23C(O)-、-NR24SO2-或-SO2NR25-;且R21至R25各自獨立地係氫、(C1-C6)烷基、(C1-C6)烷基(C6-C20)芳基或(C1-C6)烷基(C3-C20)雜芳基。
- 如請求項1之抗體-藥物共軛物,其中L包含由-(CH2CH2X)w-代表之連接單元,其中:X代表-O-、(C1-C8)伸烷基或-NR21-;R21代表氫、(C1-C6)烷基、(C1-C6)烷基(C6-C20)芳基或(C1-C6)烷基(C3-C20)雜芳基;且w係1至10之整數。
- 如請求項1之抗體-藥物共軛物,其中L包含O-經取代之肟及:a)該肟之該氧原子經將該肟共價連接至該藥物之基團取代;且該肟之該碳原子經將該肟共價連接至該抗體之基團取代;或b)該肟之該氧原子經將該肟共價連接至該抗體之基團取代;且該肟之該碳原子經將該肟共價連接至該藥物之基團取代。
- 如請求項1之抗體-藥物共軛物,其中L藉由硫醚鍵共價結合至該抗體,且該硫醚鍵包含該抗體之半胱胺酸之硫原子。
- 如請求項22之抗體-藥物共軛物,其中:該抗體之羧基末端由選自CXX、CXC、XCXC、XXCC及CYYX之異戊二烯化序列組成;C代表半胱胺酸;Y在每次出現時獨立地代表脂族胺基酸; X在每次出現時獨立地代表麩醯胺酸、麩胺酸鹽、絲胺酸、半胱胺酸、甲硫胺酸、丙胺酸或白胺酸;且該硫醚鍵包含該異戊二烯化序列之半胱胺酸之硫原子。
- 如請求項23之抗體-藥物共軛物,其中:該羧基末端由該異戊二烯化序列CYYX組成;且Y在每次出現時獨立地代表丙胺酸、異白胺酸、白胺酸、甲硫胺酸或纈胺酸。
- 如請求項24之抗體-藥物共軛物,其中該羧基末端由該異戊二烯化序列CVIM或CVLL組成。
- 如請求項23之抗體-藥物共軛物,其中在該異戊二烯化序列之前之7個胺基酸中之至少一者係甘胺酸。
- 如請求項23之抗體-藥物共軛物,其中在該異戊二烯化序列之前之該7個胺基酸中之至少三者各自獨立地選自甘胺酸及脯胺酸。
- 如請求項23之抗體-藥物共軛物,其中在該異戊二烯化序列之前之該7個胺基酸中之每一者皆係甘胺酸。
- 如請求項1之抗體-藥物共軛物,其中該抗體包含胺基酸序列GGGGGGGCVIM。
- 如請求項1之抗體-藥物共軛物,其中該抗體係單株抗體、多株抗體、抗體片段、Fab、Fab'、Fab'-SH、F(ab')2、Fv、單鏈Fv(「scFv」)、雙價抗體、直鏈抗體、雙特異性抗體、多特異性抗體、嵌合抗體、人類化抗體、人類抗體或包含抗體之抗原結合部分之融合蛋白。
- 如請求項1之抗體-藥物共軛物,其中該抗體係布利莫單抗(blinatumomab)、MEDI-551、MOR208(XmAb5574)、XmAb-5871、MDX-1342、MDX-1435、cHD37、AFM-11、AFM-12、GBR401、HD37、DI-B4、huB4、B496或hBU12。
- 如請求項31之抗體-藥物共軛物,其中該抗體係DI-B4。
- 如請求項1之抗體-藥物共軛物,其中B係化學治療劑。
- 如請求項1之抗體-藥物共軛物,其中B係選自:(a)厄洛替尼(erlotinib)、硼替佐米(bortezomib)、氟維司群(fulvestrant)、舒癌特(sutent)、來曲唑(letrozole)、甲磺酸伊馬替尼(imatinib mesylate)、PTK787/ZK 222584、奧沙利鉑(oxaliplatin)、5-氟尿嘧啶(5-fluorouracil)、甲醯四氫葉酸(leucovorin)、雷帕黴素(rapamycin)、拉帕替尼(lapatinib)、洛那法尼(lonafarnib)、索拉菲尼(sorafenib)、吉非替尼(gefitinib)、AG1478、AG1571、噻替派(thiotepa)、環磷醯胺(cyclophosphamide)、白消安(busulfan)、英丙 舒凡(improsulfan)、哌泊舒凡(piposulfan)、苯并多巴(benzodopa)、卡波醌(carboquone)、美妥替派(meturedopa)、烏瑞替派(uredopa)、伸乙亞胺、六甲蜜胺(altretamine)、三伸乙基三聚氰胺、三伸乙基磷醯胺、三伸乙基硫代磷醯胺、三羥甲基三聚氰胺、布拉他辛(bullatacin)、布拉他辛酮(bullatacinone)、喜樹鹼(camptothecin)、托泊替康(topotecan)、苔蘚蟲素(bryostatin)、卡利斯他汀(callystatin)、CC-1065、阿多來新(adozelesin)、卡折來新(carzelesin)、比折來新(bizelesin)、念珠藻素1(cryptophycin 1)、念珠藻素8(cryptophycin 8)、多拉斯他汀(dolastatin)、多卡米星(duocarmycin)、KW-2189、CB1-TM1、艾榴塞洛素(eleutherobin)、水鬼蕉鹼(pancratistatin)、匍枝珊瑚醇(sarcodictyin)、海綿抑制素(spongistatin)、氮芥苯丁酸(chlorambucil)、萘氮芥(chlornaphazine)、氯磷醯胺、雌氮芥(estramustine)、異環磷醯胺(ifosfamide)、甲基二氯乙基胺(mechlorethamine)、美法侖(melphalan)、新氮芥(novembichin)、膽甾醇對苯乙酸氮芥(phenesterine)、潑尼莫司汀(prednimustine)、曲磷胺(trofosfamide)、尿嘧啶氮芥、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)、雷莫司汀(ranimnustine)、卡奇黴素(calicheamicin)、卡奇黴素γ 1、卡奇黴素ω 1、達內黴素(dynemicin)、達內黴素A、氯膦酸(clodronate)、埃斯波黴素(esperamicin)、新製癌菌素(neocarzinostatin)發色團、阿克拉黴素(aclacinomysin)、放線菌素(actinomycin)、安麯黴素(antramycin)、氮雜絲胺酸(azaserine)、博來黴素(bleomycin)、放線菌素C(cactinomycin)、卡拉黴素 (carabicin)、洋紅黴素(carninomycin)、嗜癌黴素(carzinophilin)、色黴素(chromomycin)、放線菌素(dactinomycin)、道諾黴素(daunorubicin)、地托比星(detorubucin)、6-重氮-5-側氧基-L-正白胺酸、多柔比星(doxorubicin)、嗎啉基-多柔比星、氰基嗎啉基-多柔比星、2-吡咯啉基-多柔比星、脂質體多柔比星、去氧多柔比星、泛艾黴素(epirubicin)、依索比星(esorubicin)、麻西羅黴素(marcellomycin)、絲裂黴素C(mitomycin C)、黴酚酸(mycophenolic acid)、諾拉黴素(nogalamycin)、橄欖黴素(olivomycin)、培洛黴素(peplomycin)、泊非黴素(potfiromycin)、嘌呤黴素(puromycin)、三鐵阿黴素(quelamycin)、羅多比星(rodorubicin)、鏈黑黴素(streptomigrin)、鏈脲黴素(streptozocin)、殺結核菌素(tubercidin)、烏苯美司(ubenimex)、淨司他汀(zinostatin)、佐柔比星(zorubicin)、5-氟尿嘧啶、二甲葉酸(denopterin)、胺甲喋呤(methotrexate)、蝶羅呤(pteropterin)、三甲曲沙(trimetrexate)、氟達拉濱(fludarabine)、6-巰嘌呤、硫咪嘌呤(thiamiprine)、硫鳥嘌呤(thiguanine)、安西他濱(ancitabine)、阿紮胞苷(azacitidine)、6-氮雜尿苷、卡莫氟(carmofur)、阿糖胞苷(cytarabine)、二去氧尿苷(dideoxyuridine)、去氧氟尿苷(doxifluridine)、依諾他濱(enocitabine)、氟尿苷(floxuridine)、卡普睪酮(calusterone)、丙酸屈他雄酮(dromostanolone propionate)、環硫雄醇(epitiostanol)、美雄烷(mepitiostane)、睪內酯、胺魯米特(aminoglutethimide)、米托坦(mitotane)、曲洛司坦(trilostane)、醛葉酸、醋葡醛內酯(aceglatone)、醛磷醯胺醣苷(aldophosphamide glycoside)、胺基乙醯丙酸(aminolevulinic acid)、 恩尿嘧啶(eniluracil)、安吖啶(amsacrine)、雌二醇-瘤克寧錠複合物(bestrabucil)、比生群(bisantrene)、依達曲沙(edatraxate)、地磷醯胺(defofamine)、秋水仙胺(demecolcine)、地吖醌(diaziquone)、依氟鳥胺酸(elfornithine)、依利醋銨(elliptinium acetate)、依託格魯(etoglucid)、硝酸鎵、羥基脲、香菇多醣(lentinan)、氯尼達明(lonidainine)、美登素(maytansine)、安絲菌素(ansamitocin)、米托胍腙(mitoguazone)、米托蒽醌(mitoxantrone)、莫哌達醇(mopidanmol)、硝胺丙吖啶(nitraerine)、噴司他汀(pentostatin)、蛋胺氮芥(phenamet)、吡柔比星(pirarubicin)、洛索蒽醌(losoxantrone)、2-乙基醯肼、丙卡巴肼(procarbazine)、多醣-k、雷佐生(razoxane)、利索新(rhizoxin)、西左非蘭(sizofiran)、鍺螺胺(spirogermanium)、替奴佐酸(tenuazonic acid)、三亞胺醌(triaziquone)、2,2’,2”-三氯三乙胺、T-2毒素、疣皰菌素A(verracurin A)、桿孢菌素A(roridin A)及蛇形菌素(anguidine)、胺基甲酸酯、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)、噶薩托辛(gacytosine)、阿糖胞苷(arabinoside)、環磷醯胺、噻替派、太平洋紫杉醇(paclitaxel)、太平洋紫杉醇之經白蛋白改造之奈米粒子調配物、多西他賽(doxetaxel)、氮芥苯丁酸(chlorambucil)、吉西他濱(gemcitabine)、6-硫鳥嘌呤、巰嘌呤、順鉑(cisplatin)、卡鉑(carboplatin)、長春鹼(vinblastine)、鉑、依託泊苷(etoposide)、異環磷醯胺、米托蒽醌、長春新鹼(vincristine)、長春瑞濱(vinorelbine)、能滅瘤(novantrone)、 替尼泊苷(teniposide)、依達曲沙、道諾黴素、胺喋呤(aminopterin)、截瘤達(xeloda)、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(difluoromethylornithine)、視黃酸、卡培他濱(capecitabine)或上述任一者之醫藥上可接受之鹽、溶劑合物或酸;(b)單核因子(monokine)、淋巴因子(lymphokine)、傳統多肽激素、副甲狀腺激素、甲狀腺素、鬆弛素、鬆弛素原、醣蛋白激素、激濾泡素、甲狀腺刺激激素、黃體促素、肝生長因子、纖維母細胞生長因子、泌乳素、胎盤生乳素、腫瘤壞死因子-α、腫瘤壞死因子-β、穆勒氏(mullerian)抑制物質、小鼠促性腺激素相關肽、抑制素、活化素、血管內皮生長因子、促血小板生成素、促紅血球生成素、骨誘導因子、干擾素、干擾素-α、干擾素-β、干擾素-γ、群落刺激因子(「CSF」)、巨噬細胞-CSF、顆粒球-巨噬細胞-CSF、顆粒球-CSF、介白素(「IL」)、腫瘤壞死因子、TNF-α、TNF-β、多肽因子、LIF、kit配體或上述任一者之組合;(c)白喉毒素、肉毒菌毒素、破傷風毒素、痢疾毒素、霍亂毒素、瓢菌素、α-瓢菌素、吡咯并苯并二氮呯、河豚毒素、雙鞭甲藻毒素、雪卡藻毒素、蓖麻毒蛋白、AM毒素、奧裡斯他汀(auristatin)、微管溶素、格爾德黴素(geldanamycin)、類美登素(maytansinoid)、卡奇黴素、道諾黴素、多柔比星、胺甲喋呤、長春地辛、SG2285、多拉斯他汀、多拉斯他汀類似物、奧裡斯他汀、念珠藻素、喜樹鹼、利索新(rhizoxin)、CC-1065、多卡米星、烯二炔抗生素、埃斯波黴素、埃博黴素、類毒素或上述任一者之組合; (d)親和性配體,其中該親和性配體係受質、抑制劑、刺激劑、神經傳遞質、放射性同位素或上述任一者之組合;(e)放射性標記32P、35S、螢光染料、電子緻密試劑、酶、生物素、鏈黴抗生物素蛋白、地高辛(dioxigenin)、半抗原、免疫原性蛋白質、具有與靶標互補之序列之核酸分子或上述任一者之組合;(f)免疫調節化合物、抗癌劑、抗病毒劑、抗細菌劑、抗真菌劑及抗寄生蟲劑或上述任一者之組合;(g)他莫昔芬(tamoxifen)、雷洛昔芬(raloxifene)、屈洛昔芬(droloxifene)、4-羥基他莫昔芬、曲沃昔芬(trioxifene)、可莫昔芬(keoxifene)、LY117018、奧那司酮(onapristone)或托瑞米芬(toremifene);(h)4(5)-咪唑、胺魯米特(aminoglutethimide)、乙酸甲地孕酮(megestrol acetate)、依西美坦(exemestane)、來曲唑(letrozole)或阿那曲唑(anastrozole);(i)氟他胺(flutamide)、尼魯米特(nilutamide)、比卡魯胺(bicalutamide)、柳培林(leuprolide)、戈舍瑞林(goserelin)或曲沙他濱(troxacitabine);(j)芳香酶抑制劑;(k)蛋白激酶抑制劑;(l)脂質激酶抑制劑;(m)反義寡核苷酸;(n)核酶;(o)疫苗;及 (p)抗血管生成劑。
- 如請求項1之抗體-藥物共軛物,其中B係選自IL-1、IL-1α、IL-2、IL-3、IL-4、IL-5、IL-6、IL-7、IL-8、IL-9、IL-10、IL-11及IL-12之介白素。
- 如請求項1之抗體-藥物共軛物,其中B係瓢菌素、奧裡斯他汀、卡奇黴素、喜樹鹼、念珠藻素、道諾黴素、多拉斯他汀、多柔比星、多卡米星、埃博黴素、埃斯波黴素、格爾德黴素、類美登素、胺甲喋呤、單甲基奧裡斯他汀E(「MMAE」)、單甲基奧裡斯他汀F(「MMAF」)、吡咯并苯并二氮呯、利索新、SG2285、微管溶素、長春地辛或類毒素。
- 如請求項36之抗體-藥物共軛物,其中B係瓢菌素、MMAE或MMAF。
- 一種醫藥組合物,其包含如請求項1至38中任一項之抗體-藥物共軛物。
- 一種如請求項1至38中任一項之抗體-藥物共軛物之用途,其用於製造用以治療癌症之醫藥品。
- 如請求項40之用途,其中該癌症係白血病或淋巴瘤。
- 如請求項40之用途,其中該癌症係B細胞惡性病。
- 一種製造如請求項1至38中任一項之抗體-藥物共軛物之方法,其包含使生物分子與前藥反應,其中:該生物分子包含抗-CD19抗體及酮或醛;該前藥包含烷氧基胺;且該反應產生肟,藉此將該抗體共價連接至該前藥。
- 如請求項43之方法,其進一步包含異戊二烯化該抗體,藉此產生該生物分子,其中:該抗體包含異戊二烯化序列;該抗體之異戊二烯化包括將該抗體與類異戊二烯轉移酶及類異戊二烯轉移酶受質一起培育;且該受質包含該酮或醛。
- 如請求項44之方法,其中該類異戊二烯轉移酶係法尼基轉移酶(farnesyltransferase)或香葉基香葉基轉移酶。
- 一種製造如請求項1至38中任一項之抗體-藥物共軛物之方法,其包含異戊二烯化抗體,其中:該抗體係抗-CD19抗體;該抗體包含異戊二烯化序列;該抗體之異戊二烯化包括將該抗體與類異戊二烯轉移酶及類異戊二烯轉移酶受質一起培育;且該受質包含該藥物。
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- 2016-09-26 TW TW105131120A patent/TWI765864B/zh active
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US20170088614A1 (en) | 2017-03-30 |
US10183997B2 (en) | 2019-01-22 |
WO2017051249A1 (en) | 2017-03-30 |
TW201729844A (zh) | 2017-09-01 |
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