TW202320794A - 具有自分解肽連接子之類美登素衍生物及其結合物 - Google Patents
具有自分解肽連接子之類美登素衍生物及其結合物 Download PDFInfo
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Abstract
本發明係關於具有自分解肽連接子之新穎細胞結合劑-類美登素結合物且更特定而言係關於式(I)之結合物。本發明亦提供式(II)、(III)、(IV)或(V)之新穎類美登素化合物。本發明進一步提供可用於使用本發明之該等化合物或結合物在哺乳動物中抑制異常細胞生長或治療增殖性病症的組合物及方法。
Description
抗體-藥物結合物(ADC)作為在一系列癌症中具有功效之強大抗腫瘤劑類別不斷出現。ADC通常由三種不同元素組成:細胞結合劑;連接子;及細胞毒性劑。ADC之連接子組分在研製具有最佳治療窗(亦即在低、無毒劑量下具有高活性)之靶向型抗癌劑時為重要元素。
因此,對具有新連接子組分類別之ADC存在需要。
本發明係有關一種由下式表示之細胞結合劑-細胞毒性劑結合物:
(I)
或其醫藥學上可接受之鹽,其中:
CB為細胞結合劑;
L
2不存在或為間隔子;
A為胺基酸殘基或包含2至20個胺基酸殘基之肽;
R
1及R
2各獨立地為H或C
1-3烷基;
L
1為間隔子;
D-L
1-SH為細胞毒性劑;且
q為1至20之整數。
本發明亦關於一種式(II)化合物:
(II)
或其醫藥學上可接受之鹽,其中:
L
2 '不存在或為帶有反應性部分之間隔子,該反應性部分可與細胞結合劑形成共價鍵;
A為胺基酸或包含2至20個胺基酸之肽;
R
1及R
2各獨立地為H或C
1-3烷基;
L
1為間隔子;
D-L
1-SH為細胞毒性劑;且
q為1至20之整數。
在本發明中亦包括一種式(III)化合物:
(III)
或其醫藥學上可接受之鹽,其中:
A'為胺基酸或包含2至20個胺基酸之肽;
R
1及R
2各獨立地為H或C
1-3烷基;
L
1為間隔子;
D-L
1-SH為細胞毒性劑;且
q為1至20之整數。
本發明亦關於一種式(IV)化合物:
(IV)
或其醫藥學上可接受之鹽,其中:
L
3由下式表示:
;
R
x'及R
y'在每次出現時獨立地為H、-OH、鹵素、-O-(C
1-4烷基)、-SO
3H、-NR
40R
41R
42 +或視情況經-OH、鹵素、SO
3H或NR
40R
41R
42 +取代之C
1-4烷基,其中R
40、R
41及R
42各獨立地為H或C
1-4烷基;
k為1至10之整數;
A為胺基酸或包含2至20個胺基酸之肽;
R
1及R
2各獨立地為H或C
1-3烷基;
L
1為間隔子;
D-L
1-SH為細胞毒性劑;且
q為1至20之整數。
本發明亦關於一種包含結合物(例如式(I)之結合物)或化合物(例如式(II)、(III)或(IV)之化合物)及載劑(醫藥學上可接受之載劑)的組合物(例如醫藥組合物)。本發明亦包括一種包含本文所描述之結合物(例如式(I)之結合物)或化合物(例如式(II)、(III)或(IV)之化合物)及載劑(醫藥學上可接受之載劑)的組合物(例如醫藥組合物),其進一步包含第二治療劑。本發明組合物可用於在哺乳動物(例如人類)中抑制異常細胞生長或治療增殖性病症。本發明組合物可用於治療哺乳動物(例如人類)之諸如以下病狀:癌症、類風濕性關節炎、多發性硬化、移植物抗宿主疾病(GVHD)、移植排斥、狼瘡、肌炎、感染、免疫缺陷(諸如艾滋病)及炎性疾病。
本發明亦包括一種在哺乳動物(例如人類)中抑制異常細胞生長或治療增殖性病症的方法,其包括向該異常細胞或該哺乳動物單獨或與第二治療劑組合投與治療有效量之結合物(例如式(I)之結合物)或化合物(例如式(II)、(III)或(IV)之化合物)或其組合物。
相關申請案
本申請案根據35 U.S.C. §119 (e)主張2017年2月28日申請之美國臨時申請案第62/465,118號及2017年3月31日申請之美國臨時申請案第62/480,209號的申請日之權益。以上參考申請案中之每一者的全部內容以引用之方式併入本文中。
現將詳細提及本發明之某些實施例,其實例係以伴隨結構及式子加以說明。雖然將結合所列舉之實施例描述本發明,但應瞭解其不旨在將本發明限於彼等實施例。相反地,本發明旨在涵蓋可包括所有替代、修改以及等效形式,其在如申請專利範圍所定義之本發明範疇內。熟習此項技術者將認可可用於實踐本發明之類似或等效於本文所描述之方法及材料的許多方法及材料。
應瞭解,除非明確否認或不適當,否則本文所描述之實施例中之任一者,包括在本發明之不同態樣(例如化合物、化合物-連接子分子、結合物、組合物、製備及使用方法)及本說明書之不同部分下所描述之彼等實施例(包括僅在實例中描述之實施例)可與本發明之一個或多個其他實施例組合。實施例之組合不限於經由多個附屬項申請之彼等特定組合。
定義
如本文所用,術語「
治療(
treating/
treatment)」包括以改善或穩定個體病狀之方式逆轉、減輕或抑制病狀之症狀、臨床跡象及潛在病變。如本文所用,且如此項技術中熟知的,「治療」為用於獲得有益或所需結果,包括臨床結果之方法。有益或所需臨床結果可包括但不限於可偵測或不可偵測之與病狀(例如癌症)相關之一或多種症狀或病狀的緩解、改善或減慢進展、疾病程度之消除、疾病狀態之穩定(亦即,不惡化)、疾病進展之延遲或減慢、疾病狀態之改善或減緩及緩和(部分或總體)。「治療」亦可意謂與若不接受治療之預期存活相比延長存活。本文中描述示例性有益臨床結果。
「
視情況存在」或「
視情況」意謂隨後描述之情況可能發生或可能不發生,使得本申請案包括該情況發生之情況及其不發生之情況。舉例而言,片語「視情況經取代」意謂在給定原子上可能存在或可能不存在非氫取代基,且因此,本申請案包括存在非氫取代基之結構及不存在非氫取代基之結構。
除非特定陳述為「未經取代」,否則本文中提及化學部分應理解為包括經取代之變異體。舉例而言,提及「烷基」基團或部分隱含地包括經取代與未經取代之變異體兩者。化學部分上之取代基之實例包括但不限於鹵素、羥基、羰基(諸如羧基、烷氧羰基、甲醯基或醯基)、硫羰基(諸如硫酯、硫代乙酸酯或硫代甲酸酯)、烷氧基、烷硫基、醯氧基、磷醯基、磷酸酯、膦酸酯、胺基、醯胺基、脒、亞胺、氰基、硝基、疊氮基、硫氫基、烷硫基、硫酸酯、磺酸酯、胺磺醯基、磺醯胺基、磺醯基、雜環基、芳烷基或芳基或雜芳基部分。
如本文所用,術語「
細胞結合劑」或「
CBA」係指可較佳以特異性方式結合細胞(例如在細胞-表面配位體上)或結合與細胞相關或在細胞近端之配位體的化合物。在某些實施例中,與細胞或細胞上或細胞附近之配位體的結合為特異性的。CBA可包括肽及非肽。
如本文所用之「
烷基」係指飽和直鏈或分枝鏈單價烴基。在較佳實施例中,直鏈或分枝鏈烷基在其主鏈中具有三十個或更少個碳原子(例如對於直鏈為C
1-C
30、對於分枝鏈為C
3-C
30),且更佳為二十個或更少個。烷基之實例包括但不限於甲基、乙基、1-丙基、2-丙基、1-丁基、2-甲基-1-丙基、-CH
2CH(CH
3)
2)、2-丁基、2-甲基-2-丙基、1-戊基、2-戊基3-戊基、2-甲基-2-丁基、3-甲基-2-丁基、3-甲基-1-丁基、2-甲基-1-丁基、1-己基)、2-己基、3-己基、2-甲基-2-戊基、3-甲基-2-戊基、4-甲基-2-戊基、3-甲基-3-戊基、2-甲基-3-戊基、2,3-二甲基-2-丁基、3,3-二甲基-2-丁基、1-庚基、1-辛基及類似基團。此外,如本說明書、實例及申請專利範圍中所用之術語「烷基」旨在包括「未經取代之烷基」與「經取代之烷基」兩者,其中後者係指在烴主鏈之一或多個碳上具有代替氫之取代基的烷基部分。在某些實施例中,直鏈或分枝鏈烷基在其主鏈中具有或更少個碳原子(例如對於直鏈為C
1-C
30,對於分枝鏈為C
3-C
30)。在較佳實施例中,該鏈在其主鏈中具有十個或更少個碳(C
1-C
10)原子。在其他實施例中,該鏈在其主鏈中具有六個或更少個碳(C
1-C
6)原子。在另一實施例中,該鏈在其主鏈中具有三個或更少個碳(C
1-C
3)原子。
如本文所用之「
伸烷基」係指飽和直鏈或分枝鏈二價烴基。在較佳實施例中,直鏈或分枝鏈伸烷基在其主鏈中具有三十個或更少個碳原子(例如對於直鏈為C
1-C
30、對於分枝鏈為C
3-C
30),且更佳為二十個或更少個。此外,如本說明書、實例及申請專利範圍中所用之術語「伸烷基」旨在包括「未經取代之伸烷基」與「經取代之伸烷基」兩者,其中後者係指在烴主鏈之一或多個碳上具有代替氫之取代基的伸烷基部分。在某些實施例中,直鏈或分枝鏈伸烷基在其主鏈中具有或更少個碳原子(例如對於直鏈為C
1-C
30,對於分枝鏈為C
3-C
30)。在較佳實施例中,該鏈在其主鏈中具有十個或更少個碳(C
1-C
10)原子。在其他實施例中,該鏈在其主鏈中具有六個或更少個碳(C
1-C
6)原子。在另一實施例中,該鏈在其主鏈中具有三個或更少個碳(C
1-C
3)原子。
「
烯基」係指具有兩個至二十個碳原子以及至少一個不飽和位點(亦即碳-碳雙鍵)之直鏈或分枝鏈單價烴基,其中烯基包括具有「順式」及「反式」取向或者「E」及「Z」取向之基團。實例包括但不限於乙烯基(ethylenyl/vinyl) (-CH=CH
2)、烯丙基(-CH
2CH=CH
2)及類似基團。較佳地,烯基具有兩個至十個碳原子。更佳地,烯基具有兩個至四個碳原子。
「
伸烯基」係指具有兩個至二十個碳原子以及至少一個不飽和位點(亦即碳-碳雙鍵)之直鏈或分枝鏈二價烴基,其中烯基包括具有「順式」及「反式」取向或者「E」及「Z」取向之基團。實例包括但不限於伸乙烯基(ethylenylene/vinylene) (-CH=CH-)、伸烯丙基(-CH
2CH=CH-)及類似基團。較佳地,伸烯基具有兩個至十個碳原子。更佳地,伸烯基具有兩個至四個碳原子。
「
炔基」係指具有兩個至二十個碳原子以及至少一個不飽和位點(亦即碳-碳三鍵)之直鏈或分枝鏈單價烴基。實例包括但不限於乙炔基、丙炔基、1-丁炔基、2-丁炔基、1-戊炔基、2-戊炔基、3-戊炔基、己炔基及類似基團。較佳地,炔基具有兩個至十個碳原子。更佳地,炔基具有兩個至四個碳原子。
「
伸炔基」係指具有兩個至二十個碳原子以及至少一個不飽和位點(亦即碳-碳三鍵)之直鏈或分枝鏈二價烴基。實例包括但不限於伸乙炔基、伸丙炔基、1-伸丁炔基、2-伸丁炔基、1-伸戊炔基、2-伸戊炔基、3-伸戊炔基、伸己炔基及類似基團。較佳地,伸炔基具有兩個至十個碳原子。更佳地,伸炔基具有兩個至四個碳原子。
術語「
碳環(
carbocycle/
carbocyclic ring)」及「
碳環基」係指作為單環具有3至12個碳原子或作為雙環具有7至12個碳原子之單價非芳族、飽和或部分不飽和環。具有7至12個原子之雙環碳環可經佈置呈例如雙環[4,5]、[5,5]、[5,6]或[6,6]系統形式,且具有9或10個環原子之雙環碳環可經佈置呈雙環[5,6]或[6,6]系統形式,或呈橋接系統形式,諸如雙環[2.2.1]庚烷、雙環[2.2.2]辛烷及雙環[3.2.2]壬烷。單環碳環之實例包括但不限於環丙基、環丁基、環戊基、1-環戊-1-烯基、1-環戊-2-烯基、1-環戊-3-烯基、環己基、1-環己-1-烯基、1-環己-2-烯基、1-環己-3-烯基、環已二烯基、環庚基、環辛基、環壬基、環癸基、環十一基、環十二基及類似基團。
術語「
環狀烷基」與「
環烷基」可互換使用。如本文所用,該術語係指飽和環之基團。在較佳實施例中,環烷基在其環結構中具有3至10個碳原子,且更佳在環結構中具有5至7個碳原子。在一些實施例中,該兩個環可共同具有兩個或更多個原子,例如該等環為「稠合環」。適合之環烷基包括環庚基、環己基、環戊基、環丁基及環丙基。在一些實施例中,環烷基為單環基團。在一些實施例中,環烷基為雙環基團。在一些實施例中,環烷基為三環基團。
術語「
伸環烷基」係指飽和碳環之二價基團。在較佳實施例中,伸環烷基在其環結構中具有3至10個碳原子,且更佳在環結構中具有5至7個碳原子。在一些實施例中,該兩個環可共同具有兩個或更多個原子,例如該等環為「稠合環」。適合之伸環烷基包括伸環庚基、伸環己基、伸環戊基、伸環丁基及伸環丙基。在一些實施例中,伸環烷基為單環基團。在一些實施例中,伸環烷基為雙環基團。在一些實施例中,伸環烷基為三環基團。
術語「
環狀烯基」係指在環結構中具有至少一個雙鍵之碳環基團。
術語「
環狀炔基」係指在環結構中具有至少一個三鍵之碳環基團。
如本文所用之術語「
芳基」包括經取代或未經取代之單環芳族基,其中環之各原子為碳。較佳地,該環為5員至7員環,更佳為6員環。芳基包括苯基、苯酚、苯胺及類似基團。術語「芳基」亦包括具有兩個或更多個環之「多環基」、「多環」及「多環的」環系統,其中兩個或更多個原子為兩個相鄰環共同擁有的,例如該等環為「稠合環」,其中該等環中之至少一者為芳族環,例如其他環可為環烷基、環烯基、環炔基。在一些較佳實施例中,多環具有2至3個環。在某些較佳實施例中,多環系統具有兩個環,其中該等環中之兩者均為芳族環。多環之環中之每一者可經取代或未經取代。在某些實施例中,多環之各環在環中含有3至10個原子,較佳為5至7個。舉例而言,芳基包括但不限於苯基(苯)、甲苯基、蒽基、茀基、茚基、薁基及萘基以及苯并融合碳環部分(諸如5,6,7,8-四氫萘基)及類似基團。在一些實施例中,芳基為單環芳族基。在一些實施例中,芳基為雙環芳族基。在一些實施例中,芳基為三環芳族基。
如本文所用之「
伸芳基」為上文所描述之芳基的二價基團。
如本文所用之術語「
雜環(
heterocycle/
heterocyclic ring)」及「
雜環基」係指3員至18員環、較佳3至10員環、更佳3至7員環之經取代或未經取代之非芳族環結構,其環結構包括至少一個雜原子,較佳為一至四個雜原子,更佳為一或兩個雜原子。在某些實施例中,環結構可具有兩個環。在一些實施例中,該兩個環可共同具有兩個或更多個原子,例如該等環為「稠合環」。雜環基包括例如哌啶、哌嗪、吡咯啶、嗎啉、內酯、內醯胺及類似基團。雜環描述於Paquette, Leo A.; 「Principles of Modern Heterocyclic Chemistry」 (W. A. Benjamin, New York, 1968), 特定而言第1章、第3章、第4章、第6章、第7章及第9章;「The Chemistry of Heterocyclic Compounds, A series of Monographs」(John Wiley & Sons, New York, 1950至今), 特定而言第13卷、第14卷、第16卷、第19卷及第28卷;及J. Am. Chem. Soc. (1960) 82:5566中。雜環之實例包括但不限於四氫呋喃、二氫呋喃、四氫噻吩、四氫哌喃、二氫哌喃、四氫噻喃基、硫代嗎啉、噻噁烷、高哌嗪、氮雜環丁烷、氧雜環丁烷、硫雜環丁烷、高哌啶、氧雜環庚烷、硫雜環庚烷、氧氮雜環庚三烯、二氮雜環庚三烯、硫氮雜環庚三烯、2-吡咯啉、3-吡咯啉、吲哚啉、2H-哌喃、4H-哌喃、二氧雜環己烷基、1,3-二氧雜環戊烷、吡唑啉、二噻烷、二硫雜環戊烷、二氫哌喃、二氫噻吩、二氫呋喃、吡唑啶基咪唑啉、咪唑啉啶、3-氮雜雙環[3.1.0]己基、3-氮雜雙環[4.1.0]庚烷及氮雜雙環[2.2.2]己烷。螺部分亦包括在此定義範疇內。環原子經側氧基(=O)部分取代之雜環基之實例為嘧啶酮及1,1-二側氧基-硫代嗎啉。
術語「
伸雜環基」係指上文所描述之雜環基團之二價基團。
如本文所用之術語「
雜芳基」係指經取代或未經取代之芳族單環結構,較佳為5至7員環,更佳為5至6員環,其環結構包括至少一個雜原子(例如O、N或S),較佳為一至四個或一至3個雜原子,更佳為一或兩個雜原子。當雜芳基環中存在兩個或更多個雜原子時,其可為相同或不同的。術語「雜芳基」亦包括具有兩個或更多個環之「多環基」、「多環」及「多環的」環系統,其中兩個或更多個碳為兩個相鄰環共同擁有的,例如該等環為「稠合環」,其中該等環中之至少一者為雜芳族環,例如其他環可為環烷基、環烯基、環炔基、芳基及/或雜環基。在一些較佳實施例中,較佳多環具有2至3個環。在某些實施例中,較佳多環系統具有兩個環,其中該等環中之兩者均為芳族環。在某些實施例中,多環之各環在環中含有3至10個原子,較佳為5至7個。舉例而言,雜芳基包括但不限於吡咯、呋喃、噻吩、咪唑、噁唑、噻唑、吡唑、吡啶、吡嗪、噠嗪、喹啉、嘧啶、吲哚嗪、吲哚、吲唑、苯并咪唑、苯并噻唑、苯并呋喃、苯并噻吩、噌啉、酞嗪、喹唑啉、咔唑、吩噁嗪、喹啉、嘌呤及類似基團。在一些實施例中,雜芳基為單環芳族基。在一些實施例中,雜芳基為雙環芳族基。在一些實施例中,雜芳基為三環芳族基。
術語「
伸雜芳基」係指上文所描述之雜芳基之二價基團。
雜環或雜芳基可在可能之情況下為碳連接(碳-鍵聯)或氮連接(氮-鍵聯)的。舉例而言且不限於,碳鍵結之雜環或雜芳基係鍵結於吡啶之位置2、3、4、5或6;噠嗪之位置3、4、5或6;嘧啶之位置2、4、5或6;吡嗪之位置2、3、5或6;呋喃、四氫呋喃、噻吩、噻吩、吡咯或四氫吡咯之位置2、3、4或5;噁唑、咪唑或噻唑之位置2、4或5;異噁唑、吡唑或異噻唑之位置3、4或5;氮雜環丙烷之位置2或3;氮雜環丁烷之位置2、3或4;喹啉之位置2、3、4、5、6、7或8;或異喹啉之位置1、3、4、5、6、7或8。
舉例而言且不限於,氮鍵結之雜環或雜芳基係鍵結於氮雜環丙烷、氮雜環丁烷、吡咯、吡咯啶、2-吡咯啉、3-吡咯啉、咪唑、咪唑啉啶、2-咪唑啉、3-咪唑啉、吡唑、吡唑啉、2-吡唑啉、3-吡唑啉、哌啶、哌嗪、吲哚、吲哚啉、1H-吲唑之位置1;異吲哚或異吲哚啉之位置2;嗎啉之位置4;及咔唑或O-咔啉之位置9。
存在於雜芳基或雜環基中之雜原子包括氧化形式,諸如NO、SO及SO
2。
術語「
鹵基」或「
鹵素」係指氟(F)、氯(Cl)、溴(Br)或碘(I)。
上文所描述之烷基、伸烷基、伸烯基、炔、伸炔基、環狀烷基、伸環烷基、碳環基、芳基、伸芳基、雜環基、伸雜環烷基、雜芳基及伸雜芳基可視情況再經一個(例如2、3、4、5、6或更多個)取代基取代。
術語「經取代」係指在化合物主鏈之一或多個碳上具有代替氫之取代基的部分。應瞭解「取代」或「經……取代」包括隱含前提條件:此類取代符合經取代原子及取代基允許之價數,且該取代產生穩定化合物,例如其不諸如因重排、環化、消除等而自發地經歷轉化。如本文所用,術語「經取代」預期包括有機化合物之所有可允許之取代基。在廣泛態樣中,可允許之取代基包括有機化合物之非環及環狀、分枝及不分枝、碳環及雜環、芳族及非芳族取代基。對於適當之有機化合物,可允許之取代基可為一或多個且為相同或不同的。出於本發明之目的,諸如氮之雜原子可具有氫取代基及/或本文所描述之有機化合物之滿足雜原子之價數的任何可允許之取代基。取代基可包括本文所描述之任何取代基,例如鹵素、羥基、羰基(諸如羧基、烷氧羰基、甲醯基或醯基)、硫羰基(諸如硫酯、硫代乙酸酯或硫代甲酸酯)、烷氧基、烷硫基、醯氧基、磷醯基、磷酸酯、膦酸酯、胺基、醯胺基、脒、亞胺、氰基、硝基、疊氮基、硫氫基、烷硫基、硫酸酯、磺酸酯、胺磺醯基、磺醯胺基、磺醯基、雜環基、芳烷基或芳族或雜芳族部分。為了說明,單氟烷基為經一個氟取代基取代之烷基,且二氟烷基為經兩個氟取代基取代之烷基。應認識到,若在取代基上存在超過一個取代,則各非氫取代基可為相同或不同的(除非另外說明) 。「視情況存在」或「視情況」意謂隨後描述之情況可能發生或可能不發生,使得本申請案包括該情況發生之情況及其不發生之情況。舉例而言,片語「視情況經取代」意謂在給定原子上可能存在或可能不存在非氫取代基,且因此,本申請案包括存在非氫取代基之結構及不存在非氫取代基之結構。 若將取代基之碳描述為視情況經一系列取代基中之一或多個取代,則該碳上之氫中之一或多個(在存在任何氫之情況下)可分開地及/或一起用獨立選擇之視情況存在之取代基代替。若將取代基之氮描述為視情況經一系列取代基中之一或多個取代,則該氮上之氫中之一或多個(在存在任何氫之情況下)可各自用獨立選擇之視情況存在之取代基代替。可將一種示例性取代基描繪成-NR'R'',其中R'及R''與其所連接之氮原子一起可形成雜環。由R'及R''與其所連接之氮原子一起形成之雜環可為部分飽和或完全飽和的。在一些實施例中,雜環由3至7個原子組成。在另一實施例中,雜環係選自由以下各項組成之群:吡咯基、咪唑基、吡唑基、三唑基、四唑基、異噁唑基、吡啶基及噻唑基。
本說明書可互換地使用術語「
取代基」及「
基團」。
若將取代基之群統一描述為視情況經一系列取代基中之一或多個取代,則該群可包括:(1)不可取代之取代基,(2)未經視情況存在之取代基取代的可取代之取代基,及/或(3)經視情況存在之取代基中之一或多個取代的可取代之取代基。
若將取代基描述為視情況經至多特定數目之非氫取代基取代,則彼取代基可為(1)未經取代的;或(2)經至多該特定數目之非氫取代基取代或至多在取代基上最大數目之可取代位置經取代,無論哪個較小。因此,舉例而言,若將取代基描述為視情況經至多3個非氫取代基取代之雜芳基,則具有少於3個可取代位置之任何雜芳基將視情況經至多僅與該雜芳基所具有之可取代位置一樣多之非氫取代基取代。在非限制性實例中,此類取代基可選自具有1至10個碳原子之線性、分枝或環狀之烷基、烯基或炔基;芳基、雜芳基、雜環基、鹵素、胍鹽[-NH(C=NH)NH
2]、-OR
100、NR
101R
102、-NO
2、-NR
101COR
102、-SR
100、由-SOR
101表示之亞碸、由-SO
2R
101表示之碸、磺酸酯-SO
3M、硫酸酯-OSO
3M、由-SO
2NR
101R
102表示之磺醯胺、氰基、疊氮基、-COR
101、-OCOR
101、-OCONR
101R
102及聚乙二醇單元(-CH
2CH
2O)
nR
101,其中M為H或陽離子(諸如Na
+或K
+);R
101、R
102及R
103各獨立地選自H、具有1至10個碳原子之線性、分枝或環狀烷基、烯基或炔基、聚乙二醇單元(-CH
2CH
2O)
n-R
104(其中n為1至24之整數)、具有6至10個碳原子之芳基、具有3至10個碳原子之雜環及具有5至10個碳原子之雜芳基;且R
104為H或具有1至4個碳原子之直鏈或分枝鏈烷基,其中基團中由R
100、R
101、R
102、R
103及R
104表示之烷基、烯基、炔基、芳基、雜芳基及雜環基視情況經一或多個(例如2、3、4、5、6或更多個)獨立地選自以下之取代基取代:鹵素、-OH、-CN、-NO
2及未經取代之具有1至4個碳原子之直鏈或分枝鏈烷基。較佳地,用於上文所描述之視情況經取代之烷基、烯基、炔基、環狀烷基、環狀烯基、環狀炔基、碳環基、芳基、雜環基及雜芳基的取代基包括鹵素、-CN、-NR
102R
103、-CF
3、-OR
101、芳基、雜芳基、雜環基、-SR
101、-SOR
101、-SO
2R
101及-SO
3M。
術語「
化合物」或「
細胞毒性化合物」可互換使用。其旨在包括如下化合物,該等化合物之結構或化學式或其任何衍生物已揭示於本發明中或者結構或化學式或其任何衍生物已以引用之方式併入本文中。該術語亦包括本發明中所揭示之所有式子的化合物的立體異構體、幾何異構體、互變異構體、溶劑合物、代謝產物、鹽(例如醫藥學上可接受之鹽)及前藥以及前藥鹽。該術語亦包括前述各項中之任一者的任何溶劑合物、水合物及多晶型物。在本申請案中所描述之本發明之某些態樣中,關於「立體異構體」、「幾何異構體」、「互變異構體」、「溶劑合物」、「代謝產物」、「鹽」、「前藥」、「前藥鹽」、「結合物」、「結合物鹽」、「溶劑合物」、「水合物」或「多晶型物」之特定敍述不應解釋為在本發明之使用術語「化合物」而未敍述此等其他形式之其他態樣中意在省略此等形式。
如本文所用之術語「
結合物」係指鍵聯至細胞結合劑之本文所描述之化合物或其衍生物。
如本文所用之術語「
可鍵聯至細胞結合劑」係指本文所描述之化合物或其衍生物包含適合於將此等化合物或其衍生物鍵結至細胞結合劑之至少一個鍵聯基團或其前驅體。
術語給定基團之「
前驅體」係指可藉由任何去保護、化學改質或偶合反應而產生該基團之任何基團。
術語「
鍵聯至細胞結合劑」係指結合物分子包含經由適合之鍵聯基團或其前驅體結合於細胞結合劑之本文所描述之化合物中之至少一者或其衍生物。
術語「
對掌性」係指分子具有鏡像配偶體不可重疊之特性,而術語「非對掌性」係指分子可重疊於其鏡像配偶體。
術語「
立體異構體」係指具有相同化學組成及連接性,但原子在空間之取向不同從而不能藉由圍繞單鍵旋轉而互變的化合物。
「
非對映異構體」係指具有兩個或更多個對掌性中心且分子不為彼此之鏡像的立體異構體。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。非對映異構體之混合物可根據諸如結晶、電泳及層析之高解析率分析程序加以分離。
「
對映異構體」係指化合物之彼此為不能重疊之鏡像的兩種立體異構體。
本文中所用之立體化學定義及慣例總體上遵循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體形式存在。本發明之化合物的所有立體異構體形式(包括但不限於非對映異構體、對映異構體及阿托異構體(atropisomer)以及其混合物,諸如外消旋混合物)旨在形成本發明之一部分。許多有機化合物以光學活性形式存在,亦即其具有使平面偏振光之平面旋轉的能力。在描述光學活性化合物時,字首D及L或R及S用於表示分子圍繞其對掌性中心之絕對組態。字首d及l或(+)及(-)用於指定由化合物引起之平面偏振光旋轉之符號,其中(-)或l意謂化合物為左旋的。具有字首(+)或d之化合物為右旋的。對於給定化學結構,此等立體異構體相同,除了其為彼此之鏡像。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常常稱為對映異構體混合物。對映異構體之50:50混合物稱為外消旋混合物或外消旋物,在化學反應或方法中在一直不存在立體選擇或立體特異性之情況下其可存在。術語「外消旋混合物」及「外消旋物」係指兩種對映異構體種類之等莫耳混合物,沒有光學活性。
術語「
互變異構體」或「
互變異構體形式」係指具有不同能量之結構異構體,其可經由低能量障壁互變。舉例而言,質子互變異構體(亦稱為質子異變互變異構體)包括經由質子遷移而互變,諸如酮-烯醇及亞胺-烯胺異構化。價互變異構體包括藉由一些成鍵電子之再組織而互變。
如本申請案中所用之術語「
前藥」係指本發明化合物之前驅體或衍生形式,其能夠酶促或水解活化或轉化成更具活性之母體形式。參見例如Wilman, 「Prodrugs in Cancer Chemotherapy」 Biochemical Society Transactions, 14, 第375-382頁, 貝爾法斯特第615次會議(615th Meeting Belfast) (1986)及Stella等人, 「Prodrugs: A Chemical Approach to Targeted Drug Delivery」, Directed Drug Delivery, Borchardt等人, (編), 第247-267頁, Humana Press (1985)。本發明之前藥包括但不限於含酯前藥、含磷酸酯前藥、含硫代磷酸酯前藥、含硫酸酯前藥、含肽前藥、D-胺基酸修飾之前藥、糖基化前藥、含β-內醯胺前藥、含視情況經取代之苯氧乙醯胺的前藥、含視情況經取代之苯乙醯胺的前藥、5-氟胞嘧啶及其他5-氟尿苷前藥,其可轉化成更具活性之細胞毒性游離藥物。可衍生為用於本發明中之前藥形式的細胞毒性藥物之實例包括但不限於諸如上文所描述之本發明化合物及化學治療劑。
術語「
前藥」亦意在包括可在生物條件下(活體外或活體內)水解、氧化或以其他方式反應以提供本發明化合物之化合物衍生物。前藥可僅在生物條件下在此類反應後變得具活性,或其可以其未反應形式具有活性。本發明中所涵蓋之前藥的實例包括但不限於本文所揭示之任一式子之化合物的類似物或衍生物,其包含生物可水解部分,諸如生物可水解醯胺、生物可水解酯、生物可水解胺基甲酸酯、生物可水解碳酸酯、生物可水解醯脲及生物可水解磷酸酯類似物。前藥之其他實例包括本文所揭示之任一式子之化合物的包含-NO、-NO
2、-ONO或-ONO
2部分的衍生物。前藥可典型地使用熟知方法來製備,諸如由Burger, Medicinal Chemistry and Drug Discovery (1995) 172-178, 949-982 (Manfred E. Wolff編, 第5版)描述之彼等方法;亦參見Goodman及Gilman, The Pharmacological basis of Therapeutics, 第8版, McGraw-Hill, Int.編1992, 「Biotransformation of Drugs」。
如本文所用之片語「
醫藥學上可接受之鹽」係指本發明化合物之醫藥學上可接受之有機或無機鹽。示例性鹽包括但不限於硫酸鹽、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、水楊酸鹽、酸式檸檬酸鹽、酒石酸鹽、油酸鹽、丹寧酸鹽、泛酸鹽、酒石酸氫鹽、抗壞血酸鹽、丁二酸鹽、順丁烯二酸鹽、龍膽酸鹽、反丁烯二酸鹽、葡糖酸鹽、葡糖醛酸鹽、蔗糖酸鹽、甲酸鹽、苯甲酸鹽、麩胺酸鹽、甲烷磺酸鹽「甲磺酸鹽」、乙烷磺酸鹽、苯磺酸鹽、對甲苯磺酸鹽及雙羥萘酸鹽(亦即1,1'-亞甲基-雙-(2-羥基-3-萘甲酸鹽))。醫藥學上可接受之鹽可涉及包括另一分子,諸如乙酸根離子、丁二酸根離子或其他相對離子。相對離子可為使母體化合物上之電荷穩定的任何有機或無機部分。此外,醫藥學上可接受之鹽在其結構中可具有超過一個帶電荷原子。多個帶電荷原子為醫藥學上可接受之鹽的一部分之情況可具有多個相對離子。因此,醫藥學上可接受之鹽可具有一或多個帶電荷原子及/或一或多個相對離子。
若本發明之化合物為鹼,則所需醫藥學上可接受之鹽可藉由此項技術中可獲得之任何適合之方法來製備,例如用無機酸或用有機酸處理游離鹼,該無機酸為諸如鹽酸、氫溴酸、硫酸、硝酸、甲磺酸、磷酸及類似物,該有機酸為諸如乙酸、順丁烯二酸、丁二酸、苦杏仁酸、反丁烯二酸、丙二酸、丙酮酸、草酸、乙醇酸、水楊酸、哌喃糖苷酸(諸如葡糖醛酸或半乳糖醛酸)、α羥基酸(諸如檸檬酸或酒石酸)、胺基酸(諸如天冬胺酸或麩胺酸)、芳族酸(諸如苯甲酸或肉桂酸)、磺酸(諸如對甲苯磺酸或乙磺酸)或類似物。
若本發明之化合物為酸,則所需醫藥學上可接受之鹽可藉由任何適合之方法來製備,例如用諸如以下之無機或有機鹼處理游離酸:胺(一級、二級或三級)、鹼金屬氫氧化物或鹼土金屬氫氧化物或類似物。適合之鹽的說明性實例包括但不限於來源於胺基酸(諸如甘胺酸及精胺酸)、氨水、一級、二級及三級胺及環狀胺(諸如哌啶、嗎啉及哌嗪)之有機鹽以及來源於鈉、鈣、鉀、鎂、錳、鐵、銅、鋅、鋁及鋰之無機鹽。
如本文所用,術語「
溶劑合物」意謂進一步包括藉由非共價分子間作用力結合之化學計量或非化學計量量之諸如以下之溶劑的化合物:水、異丙醇、丙酮、乙醇、甲醇、DMSO、乙酸乙酯、乙酸及乙醇胺二氯甲烷、2-丙醇或類似物。化合物之溶劑合物或水合物係藉由添加至少一莫耳當量之諸如甲醇、乙醇、1-丙醇、2-丙醇之羥基溶劑或水至化合物中以引起亞胺部分之溶解或水合作用而容易地製備。
術語「
異常細胞生長」及「
增殖性病症」可在本申請案中互換使用。如本文所用之「
異常細胞生長」除非另外指出,否則係指與正常調控機制(例如接觸抑制之損失)無關之細胞生長。此術語包括例如以下各項之異常生長:(1)藉由表現突變酪胺酸激酶或受體酪胺酸激酶之過表現而增殖的腫瘤細胞(腫瘤);(2)發生異常酪胺酸激酶活化之其他增殖性疾病之良性及惡性細胞;(3)因受體酪胺酸激酶而增殖之任何腫瘤;(4)因異常絲胺酸/蘇胺酸激酶活化而增殖之任何腫瘤;及(5)發生異常絲胺酸/蘇胺酸激酶活化之其他增殖性疾病之良性及惡性細胞。
術語「
癌症」及「
癌性」係指或描述哺乳動物中典型地以無秩序細胞生長為特徵的生理條件。「
腫瘤」包含一或多個癌細胞,及/或良性或癌前細胞。
「
治療劑」涵蓋諸如抗體、肽、蛋白質、酶之生物製劑或化學治療劑兩者。
「
化學治療劑」為可用於治療癌症之化合物。
「
代謝產物」為通過指定化合物、其衍生物或其結合物或其鹽在體內之代謝產生的產物。化合物、其衍生物或其結合物之代謝產物可使用此項技術中已知之常規技術來鑑定且使用諸如本文所描述之彼等測試來測定其活性。此類產物可例如由所投與化合物之氧化、羥基化、還原、水解、醯胺化、去醯胺化、酯化、去酯化、酶促裂解及類似過程產生。因此,本發明包括本發明之化合物、其衍生物或其結合物之代謝產物,包括藉由如下方法產生之化合物、其衍生物或其結合物,該方法包括使本發明之化合物、其衍生物或其結合物與哺乳動物接觸足以產生其代謝產物的一段時間。
片語「
醫藥學上可接受」表明物質或組合物必須與包含調配物之其他成分及/或用其處理之哺乳動物在化學上及/或毒理學上為相容的。
術語「
保護基」或「
保護部分」係指通常用於阻斷或保護特定官能基,而使化合物、其衍生物或其結合物上之其他官能基發生反應的取代基。舉例而言,「
胺保護基」或「
胺基保護部分」為附接至胺基從而阻斷或保護化合物中之胺基官能基的取代基。此類基團為此項技術中熟知的(參見例如P. Wuts及T. Greene, 2007, Protective Groups in Organic Synthesis, 第7章, J. Wiley & Sons, NJ)且藉由以下各項來例示:胺基甲酸酯(諸如胺基甲酸甲酯及胺基甲酸乙酯)、FMOC、經取代之胺基甲酸乙酯、藉由1,6-β-消除(亦稱為「
自分解」)裂解之胺基甲酸酯、脲、醯胺、肽、烷基及芳基衍生物。適合之胺基保護基包括乙醯基、三氟乙醯基、第三丁氧基羰基(BOC)、苯甲氧基羰基(CBZ)及9-茀基亞甲氧基羰基(Fmoc)。關於保護基及其用途之一般描述,參見P. G.M. Wuts及T. W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 2007。
術語「
離去基」係指在取代或置換期間離開之帶電荷或不帶電荷部分的基團。此類離去基為此項技術中熟知的且包括但不限於鹵素、酯、烷氧基、羥基、甲苯磺酸酯、三氟甲磺酸酯、甲磺酸酯、腈、疊氮化物、胺基甲酸酯、二硫化物、硫酯、硫醚及重氮化合物。
術語「
雙官能交聯劑」、「
雙官能連接子」或「
交聯劑」係指具有兩個反應性基團之改質劑;其中之一者能夠與細胞結合劑反應,而另一者與細胞毒性化合物反應,從而將兩個部分鍵聯在一起。此類雙官能交聯劑為此項技術中熟知的(參見例如Isalm及Dent,
Bioconjugation第5章, 第218-363頁, Groves Dictionaries Inc., New York, 1999)。舉例而言,能夠經由硫醚鍵實現鍵聯之雙官能交聯劑包括用於引入順丁烯二醯亞胺基之
N-丁二醯亞胺基-4-(N-順丁烯二醯亞胺基甲基)-環己烷-1-甲酸酯(SMCC)或用於引入碘乙醯基之
N-丁二醯亞胺基-4-(碘乙醯基)-胺基苯甲酸酯(SIAB)。將順丁烯二醯亞胺基或鹵乙醯基引入至細胞結合劑上之其他雙官能交聯劑為此項技術中熟知的(參見美國專利申請案2008/0050310、20050169933,其可自Pierce Biotechnology Inc. P.O. Box 117, Rockland, IL 61105, USA獲得)且包括但不限於雙順丁烯二醯亞胺基聚乙二醇(BMPEO)、BM(PEO)
2、BM(PEO)
3、N-(β-順丁烯二醯亞胺基丙氧基)丁二醯亞胺酯(BMPS)、γ-順丁烯二醯亞胺基丁酸N-丁二醯亞胺酯(GMBS)、ε-順丁烯二醯亞胺基己酸N-羥基丁二醯亞胺酯(EMCS)、5-順丁烯二醯亞胺基戊酸NHS、HBVS、N-丁二醯亞胺基-4-(N-順丁烯二醯亞胺基甲基)-環己烷-1-羧基-(6-醯胺基己酸酯) (其為SMCC之「長鏈」類似物(LC-SMCC))、間順丁烯二醯亞胺基苯甲醯基-N-羥基丁二醯亞胺酯(MBS)、4-(4-N-順丁烯二醯亞胺基苯基)-丁酸醯肼或鹽酸鹽(MPBH)、3-(溴乙醯胺基)丙酸N-丁二醯亞胺酯(SBAP)、碘乙酸N-丁二醯亞胺酯(SIA)、κ-順丁烯二醯亞胺基十一烷酸N-丁二醯亞胺酯(KMUA)、4-(對順丁烯二醯亞胺基苯基)-丁酸N-丁二醯亞胺酯(SMPB)、丁二醯亞胺基-6-(β-順丁烯二醯亞胺基丙醯胺基)己酸酯(SMPH)、丁二醯亞胺基-(4-乙烯基磺醯基)苯甲酸鹽(SVSB)、二硫代雙順丁烯二醯亞胺基乙烷(DTME)、1,4-雙順丁烯二醯亞胺基丁烷(BMB)、1,4雙順丁烯二醯亞胺基-2,3-二羥基丁烷(BMDB)、雙順丁烯二醯亞胺基己烷(BMH)、雙順丁烯二醯亞胺基乙烷(BMOE)、4-(N-順丁烯二醯亞胺基-甲基)環己烷-1-甲酸磺基丁二醯亞胺酯(磺基-SMCC)、(4-碘-乙醯基)胺基苯甲酸磺基丁二醯亞胺酯(磺基-SIAB)、間順丁烯二醯亞胺基苯甲醯基-N-羥基磺基丁二醯亞胺酯(磺基-MBS)、N-(γ-順丁烯二醯亞胺基丁醯氧基)磺基丁二醯亞胺酯(磺基-GMBS)、N-(ε-順丁烯二醯亞胺基己醯氧基)磺基丁二醯亞胺酯(磺基-EMCS)、N-(κ-順丁烯二醯亞胺基十一醯氧基)磺基丁二醯亞胺酯(磺基-KMUS)及4-(對順丁烯二醯亞胺基苯基)丁酸磺基丁二醯亞胺酯(磺基-SMPB)。
雜雙官能交聯劑為具有兩個不同反應性基團之雙官能交聯劑。含有胺反應性
N-羥基丁二醯亞胺基(NHS基團)與羰基反應性肼基之雜雙官能交聯劑亦可用於使本文所描述之細胞毒性化合物與細胞結合劑(例如抗體)鍵聯。此類可商購獲得之雜雙官能交聯劑之實例包括丁二醯亞胺基6-肼基菸醯胺丙酮腙(SANH)、丁二醯亞胺基4-醯肼基對苯二甲酸酯鹽酸鹽(SHTH)及丁二醯亞胺基菸酸肼鹽酸鹽(SHNH)。可使用之雙官能交聯劑之實例包括苯甲酸丁二醯亞胺基-對甲醯酯(SFB)及丁二醯亞胺基-對甲醯基苯氧基乙酸酯(SFPA)。
能夠使細胞結合劑與細胞毒性化合物經由二硫鍵鍵聯之雙官能交聯劑為此項技術中已知的且包括用於引入二硫代吡啶基之
N-丁二醯亞胺基-3-(2-吡啶基二硫代)丙酸酯(SPDP)、
N-丁二醯亞胺基-4-(2-吡啶基二硫代)戊酸酯(SPP)、
N-丁二醯亞胺基-4-(2-吡啶基二硫代)丁酸酯(SPDB)、
N-丁二醯亞胺基-4-(2-吡啶基二硫代)2-磺基丁酸酯(磺基-SPDB)。可用於引入二硫基之其他雙官能交聯劑為此項技術中已知的且揭示於美國專利6,913,748、6,716,821及美國專利公開案20090274713及20100129314中,該等專利全部以引用之方式併入本文中。或者,亦可使用引入硫醇基之交聯劑,諸如2-亞胺基硫雜環戊烷、高半胱胺酸硫代內酯或S-乙醯基丁二酸酐。
如本文所定義之「
反應性部分」或「
反應性基團」係指與另一化學基團形成共價鍵之化學部分。舉例而言,反應性部分可與細胞結合劑(CBA)上之某些基團反應以形成共價鍵。在一些實施例中,反應性部分為胺反應性基團,其可與定位於CBA上之離胺酸殘基之ε-胺形成共價鍵。在另一實施例中,反應性部分為醛反應性基團,其可與定位於CBA上之醛基形成共價鍵。在另一實施例中,反應性部分為硫醇反應性基團,其可與定位於CBA上之半胱胺酸殘基之硫醇基形成共價鍵。
如本文所定義之「
連接子」、「
連接子部分」或「
鍵聯基團」係指將兩個基團(諸如細胞結合劑及細胞毒性化合物)連接在一起之部分。典型地,連接子在鍵聯與其連接之兩個基團的條件下為實質上惰性的。雙官能交聯劑可包含兩個反應性基團,連接子部分之每個末端各一個,使得一個反應性基團可首先與細胞毒性化合物反應以提供帶有連接子部分及第二反應性基團之化合物,第二反應性基團然後可與細胞結合劑反應。或者,首先可使雙官能交聯劑之一個末端與細胞結合劑反應,以提供帶有連接子部分及第二反應性基團之細胞結合劑,第二反應性基團然後可與細胞毒性化合物反應。鍵聯部分可含有化學鍵,其允許在特定位點釋放細胞毒性部分。適合之化學鍵為此項技術中熟知的且包括二硫鍵、硫醚鍵、酸不穩定鍵、光不穩定鍵、肽酶不穩定鍵及酯酶不穩定鍵(參見例如美國專利5,208,020;5,475,092;6,441,163;6,716,821;6,913,748;7,276,497;7,276,499;7,368,565;7,388,026及7,414,073)。較佳為二硫鍵、硫醚及肽酶不穩定鍵。可用於本發明中之其他連接子包括不可裂解連接子,諸如美國公開案第20050169933號中詳細描述之彼等不可裂解連接子;或帶電荷連接子或親水性連接子,其描述於US 2009/0274713、US 2010/01293140及WO 2009/134976中,該等專利中之每一者明確地以引用之方式併入本文中。
術語「
胺基酸」係指天然存在及合成之胺基酸以及以類似於天然存在之胺基酸的方式發揮功能的胺基酸類似物及胺基酸模擬物。天然存在之胺基酸為由遺傳密碼編碼之彼等胺基酸,以及隨後經修飾之彼等胺基酸,例如羥基脯胺酸、γ-羧基麩胺酸鹽、硒代半胱胺酸及O-磷酸絲胺酸。胺基酸類似物係指具有與天然存在之胺基酸相同之基礎化學結構(亦即結合於氫、羧基、胺基及R基團之α碳)的化合物,例如高絲胺酸、正白胺酸、甲硫胺酸亞碸、甲硫胺酸甲基鋶。此類類似物具有經修飾之R基團(例如正白胺酸)或經修飾之肽主鏈,但保留與天然存在之胺基酸相同之基礎化學結構。尤其可使用之一種胺基酸為瓜胺酸,其為精胺酸之衍生物且參與肝臟中尿素之形成。胺基酸模擬物係指結構不同於胺基酸之一般化學結構,但以類似於天然存在之胺基酸的方式發揮功能的化合物。術語「非天然胺基酸」旨在表示上文所描述之二十種天然存在之胺基酸的「D」立體化學形式。應進一步理解,術語非天然胺基酸包括天然胺基酸之同系物或其D異構體,及天然胺基酸之合成修飾形式。合成修飾形式包括但不限於側鏈縮短或延長至多兩個碳原子之胺基酸、包含視情況經取代之芳基的胺基酸及包含鹵化基團(較佳為鹵化烷基及芳基)之胺基酸以及N取代之胺基酸,例如N-甲基-丙胺酸。胺基酸或肽可通過胺基酸或肽之未端胺或未端羧酸附接至連接子/間隔子或細胞結合劑。胺基酸亦可通過諸如但不限於以下之側鏈反應性基團附接至連接子/間隔子或細胞結合劑:半胱胺酸之硫醇基、離胺酸之ε胺或絲胺酸或蘇胺酸之側鏈羥基。
在一些實施例中,胺基酸由NH
2-C(R
aa'R
aa)-C(=O)OH表示,其中R
aa及R
aa'各獨立地為H、視情況經取代之具有1至10個碳原子之線性、分枝或環狀烷基、烯基或炔基、芳基、雜芳基或雜環基,或R
aa及N端氮原子可一起形成雜環(例如如在脯胺酸中)。術語「
胺基酸殘基」係指當自胺移除一個氫原子及/或自胺基酸之羧基末端移除羥基時的對應殘基,諸如-NH-C(R
aa'R
aa)-C(=O)O-。
如本文所用,胺基酸可為L或D異構體。除非另外指明,否則當提及胺基酸時,其可為L或D異構體或其混合物。在某些實施例中,除非另外指明,否則當藉由胺基酸序列提及肽時,胺基酸中之每一者可為L或D異構體。除非另外指明,否則若將肽中之胺基酸中之一者指定為D異構體,則其他胺基酸為L異構體。舉例而言,肽D-Ala-Ala意謂D-Ala-L-Ala。
胺基酸及肽可由阻斷基保護。阻斷基為保護胺基酸或肽之N端不發生不希望之反應的原子或化學部分且可在藥物-配位體結合物之合成期間使用。其在整個合成中應保持附接至N端,且在藥物結合物之合成完成之後可藉由選擇性實現其移除之化學或其他條件來移除。適合用於N端保護之阻斷基為肽化學技術中熟知的。示例性阻斷基包括但不限於甲酯、第三丁酯、胺基甲酸9-茀基甲酯(Fmoc)及苄氧羰基(Cbz)。
術語「
可由蛋白酶裂解之肽」係指含有蛋白酶之裂解識別序列的肽。如本文所用,蛋白酶為可裂解肽鍵之酶。蛋白酶之裂解識別序列為在蛋白水解裂解期間由蛋白酶識別之特定胺基酸序列。許多蛋白酶裂解位點為此項技術中已知的,且連接子部分中可包括此等及其他裂解位點。參見例如Matayoshi等人
Science 247: 954 (1990);Dunn等人
Meth. Enzymol. 241: 254 (1994);Seidah等人
Meth. Enzymol. 244: 175 (1994);Thornberry,
Meth. Enzymol. 244: 615 (1994);Weber等人
Meth. Enzymol. 244: 595 (1994);Smith等人
Meth. Enzymol. 244: 412 (1994);Bouvier等人
Meth. Enzymol. 248: 614 (1995);Hardy等人, AMYLOID PROTEIN PRECURSOR IN DEVELOPMENT, AGING, AND ALZHEIMER'S DISEASE編, Masters等人, 第190-198頁(1994)。
基於由蛋白酶裂解之能力來選擇肽序列,該蛋白酶之非限制性實例包括組織蛋白酶B、C、D、H、L及S以及弗林蛋白酶(furin)。較佳地,肽序列能夠由適當之分離之蛋白酶在活體外裂解,此可使用此項技術中已知之活體外蛋白酶裂解分析來進行測試。
在另一實施例中,基於由溶酶體蛋白酶裂解之能力選擇肽序列。溶酶體蛋白酶為主要定位於溶酶體中之蛋白酶,但亦可定位於內體中。溶酶體蛋白酶之實例包括但不限於組織蛋白酶B、C、D、H、L及S以及弗林蛋白酶。
在另一實施例中,基於由腫瘤相關蛋白酶(諸如存在於癌細胞表面上或細胞外腫瘤細胞附近之蛋白酶)裂解之能力來選擇肽序列,此類蛋白酶之非限制性實例包括甲拌磷寡肽酶(thimet oligopeptidase,TOP)、CD10 (中性溶酶(neprilysin))、基質金屬蛋白酶(諸如MMP2或MMP9)、II型跨膜絲胺酸蛋白酶(諸如Hepsin、睪蛋白、TMPRSS4或間質蛋白酶/MT-SP1)、豆莢蛋白及以下參考文獻中所描述之酶(Current Topics in Developmental Biology: Cell Surface Proteases, 第54卷Zucker S. 2003, Boston, MA)。肽由腫瘤相關蛋白酶裂解之能力可使用此項技術中已知之活體外蛋白酶裂解分析來測試。
術語「
陽離子」係指具有正電荷之離子。陽離子可為單價的(例如Na
+、K
+等)、二價的(例如Ca
2+、Mg
2+等)或多價的(例如Al
3+等)。在一些實施例中,陽離子為單價的。
術語「
治療有效量」意謂活性化合物或結合物在個體中引發所需生物反應之量。此類反應包括正在治療之疾病或病症之症狀的緩解;疾病症狀或疾病本身之復發的預防、抑制或延遲;與不進行治療相比個體之壽命增加;或疾病症狀或疾病本身之進展的預防、抑制或延遲。有效量之測定完全在熟習此項技術者能力範圍之內,尤其根據本文所提供之詳細揭示內容。可藉由標準醫藥程序在細胞培養物中及實驗動物中確定化合物I之毒性及治療功效。要向個體投與之本發明化合物或結合物或其他治療劑之有效量將視多發性骨髓瘤之階段、類別及狀態;以及個體之特徵,諸如總體健康、年齡、性別、體重及耐藥性而定。所要投與之本發明化合物或結合物或其他治療劑之有效量亦將視投藥途徑及劑型而定。可個別調整劑量及時間間隔以提供足以維持所需治療效果之活性化合物血漿含量。
細胞結合劑-細胞毒性劑結合物
在第一態樣中,本發明提供細胞結合劑-細胞毒性劑結合物,其包含共價鍵聯至本文所描述之細胞毒性化合物之一或多個分子的本文所描述之細胞結合劑。
在第一實施例中,本發明之結合物由下式表示:
(I)
或其醫藥學上可接受之鹽,其中:
CB為細胞結合劑;
L
2不存在或為間隔子;
A為胺基酸殘基或包含2至20個胺基酸殘基之肽;
R
1及R
2各獨立地為H或C
1-6烷基(例如R
1及R
2各獨立地為H或C
1-3烷基);
L
1為間隔子;
D-L
1-SH為細胞毒性劑;且
q為1至20之整數。
在一個實施例中,L
1為-L
1'-C(=O)-;且L
1'為伸烷基、伸烯基、伸炔基、伸環烷基、伸雜環烷基、伸芳基或伸雜芳基,其中L
1中之-C(=O)-基團連接至D。
在另一實施例中,R
1及R
2中之至少一者為H。在一更特定實施例中,R
1及R
2中之一者為H且另一者為Me。
在第1特定實施例中,對於式(I)之結合物,R
1及R
2各獨立地為H或Me。在一更特定實施例中,R
1與R
2均為H。
在第2特定實施例中,對於式(I)之結合物,L
1為-L
1'-C(=O)-;且L
1'為伸烷基或伸環烷基,其中L
1中之-C(=O)-基團連接至D;且其餘變數如上文在第一實施例或第1特定實施例中所描述。在一更特定實施例中,L
1'為C
1-10伸烷基。在另一更特定實施例中,L
1'為C
1-20伸烷基。
在第3特定實施例中,對於式(I)之結合物,L
1為-CR
3R
4-(CH
2)
1-8-C(=O)-;R
3及R
4各獨立地為H或Me;且其餘變數如上文在第一實施例或第1特定實施例中所描述。在一更特定實施例中,R
3與R
4均為Me。
在第4特定實施例中,對於式(I)之結合物,L
1為-CR
3R
4-(CH
2)
2-5-C(=O)-或-CR
3R
4-(CH
2)
3-5-C(=O)-;R
3及R
4各獨立地為H或Me;且其餘變數如上文在第一實施例或第1特定實施例中所描述。在一更特定實施例中,R
3與R
4均為Me。在另一更特定實施例中,R
3與R
4均為H。
在第5特定實施例中,對於式(I)之結合物,L
1為-(CH
2)
4-6-C(=O)-;且其餘變數如上文在第一實施例或第1特定實施例中所描述。
在第6特定實施例中,對於式(I)之結合物,L
2由以下結構式表示:
;
其中:
R
A為伸烷基、環烷基伸烷基、伸芳基、伸雜芳基或伸雜環基;
R
B及R
C各獨立地不存在,為伸烷基、伸環烷基或伸芳基;
V及V'各獨立地為-(O-CH
2-CH
2)
p-或-(CH
2-CH
2-O)
p-;
p為0或1至10之整數;
W不存在,為
、
或
,其中s2'指示連接至V、R
A或J
CB之位點且s3'指示連接至R
B、V'、R
C或J
A之位點;
J
CB為-C(=O)-、
、
、
、
、
、
、
、
、
、
、
、
、
、
、
、
、
或
,其中s1指示連接至細胞結合劑CB之位點且s2指示連接至R
A之位點;
R
a、R
b、R
c及R
e在每次出現時獨立地為H或烷基;
J
A為-C(=O)-;且其餘變數如上文在第一實施例或第1、第2、第3、第4或第5特定實施例中所描述。
在一更特定實施例中,p為0且R
C不存在;且其餘變數如上文在第6特定實施例中所描述。
在第7實施例中,對於式(I)之結合物,L
2由以下結構式表示:
(L2a);
(L2b);
(L2c);
(L2d);或
(L2e);
其中:
R
x、R
y、R
x'及R
y'在每次出現時獨立地為H、-OH、鹵素、-O-(C
1-4烷基)、-SO
3H、-NR
40R
41R
42 +或視情況經-OH、鹵素、-SO
3H或NR
40R
41R
42 +取代之C
1-4烷基,其中R
40、R
41及R
42各獨立地為H或C
1-4烷基;
l及k各獨立地為1至10之整數;
s1指示連接至CBA之位點且s3指示連接至基團A之位點;
且其餘變數如上文在第一實施例或第1、第2、第3、第4或第5特定實施例中所描述。
在一更特定實施例中,R
x、R
y、R
x '及R
y '全部為H;且其餘變數如上文在第7特定實施例中所描述。
在另一更特定實施例中,l及k各獨立地為2至6之整數;且其餘變數如上文在第7特定實施例中所描述。
在一甚至更特定實施例中,R
x、R
y、R
x '及R
y '全部為H;l及k各獨立地為2至6之整數;且其餘變數如上文在第7特定實施例中所描述。
在另一更特定實施例中,L
2由以下結構式表示:
(L2d),或
(L2f);
其中:
R
x與R
y均為H;
l及l1各獨立地為1至10之整數;且
k1為1至12之整數(例如2、4、6、8、10或12)。
在一個實施例中,l及l1各為2至6之整數;且k1為2至6之整數(例如2、4或6)。
在第8特定實施例中,對於式(I)之結合物,A為可由蛋白酶裂解之肽;其餘變數如上文在第一實施例或第1、第2、第3、第4、第5、第6或第7特定實施例中所描述。在一更特定實施例中,A為可由在腫瘤組織中表現之蛋白酶裂解之肽。
在第9特定實施例中,對於式(I)之結合物,A為具有選自由以下組成之群的與-NH-CR
1R
2-S-L
1-D共價鍵聯之胺基酸的肽:Ala、Arg、Asn、Asp、Cit、Cys、硒代-Cys、Gln、Glu、Gly、Ile、Leu、Lys、Met、Phe、Pro、Ser、Thr、Trp、Tyr及Val,其各獨立地呈L或D異構體形式;其餘變數如上文在第一實施例或第1、第2、第3、第4、第5、第6或第7特定實施例中所描述。在一更特定實施例中,連接至-NH-CR
1R
2-S-L
1-D之胺基酸為L胺基酸。
在第10特定實施例中,對於式(I)之結合物,A係選自由以下組成之群:Gly-Gly-Gly、Ala-Val、Val-Ala、D-Val-Ala、Val-Cit、D-Val-Cit、Val-Lys、Phe-Lys、Lys-Lys、Ala-Lys、Phe-Cit、Leu-Cit、Ile-Cit、Phe-Ala、Phe-N
9-甲苯磺醯基-Arg、Phe-N
9-硝基-Arg、Phe-Phe-Lys、D-Phe-Phe-Lys、Gly-Phe-Lys、Leu-Ala-Leu、Ile-Ala-Leu、Val-Ala-Val、Ala-Ala-Ala、D-Ala-Ala-Ala、Ala-D-Ala-Ala、Ala-Ala-D-Ala、Ala-Leu-Ala-Leu (SEQ ID NO: 1)、β-Ala-Leu-Ala-Leu (SEQ ID NO: 2)、Gly-Phe-Leu-Gly (SEQ ID NO: 3)、Val-Arg、Arg-Arg、Val-D-Cit、Val-D-Lys、Val-D-Arg、D-Val-Cit、D-Val-Lys、D-Val-Arg、D-Val-D-Cit、D-Val-D-Lys、D-Val-D-Arg、D-Arg-D-Arg、Ala-Ala、Ala-D-Ala、D-Ala-Ala、D-Ala-D-Ala、Ala-Met、Gln-Val、Asn-Ala、Gln-Phe、Gln-Ala、D-Ala-Pro及D-Ala-tBu-Gly,其中各肽中之第一個胺基酸連接至L
2基團且各肽中之最後一個胺基酸連接至-NH-CR
1R
2-S-L
1-D;且其餘變數如上文在第一實施例或第1、第2、第3、第4、第5、第6或第7特定實施例中所描述。在一更特定實施例中,A為Ala-Ala-Ala、Ala-D-Ala-Ala、D-Ala-Ala-Ala、Ala-Ala-D-Ala、Ala-Ala、D-Ala-Ala、Val-Ala、D-Val-Ala、D-Ala-Pro或D-Ala-tBu-Gly。在另一更特定實施例中,A為Ala-Ala-Ala、Ala-D-Ala-Ala、Ala-Ala、D-Ala-Ala、Val-Ala、D-Val-Ala、D-Ala-Pro或D-Ala-tBu-Gly。
在第11特定實施例中,對於式(I)之結合物,D為類美登素;且其餘變數如上文在第一實施例或第1、第2、第3、第4、第5、第6、第7、第8、第9或第10特定實施例中所描述。在一更特定實施例中,D由下式表示:
。
在第12特定實施例中,本發明之結合物由下式表示:
;
;
;
;或
;
或其醫藥學上可接受之鹽,其中:
為通過胺基(例如Lys胺基)連接至L
2基團之細胞結合劑;
為通過硫醇基(例如Cys硫醇基)連接至L
2基團之細胞結合劑;
R
3及R
4各獨立地為H或Me;
m1、m3、p1、n1、r1及t1各獨立地為1至10之整數;
m2、n2、p2、r2及t2各獨立地為1至19之整數;
t3為1至12之整數;
D
1由下式表示:
;且
A如上文在第8、第9或第10特定實施例中所描述。
在一更特定實施例中,m1、m3、p1、n1及r1各獨立地為1至6之整數;且m2、n2、p2及r2各獨立地為1至7之整數。
在一更特定實施例中,A為Ala-Ala-Ala、Ala-D-Ala-Ala、D-Ala-Ala-Ala、Ala-Ala-D-Ala、Ala-Ala、D-Ala-Ala、Val-Ala、D-Val-Ala、D-Ala-Pro或D-Ala-tBu-Gly (更特定而言,A為Ala-Ala-Ala、Ala-D-Ala-Ala、Ala-Ala、D-Ala-Ala、Val-Ala、D-Val-Ala、D-Ala-Pro或D-Ala-tBu-Gly);且其餘變數如上文在第12特定實施例中所描述。
在另一更特定實施例中,m1、r1、n1、p1及m3各獨立地為2至4之整數;且m2、n2、p2及r2各獨立地為3至5之整數。在一更特定實施例中,m1、m3、p1、n1、r1及t1各獨立地為2至10之整數。在一更特定實施例中,m1、m3、p1、n1、r1及t1各獨立地為3至6之整數。
在一更特定實施例中,m2、n2、p2、r2及t2各獨立地為2至10之整數。在一更特定實施例中,m2、n2、p2、r2及t2各獨立地為3至6之整數。在一更特定實施例中,m2、n2、p2、r2及t2各獨立地為5。
在一更特定實施例中,m1、m3、p1、n1、r1及t1各獨立地為2至10之整數,且m2、n2、p2、r2及t2各獨立地為2至10之整數。在一更特定實施例中,m1、m3、p1、n1、r1及t1各獨立地為3至6之整數,且m2、n2、p2、r2及t2各獨立地為2至10之整數。在一更特定實施例中,m1、m3、p1、n1、r1及t1各獨立地為3至6之整數,且m2、n2、p2、r2及t2各獨立地為3至6之整數。
在一更特定實施例中,r2及t2各獨立地為2至6之整數,r1及t1各獨立地為2至6之整數,且t3為1至12之整數。在一更特定實施例中,r2及t2各獨立地為2至6之整數,r1及t1各獨立地為2至6之整數,且t3為1至6之整數。在一更特定實施例中,r2及t2各獨立地為2至6之整數,r1及t1各獨立地為2至6之整數,且t3 為1至4之整數。在一更特定實施例中,r2及t2各獨立地為3至5之整數,r1及t1各獨立地為2至6之整數,且t3為1至12之整數。在一更特定實施例中,r2及t2各獨立地為3至5之整數,r1及t1各獨立地為2至6之整數,且t3為1至6之整數。在一更特定實施例中,r2及t2各獨立地為3至5之整數,r1及t1各獨立地為2至6之整數,且t3為1至4之整數。
在一更特定實施例中,r2及r1各獨立地為2至6之整數。在一更特定實施例中,r2為3至5之整數,且r1為2至6之整數。在一更特定實施例中,r2為3至5之整數,且r1為2至4之整數。在一更特定實施例中,r2為4且r1為2。在一更特定實施例中,r2為4且r1為3。在一更特定實施例中,r2為4且r1為4。在一更特定實施例中,r2為4且r1為5。在一更特定實施例中,r2為4且r1為6。
在另一更特定實施例中,R
3與R
4均為Me。或者,R
3與R
4均為H。
在一更特定實施例中,r1及t1各為2至6之整數;r2及t2各為2至5之整數;且t3為2至6之整數(例如t3為2、4或6)。
在第13特定實施例中,本發明之結合物由下式表示:
;
;
;
;
;
;
;
;
;
;
;
;
;
;
;
;
;
;
;或
;
;
;
;
;
;
;
;
;
;
;
;
;
;
;或
;
或其醫藥學上可接受之鹽,其中:
A為Ala-Ala-Ala、Ala-D-Ala-Ala、D-Ala-Ala-Ala、Ala-Ala-D-Ala、Ala-Ala、D-Ala-Ala、Val-Ala、D-Val-Ala、D-Ala-Pro或D-Ala-tBu-Gly (更特定而言,A為Ala-Ala-Ala、Ala-D-Ala-Ala、Ala-Ala、D-Ala-Ala、Val-Ala、D-Val-Ala、D-Ala-Pro或D-Ala-tBu-Gly),且
D
1由下式表示:
。
亦在第13特定實施例中,本發明之結合物由下式表示:
;
;
;
;
;
;
;
;
;
;
;
;
;
;
;
;
;
;
;
;
;
;
;
;
;
;
;
;或
;
或其醫藥學上可接受之鹽,其中:
A為Ala-Ala-Ala、Ala-D-Ala-Ala、D-Ala-Ala-Ala、Ala-Ala-D-Ala、Ala-Ala、D-Ala-Ala、Val-Ala、D-Val-Ala、D-Ala-Pro或D-Ala-tBu-Gly (更特定而言,A為Ala-Ala-Ala、Ala-D-Ala-Ala、Ala-Ala、D-Ala-Ala、Val-Ala、D-Val-Ala、D-Ala-Pro或D-Ala-tBu-Gly),且
D
1由下式表示:
。
在一些實施例中,對於上文所描述之本發明之結合物(例如在第一實施例或第1、第2、第3、第4、第5、第6、第7、第8、第9、第10、第11、第12或第13特定實施例中所描述之結合物),細胞結合劑(CBA)可為本文所描述之細胞結合劑(CBA)中之任一者。
在一些實施例中,對於上文所描述之本發明之結合物(例如在第一實施例或第1、第2、第3、第4、第5、第6、第7、第8、第9、第10、第11、第12或第13特定實施例中所描述之結合物),細胞結合劑(CBA)結合於選自以下之目標細胞:腫瘤細胞、病毒感染細胞、微生物感染細胞、寄生蟲感染細胞、自體免疫細胞、活化細胞、骨髓細胞、活化T細胞、B細胞或黑素細胞;表現CA6、CAK1、CD4、CD6、CD19、CD20、CD22、CD30、CD33、CD37、CD38、CD40、CD44、CD56、CD123、CD138、CanAg、CALLA、CEACAM5、FGFR3、LAMP1、p-鈣黏蛋白、CA6、TROP-2、DLL-3、CDH6、AXL、SLITRK6、ENPP3、BCMA、組織因子(TF)、CD352、Her-2或Her-3抗原之細胞;或表現胰島素生長因子受體、表皮生長因子受體、結合素-4 (Nectin-4)、間皮素、GD3、泌乳素受體及葉酸受體之細胞。
(例如在第一實施例或第1、第2、第3、第4、第5、第6、第7、第8、第9、第10、第11、第12或第13特定實施例中所描述之結合物),細胞結合劑為特異性結合於目標細胞之抗體或其抗原結合片段、單鏈抗體、單鏈抗體片段、特異性結合於目標細胞之單株抗體、單鏈單株抗體或單株抗體片段、特異性結合於目標細胞之嵌合抗體、嵌合抗體片段、特異性結合於目標細胞之結構域抗體、結構域抗體片段、抗體前藥(probody)、奈米抗體(nanobody)、淋巴介質、激素、維生素、生長因子、群落刺激因子、營養物運送分子、Bicycles
®肽或噴他林(pentarin)。
在一些實施例中,對於上文所描述之本發明之結合物(例如在第一實施例或第1、第2、第3、第4、第5、第6、第7、第8、第9、第10、第11、第12或第13特定實施例中所描述之結合物),細胞結合劑為抗體或其抗原結合片段。在其他實施例中,細胞結合劑為表面整修抗體或其表面整修抗體片段。在一些實施例中,細胞結合劑為單株抗體或其單株抗體片段。在一些實施例中,細胞結合劑為人類化抗體或其人類化抗體片段。在其他實施例中,細胞結合劑為嵌合抗體或其嵌合抗體片段。在一些實施例中,細胞結合劑為抗葉酸受體抗體或其抗體片段、抗EGFR抗體或其抗體片段、抗CD33抗體或其抗體片段、抗CD19抗體或其抗體片段、抗Muc1抗體或其抗體片段或抗CD37抗體或其抗體片段。
在另一實施例中,本發明之結合物由下式表示:
;
其中Ab為抗葉酸受體抗體。在一特定實施例中,抗葉酸受體抗體包含(a)包含GYFMN (SEQ ID NO: 4)之重鏈CDR1、包含RIHPYDGDTFYNQXaa
1FXaa
2Xaa
3(SEQ ID NO: 5)之重鏈CDR2及包含YDGSRAMDY (SEQ ID NO: 6)之重鏈CDR3;及(b)包含KASQSVSFAGTSLMH (SEQ ID NO: 7)之輕鏈CDR1、包含RASNLEA (SEQ ID NO: 8)之輕鏈CDR2及包含QQSREYPYT (SEQ ID NO: 9)之輕鏈CDR3;其中Xaa
1係選自K、Q、H及R;Xaa
2係選自Q、H、N及R;且Xaa
3係選自G、E、T、S、A及V。較佳地,重鏈CDR2序列包含RIHPYDGDTFYNQKFQG (SEQ ID NO: 10)。在另一特定實施例中,抗葉酸受體抗體包含具有SEQ ID NO: 14之胺基酸序列的重鏈可變域,及具有SEQ ID NO: 15或SEQ ID NO: 16之胺基酸序列的輕鏈可變域。在另一特定實施例中,抗葉酸受體抗體包含具有SEQ ID NO: 11之胺基酸序列的重鏈,及具有SEQ ID NO: 12或SEQ ID NO: 13之胺基酸序列的輕鏈。較佳地,抗體包含具有SEQ ID NO: 11之胺基酸序列的重鏈及具有SEQ ID NO: 13之胺基酸序列的輕鏈(huFOLR1)。在另一特定實施例中,抗葉酸受體抗體係由於2010年4月7日保藏在ATCC且具有ATCC保藏號PTA-10772及PTA-10773或10774之質體DNA編碼。參見WO2011/106528,其以引用之方式併入本文中。
在一些實施例中,對於上文所描述之本發明之結合物(例如在第一實施例或第1、第2、第3、第4、第5、第6、第7、第8、第9、第10、第11、第12或第13特定實施例中所描述之結合物),q為1至10、1至8或2至5之整數。在一些實施例中,對於通過Cys硫醇基共價鍵聯至細胞毒性劑之結合物,q為1或2。在一個實施例中,q為2。
在一些實施例中,對於包含上文所描述之本發明之結合物(例如在第一實施例或第1、第2、第3、第4、第5、第6、第7、第8、第9、第10、第11、第12或第13特定實施例中所描述之結合物)的組合物(例如醫藥組合物),每一細胞結合劑(CBA,例如抗體)之細胞毒性劑平均數目(亦即q之平均值),亦稱為組合物中之藥物-抗體比率(DAR),在1.0至8.0範圍內。在一些實施例中,DAR在1.0至5.0、1.0至4.0、1.0至3.4、1.0至3.0、1.5至2.5、2.0至2.5或1.8至2.2範圍內。
本發明之化合物
在第二態樣中,本發明提供本文所描述之類美登素衍生物。
在第二實施例中,本發明之化合物由式(II)、(III)或(IV)表示:
(II),
(III),或
(IV)
或其醫藥學上可接受之鹽,其中:
L
2 '不存在或為帶有反應性部分之間隔子,該反應性部分可與細胞結合劑形成共價鍵;
A為胺基酸殘基或包含2至20個胺基酸殘基之肽;
R
1及R
2各獨立地為H或C
1-6烷基(例如R
1及R
2各獨立地為H或C
1-3烷基);
L
1為間隔子;
D-L
1-SH為細胞毒性劑;
q為1至20之整數;
A'為胺基酸或包含2至20個胺基酸之肽;
L
3由下式表示:
;
R
x '及R
y '在每次出現時獨立地為H、-OH、鹵素、-O-(C
1-4烷基)、-SO
3H、-NR
40R
41R
42 +或視情況經-OH、鹵素、SO
3H或NR
40R
41R
42 +取代之C
1-4烷基,其中R
40、R
41及R
42各獨立地為H或C
1-4烷基;且
k為1至10之整數。
在一個實施例中,L
1為-L
1'-C(=O)-;且L
1'為伸烷基、伸烯基、伸炔基、伸環烷基、伸雜環烷基、伸芳基或伸雜芳基,其中L
1中之-C(=O)-基團連接至D。
在另一實施例中,R
1及R
2中之至少一者為H。在一更特定實施例中,R
1及R
2中之一者為H且另一者為Me。
在第14特定實施例中,對於式(II)、(III)及(IV)之化合物,R
1及R
2各獨立地為H或Me;且其餘變數如上文在第二實施例中所描述。在一更特定實施例中,R
1與R
2均為H。
在第15特定實施例中,對於式(II)、(III)及(IV)之化合物,L
1為-L
1'-C(=O)-;且L
1'為伸烷基或伸環烷基,其中L
1中之-C(=O)-基團連接至D;且其餘變數如上文在第二實施例或第14特定實施例中所描述。在一更特定實施例中,L
1'為C
1-10伸烷基。在另一更特定實施例中,L
1'為C
1-20伸烷基。
在第16特定實施例中,對於式(II)、(III)及(IV)之化合物,L
1為-CR
3R
4-(CH
2)
1-8-C(=O)-;R
3及R
4各獨立地為H或Me;且其餘變數如上文在第二實施例或第14特定實施例中所描述。在一更特定實施例中,R
3與R
4均為Me。
在第17特定實施例中,對於式(II)、(III)及(IV)之化合物,L
1為-CR
3R
4-(CH
2)
2-5-C(=O)-或-CR
3R
4-(CH
2)
3-5-C(=O)-;R
3及R
4各獨立地為H或Me;且其餘變數如上文在第二實施例或第14特定實施例中所描述。在一更特定實施例中,R
3與R
4均為Me。在另一更特定實施例中,R
3與R
4均為H。
在第18特定實施例中,對於式(II)、(III)及(IV)之化合物,L
1為-(CH
2)
4-6-C(=O)-;且其餘變數如上文在第二實施例或第14特定實施例中所描述。
在第19特定實施例中,對於式(II)、(III)及(IV)之化合物,A或A'為可由蛋白酶裂解之肽;其餘變數如上文在第二實施例或第14、第15、第16、第17或第18特定實施例中所描述。在一更特定實施例中,A或A'為可由在腫瘤組織中表現之蛋白酶裂解之肽。
在第20特定實施例中,對於式(II)、(III)及(IV)之化合物,A或A'為具有選自由以下組成之群的與-NH-CR
1R
2-S-L
1-D共價鍵聯之胺基酸的肽:Ala、Arg、Asn、Asp、Cit、Cys、硒代-Cys、Gln、Glu、Gly、Ile、Leu、Lys、Met、Phe、Pro、Ser、Thr、Trp、Tyr及Val,其各獨立地呈L或D異構體形式;其餘變數如上文在第二實施例或第14、第15、第16、第17或第18特定實施例中所描述。在一更特定實施例中,連接至-NH-CR
1R
2-S-L
1-D之胺基酸為L胺基酸。
在第21特定實施例中,對於式(II)、(III)及(IV)之化合物,A或A'係選自由以下組成之群:Gly-Gly-Gly、Ala-Val、Val-Ala、D-Val-Ala、Val-Cit、D-Val-Cit、Val-Lys、Phe-Lys、Lys-Lys、Ala-Lys、Phe-Cit、Leu-Cit、Ile-Cit、Phe-Ala、Phe-N
9-甲苯磺醯基-Arg、Phe-N
9-硝基-Arg、Phe-Phe-Lys、D-Phe-Phe-Lys、Gly-Phe-Lys、Leu-Ala-Leu、Ile-Ala-Leu、Val-Ala-Val、Ala-Ala-Ala、D-Ala-Ala-Ala、Ala-D-Ala-Ala、Ala-Ala-D-Ala、Ala-Leu-Ala-Leu (SEQ ID NO: 1)、β-Ala-Leu-Ala-Leu (SEQ ID NO: 2)、Gly-Phe-Leu-Gly (SEQ ID NO: 3)、Val-Arg、Arg-Arg、Val-D-Cit、Val-D-Lys、Val-D-Arg、D-Val-Cit、D-Val-Lys、D-Val-Arg、D-Val-D-Cit、D-Val-D-Lys、D-Val-D-Arg、D-Arg-D-Arg、Ala-Ala、Ala-D-Ala、D-Ala-Ala、D-Ala-D-Ala、Ala-Met、Gln-Val、Asn-Ala、Gln-Phe、Gln-Ala、D-Ala-Pro及D-Ala-tBu-Gly,其中各肽中之第一個胺基酸連接至L
2基團且各肽中之最後一個胺基酸連接至-NH-CR
1R
2-S-L
1-D;且其餘變數如上文在第二實施例或第14、第15、第16、第17或第18特定實施例中所描述。在一更特定實施例中,A為Ala-Ala-Ala、Ala-D-Ala-Ala、D-Ala-Ala-Ala、Ala-Ala-D-Ala、Ala-Ala、D-Ala-Ala、Val-Ala、D-Val-Ala、D-Ala-Pro或D-Ala-tBu-Gly。在另一更特定實施例中,A為Ala-Ala-Ala、Ala-D-Ala-Ala、Ala-Ala、D-Ala-Ala、Val-Ala、D-Val-Ala、D-Ala-Pro或D-Ala-tBu-Gly。
對於本文所描述之A,當提及特定胺基酸或肽序列時,其意謂如下之胺基酸殘基或包含胺基酸殘基之肽,其中氫原子自連接至L
2基團之胺基酸的胺基末端移除,且羥基自連接至-NH-CR
1R
2-S-L
1-D之胺基酸的羧基末端移除。舉例而言,當A由Ala-Ala-Ala表示時,其係指-NH-CH(CH
3)-C(=O)-NH-CH(CH
3)-C(=O)-NH-CH(CH
3)-C(=O)-。
對於本文所描述之A',當提及特定胺基酸或肽序列時,其意謂如下之胺基酸殘基或包含胺基酸殘基之肽,其中羥基自連接至-NH-CR
1R
2-S-L
1-D之胺基酸的羧基末端移除。舉例而言,當A'由Ala-Ala-Ala表示時,其係指NH
2-CH(CH
3)-C(=O)-NH-CH(CH
3)-C(=O)-NH-CH(CH
3)-C(=O)-。
在第22特定實施例中,對於式(II)、(III)及(IV)之化合物,D為類美登素;且其餘變數如上文在第二實施例或第14、第15、第16、第17、第18、第19、第20或第21特定實施例中所描述。在一更特定實施例中,D由下式表示:
。
在第23特定實施例中,對於式(II)之化合物,L
2 '由以下結構式表示:
;
其中:
R
A為伸烷基、環烷基伸烷基、伸芳基、伸雜芳基或伸雜環基;
R
B及R
C各獨立地不存在,為伸烷基、伸環烷基或伸芳基;
V及V'各獨立地為-(O-CH
2-CH
2)
p-或-(CH
2-CH
2-O)
p-;
p為0或1至10之整數;
W不存在,為
、
或
,其中s2'指示連接至V、R
A或J
CB之位點且s3'指示連接至R
B、V'、R
C或J
A之位點;
J
CB '為-C(=O)OH、-COE、
、X
1-CR
bR
c-C(=O)-、X
1-CR
bR
c-C(=O)-NR
e-、
、
、
、
、
、
、
、
、
、
、
或
;
R
a、R
b、R
c及R
e在每次出現時獨立地為H或烷基;
X
1為鹵素(例如-Cl、-Br或-I);
COE為反應性酯;
J
A為-C(=O)-;且其餘變數如上文在第二實施例或第14、第15、第16、第17、第18、第19、第20、第21或第22特定實施例中所描述。
在一更特定實施例中,對於第23特定實施例中之化合物,R
A為伸烷基、環烷基伸烷基或伸芳基;W不存在或為
;且J
CB '為-C(=O)OH、-COE、
、
、
或
;且其餘變數如上文在第23特定實施例中所描述。
在一更特定實施例中,p為0且R
c不存在;且其餘變數如上文在第23特定實施例中所描述。
在第24實施例中,對於式(II)之化合物,L
2 '由以下結構式表示:
(L2a');
(L2b');
(L2c');
(L2d');
(L2e');
其中:
R
x、R
y、R
x'及R
y'在每次出現時獨立地為H、-OH、鹵素、-O-(C
1-4烷基)、-SO
3H、-NR
40R
41R
42 +或視情況經-OH、鹵素、-SO
3H或NR
40R
41R
42 +取代之C
1-4烷基,其中R
40、R
41及R
42各獨立地為H或C
1-4烷基;
l及k各獨立地為1至10之整數;
J
CB '為-C(=O)OH或-COE;
且其餘變數如上文在第二實施例或第14、第15、第16、第17、第18、第19、第20、第21、第22或第23特定實施例中所描述。
在一更特定實施例中,R
x、R
y、R
x'及R
y'全部為H;且其餘變數如上文在第24特定實施例中所描述。
在另一更特定實施例中,l及k各獨立地為2至6之整數;且其餘變數如上文在第24特定實施例中所描述。
在一甚至更特定實施例中,R
x、R
y、R
x '及R
y '全部為H;l及k各獨立地為2至6之整數;且其餘變數如上文在第24特定實施例中所描述。
在一甚至更特定實施例中,l及l1各為2至6之整數。
在第25特定實施例中,對於式(IV)化合物,R
x '與R
y '均為H;且其餘變數如上文在第二實施例或第14、第15、第16、第17、第18、第19、第20、第21或第22特定實施例中所描述。
在一更特定實施例中,k為2至6之整數;其餘變數如上文在第25特定實施例中所描述。
在另一更特定實施例中,k為3;其餘變數如上文在第25特定實施例中所描述。
在第26特定實施例中,式(II)化合物由下式表示:
;
;
;
;或
;
或其醫藥學上可接受之鹽,其中:
R
3及R
4各獨立地為H或Me;
m1、m3、n1、r1、p1及t1各獨立地為1至10之整數;
m2、n2、r2、p2及t2各獨立地為1至19之整數;
t3為1至12之整數;
J
CB '為-C(=O)OH或-COE;
D
1由下式表示:
;且
其餘變數如在第二實施例或第19、第20或第21特定實施例中所描述。
在一更特定實施例中,A為Ala-Ala-Ala、Ala-D-Ala-Ala、D-Ala-Ala-Ala、Ala-Ala-D-Ala、Ala-Ala、D-Ala-Ala、Val-Ala、D-Val-Ala、D-Ala-Pro或D-Ala-tBu-Gly。在另一更特定實施例中,A為Ala-Ala-Ala、Ala-D-Ala-Ala、Ala-Ala、D-Ala-Ala、Val-Ala、D-Val-Ala、D-Ala-Pro或D-Ala-tBu-Gly。
在一更特定實施例中,m1、m3、p1、n1及r1各獨立地為1至6之整數;且m2、n2、p2及r2各獨立地為1至7之整數。
在另一更特定實施例中,m1、p1、r1、n1及m3各獨立地為2至4之整數;且m2、n2、p2及r2各獨立地為3至5之整數。在一更特定實施例中,m1、m3、p1、n1、r1及t1各獨立地為2至10之整數。在一更特定實施例中,m1、m3、p1、n1、r1及t1各獨立地為3至6之整數。
在一更特定實施例中,m2、n2、p2、r2及t2各獨立地為2至10之整數。在一更特定實施例中,m2、n2、p2、r2及t2各獨立地為3至6之整數。在一更特定實施例中,m2、n2、p2、r2及t2各獨立地為5。
在一更特定實施例中,m1、m3、p1、n1、r1及t1各獨立地為2至10之整數,且m2、n2、p2、r2及t2各獨立地為2至10之整數。在一更特定實施例中,m1、m3、p1、n1、r1及t1各獨立地為3至6之整數,且m2、n2、p2、r2及t2各獨立地為2至10之整數。在一更特定實施例中,m1、m3、p1、n1、r1及t1各獨立地為3至6之整數,且m2、n2、p2、r2及t2各獨立地為3至6之整數。
在一更特定實施例中,r2及t2各獨立地為2至6之整數,r1及t1各獨立地為2至6之整數,且t3為1至12之整數。在一更特定實施例中,r2及t2各獨立地為2至6之整數,r1及t1各獨立地為2至6之整數,且t3為1至6之整數。在一更特定實施例中,r2及t2各獨立地為2至6之整數,r1及t1各獨立地為2至6之整數,且t3 為1至4之整數。在一更特定實施例中,r2及t2各獨立地為3至5之整數,r1及t1各獨立地為2至6之整數,且t3為1至12之整數。在一更特定實施例中,r2及t2各獨立地為3至5之整數,r1及t1各獨立地為2至6之整數,且t3為1至6之整數。在一更特定實施例中,r2及t2各獨立地為3至5之整數,r1及t1各獨立地為2至6之整數,且t3為1至4之整數。
在一更特定實施例中,r2及r1各獨立地為2至6之整數。在一更特定實施例中,r2為3至5之整數,且r1為2至6之整數。在一更特定實施例中,r2為3至5之整數,且r1為2至4之整數。在一更特定實施例中,r2為4且r1為2。在一更特定實施例中,r2為4且r1為3。在一更特定實施例中,r2為4且r1為4。在一更特定實施例中,r2為4且r1為5。在一更特定實施例中,r2為4且r1為6。
在另一更特定實施例中,R
3與R
4均為Me。或者,R
3與R
4均為H。
在一更特定實施例中,r1及t1各為2至6之整數;r2及t2各為2至5之整數;且t3為2至6之整數(例如t3為2、4或6)。
在第27特定實施例中,式(II)化合物由下式表示:
;
;
;
;
;
;
;
;
;
;
;
;
;
;
;
;
;
;
;
;
;
;
;
;
;
;
;
;
;
;
;
;
;
;或
或其醫藥學上可接受之鹽,其中:
A為Ala-Ala-Ala、Ala-D-Ala-Ala、D-Ala-Ala-Ala、Ala-Ala-D-Ala、Ala-Ala、D-Ala-Ala、Val-Ala、D-Val-Ala、D-Ala-Pro或D-Ala-tBu-Gly (更特定而言,A為Ala-Ala-Ala、Ala-D-Ala-Ala、Ala-Ala、D-Ala-Ala、Val-Ala、D-Val-Ala、D-Ala-Pro或D-Ala-tBu-Gly),
J
CB'為-C(=O)OH或-COE;且
D
1由下式表示:
。
亦在第27特定實施例中,式(II)化合物由下式表示:
;
;
;
;
;
;
;
;
;
;
;
;
;
;
;
;
;
;
;
;
;
;
;
;
;
;
;或
;
或其醫藥學上可接受之鹽,其中:
A為Ala-Ala-Ala、Ala-D-Ala-Ala、D-Ala-Ala-Ala、Ala-Ala-D-Ala、Ala-Ala、D-Ala-Ala、Val-Ala、D-Val-Ala、D-Ala-Pro或D-Ala-tBu-Gly (更特定而言,A為Ala-Ala-Ala、Ala-D-Ala-Ala、Ala-Ala、D-Ala-Ala、Val-Ala、D-Val-Ala、D-Ala-Pro或D-Ala-tBu-Gly),
J
CB'為-C(=O)OH或-COE;且
D
1由下式表示:
。
在一些實施例中,-COE為選自以下之反應性酯:N-羥基丁二醯亞胺酯、N-羥基磺基丁二醯亞胺酯、硝基苯基(例如2-或4-硝基苯基)酯、二硝基苯基(例如2,4-二硝基苯基)酯、磺基-四氟苯基(例如4-磺基-2,3,5,6-四氟苯基)酯及五氟苯基酯。更特定而言,-COE為N-羥基丁二醯亞胺酯或N-羥基磺基丁二醯亞胺酯。
在第28特定實施例中,式(III)化合物由下式表示:
;
或其醫藥學上可接受之鹽,其中:
R
3及R
4各獨立地為H或Me;
m2為1至19之整數;且
D
1由下式表示:
;且
其餘變數如第二實施例或第19、第20或第21特定實施例中所描述。
在一更特定實施例中,A為Ala-Ala-Ala、Ala-D-Ala-Ala、D-Ala-Ala-Ala、Ala-Ala-D-Ala、Ala-Ala、D-Ala-Ala、Val-Ala、D-Val-Ala、D-Ala-Pro或D-Ala-tBu-Gly。在一甚至更特定實施例中,A為Ala-Ala-Ala、Ala-D-Ala-Ala、Ala-Ala、D-Ala-Ala、Val-Ala、D-Val-Ala、D-Ala-Pro或D-Ala-tBu-Gly。
在一更特定實施例中,m2為2至10之整數。在另一更特定實施例中,m2為1至7之整數。在另一更特定實施例中,m2為2至6之整數。在另一更特定實施例中,m2為2至5之整數。在另一更特定實施例中,m2為4。
在另一更特定實施例中,R
3與R
4均為Me。或者,R
3與R
4均為H。
在第29特定實施例中,式(III)化合物由下式表示:
;
;
;
;
;
或其醫藥學上可接受之鹽,其中:
A'為Ala-Ala-Ala、Ala-D-Ala-Ala、D-Ala-Ala-Ala、Ala-Ala-D-Ala、Ala-Ala、D-Ala-Ala、Val-Ala、D-Val-Ala、D-Ala-Pro或D-Ala-tBu-Gly (更特定而言,A為Ala-Ala-Ala、Ala-D-Ala-Ala、Ala-Ala、D-Ala-Ala、Val-Ala、D-Val-Ala、D-Ala-Pro或D-Ala-tBu-Gly),
D
1由下式表示:
。
亦在第29特定實施例中,式(III)化合物由下式表示:
;
;
;
;或
,
或其醫藥學上可接受之鹽,其中:
A'為Ala-Ala-Ala、Ala-D-Ala-Ala、D-Ala-Ala-Ala、Ala-Ala-D-Ala、Ala-Ala、D-Ala-Ala、Val-Ala、D-Val-Ala、D-Ala-Pro或D-Ala-tBu-Gly (更特定而言,A為Ala-Ala-Ala、Ala-D-Ala-Ala、Ala-Ala、D-Ala-Ala、Val-Ala、D-Val-Ala、D-Ala-Pro或D-Ala-tBu-Gly),
D
1由下式表示:
。
在第30特定實施例中,式(IV)化合物由下式表示:
;
或其醫藥學上可接受之鹽,其中:
R
3及R
4各獨立地為H或Me;
m3為1至10之整數;
m2為1至19之整數;
D
1由下式表示:
;且
其餘變數如第二實施例或第19、第20或第21特定實施例中所描述。在一更特定實施例中,A為Ala-Ala-Ala、Ala-D-Ala-Ala、D-Ala-Ala-Ala、Ala-Ala-D-Ala、Ala-Ala、D-Ala-Ala、Val-Ala、D-Val-Ala、D-Ala-Pro或D-Ala-tBu-Gly。在另一更特定實施例中,A為Ala-Ala-Ala、Ala-D-Ala-Ala、Ala-Ala、D-Ala-Ala、Val-Ala、D-Val-Ala、D-Ala-Pro或D-Ala-tBu-Gly。
在一更特定實施例中,m3為1至6之整數,且m2為1至7之整數。在另一更特定實施例中,m3為2至4之整數;且m2為3至5之整數。在一更特定實施例中,m3為2至10之整數,且m2為2至10之整數。在一更特定實施例中,m3為3至6之整數,且m2為2至10之整數。在一更特定實施例中,m3為3至6之整數,且m2為3至6之整數。
在另一更特定實施例中,R
3與R
4均為Me。或者,R
3與R
4均為H。
在第31特定實施例中,式(IV)化合物由下式表示:
;
;
;
;或
;
或其醫藥學上可接受之鹽,其中:
A為Ala-Ala-Ala、Ala-D-Ala-Ala、D-Ala-Ala-Ala、Ala-Ala-D-Ala、Ala-Ala、D-Ala-Ala、Val-Ala、D-Val-Ala、D-Ala-Pro或D-Ala-tBu-Gly (更特定而言,A為Ala-Ala-Ala、Ala-D-Ala-Ala、Ala-Ala、D-Ala-Ala、Val-Ala、D-Val-Ala、D-Ala-Pro或D-Ala-tBu-Gly)且
D
1由下式表示:
。
亦在第31特定實施例中,式(IV)化合物由下式表示:
;
;
;
;
;
或其醫藥學上可接受之鹽,其中:
A為Ala-Ala-Ala、Ala-D-Ala-Ala、D-Ala-Ala-Ala、Ala-Ala-D-Ala、Ala-Ala、D-Ala-Ala、Val-Ala、D-Val-Ala、D-Ala-Pro或D-Ala-tBu-Gly (更特定而言,A為Ala-Ala-Ala、Ala-D-Ala-Ala、Ala-Ala、D-Ala-Ala、Val-Ala、D-Val-Ala、D-Ala-Pro或D-Ala-tBu-Gly)且
D
1由下式表示:
。
在某些實施例中,本發明之結合物可經由在由變數A表示之肽部分處的鍵裂解繼之以-NH-CR
1R
2-S-部分之自分解以釋放具有硫醇基之游離細胞毒性劑來釋放游離細胞毒性劑(例如類美登素),該細胞毒性劑可進一步經甲基化。
因此,在第三實施例中,本發明係有關一種式(V)化合物:
(V),
其中:
L
1為間隔子;
Z
0為H或Me,前提條件為當Z
0為H時,L
1不為-C(=O)-(CH
2)
q-或-C(=O)-CH
2-CH
2-C(CH
3)
2-,其中q為1至3之整數;且當Z
0為Me時,L
1不為-C(=O)-(CH
2)
2-或-C(=O)-CH
2-CH
2-C(CH
3)
2-;且D-L
1-SH為細胞毒性劑。
在第32特定實施例中,L
1為-L
1'-C(=O)-;且L
1'為伸烷基或伸環烷基。更特定而言,L
1'為C
1-10伸烷基。在另一更特定實施例中,L
1'為C
1-20伸烷基
在第33特定實施例中,L
1為-CR
3R
4-(CH
2)
1-8-C(=O)-;且R
3及R
4各獨立地為H或Me。
在第34特定實施例中,L
1為-CR
3R
4-(CH
2)
2-5-C(=O)-或-CR
3R
4-(CH
2)
3-5-C(=O)-。在一更特定實施例中,R
3與R
4均為Me。在另一更特定實施例中,R
3與R
4均為H。
在第35特定實施例中,L
1為-(CH
2)
2-10-C(=O)-。在一更特定實施例中,L
1為-(CH
2)
4-6-C(=O)-。在另一更特定實施例中,L
1為-(CH
2)
5-C(=O)-。在另一更特定實施例中,L
1為-(CH
2)
6-C(=O)-。在另一更特定實施例中,L
1為-(CH
2)
7-C(=O)-。在另一更特定實施例中,L
1為-(CH
2)
8-C(=O)-。在另一更特定實施例中,L
1為-(CH
2)
10-C(=O)-。在另一更特定實施例中,L
1為-(CH
2)
15-C(=O)-。
本發明之結合物作為治療劑之有效性取決於適當細胞結合劑之謹慎選擇。細胞結合劑可屬於目前已知或變得已知之任何種類,包括肽及非肽。通常,此等細胞結合劑可為抗體(諸如多株抗體及單株抗體,尤其單株抗體)、淋巴介質、激素、生長因子、維生素(諸如葉酸等,其可結合於其細胞表面受體,例如葉酸受體)、營養物運送分子(諸如轉鐵蛋白)或任何其他細胞結合分子或物質。
適當細胞結合劑之選擇為部分視所要靶向之特定細胞群體而定的選擇問題,但在許多(但並非所有)情況下,若適當之人類單株抗體為可獲得的,則人類單株抗體為良好選擇。舉例而言,單株抗體MY9為鼠IgG
1抗體,其特異性結合於CD33抗原(J.D. Griffin等人
, Leukemia Res., 8:521 (1984)),且若如在急性骨髓性白血病(AML)中目標細胞表現CD33,則可使用。
在某些實施例中,細胞結合劑不為蛋白質。舉例而言,在某些實施例中,細胞結合劑可為結合於維生素受體(諸如細胞表面受體)之維生素。在此方面,維生素A結合於視黃醇結合蛋白(RBP)以形成複合物,該複合物又以高親和力結合STRA6受體且增加維生素A攝入。在另一實例中,葉酸/葉酸鹽/維生素B
9以高親和力結合細胞表面葉酸受體(FR),例如FRα。葉酸或結合於FRα之抗體可用於靶向表現於卵巢及其他腫瘤上之葉酸受體。此外,維生素D及其類似物結合於維生素D受體。
在其他實施例中,細胞結合劑為蛋白質或多肽或包含蛋白質或多肽之化合物,包括抗體、非抗體蛋白質或多肽。較佳地,蛋白質或多肽包含一或多個具有側鏈-NH
2基團之Lys殘基。Lys側鏈-NH
2基團可共價鍵聯至雙官能交聯劑,該等雙官能交聯劑又鍵聯至本發明之二聚體化合物,由此使細胞結合劑結合至本發明之二聚體化合物。各基於蛋白質之細胞結合劑可含有可用於通過雙官能交聯劑鍵聯本發明之化合物的多個Lys側鏈-NH
2基團。
在一些實施例中,結合於骨髓細胞之GM-CSF (一種配位體/生長因子)可用作來自急性骨髓性白血病之患病細胞的細胞結合劑。結合於活化T細胞之IL-2可用於預防移植排斥、治療及預防移植物抗宿主疾病及治療急性T細胞白血病。結合於黑素細胞之MSH可用於治療黑素瘤,針對黑素瘤之抗體亦可使用。表皮生長因子可用於靶向鱗狀癌症,諸如肺癌及頭頸癌及牙齦鱗狀細胞癌瘤。體抑素可用於靶向神經母細胞瘤及其他腫瘤類型。雌激素(或雌激素類似物)可用於靶向乳癌。雄激素(或雄激素類似物)可用於靶向睪丸。
在某些實施例中,細胞結合劑可為淋巴介質、激素、生長因子、群落刺激因子或營養物運送分子。
在某些實施例中,細胞結合劑為抗體模擬物,諸如錨蛋白重複蛋白、生替素(Centyrin)或阿德奈汀(adnectin)/單體(monobody)。
在其他實施例中,細胞結合劑為特異性結合於目標細胞之抗體、單鏈抗體、抗體片段、特異性結合於目標細胞之單株抗體、單鏈單株抗體、單株抗體片段(或「抗原結合部分」)、特異性結合於目標細胞之嵌合抗體、嵌合抗體片段(或「抗原結合部分」)、特異性結合於目標細胞之結構域抗體(例如sdAb)或結構域抗體片段。
在某些實施例中,細胞結合劑為人類化抗體、人類化單鏈抗體或人類化抗體片段(或「抗原結合部分」)。在一特定實施例中,人類化抗體為huMy9-6或另一相關抗體,其描述於美國專利第7,342,110號及第7,557,189號中。在另一特定實施例中,人類化抗體為WO2011/106528及美國專利第8557966號、第9133275號、第9598490號、第9657100號、第9670278號、第9670279號及第9670280號中所描述之抗葉酸受體抗體。所有此等申請案之教示以全文引用之方式併入本文中。
在某些實施例中,細胞結合劑為表面整修抗體、表面整修單鏈抗體、表面整修抗體片段(或「抗原結合部分」)或雙特異性抗體。
在某些實施例中,細胞結合劑為微型抗體、avibody、雙功能抗體、三抗體、四功能抗體、奈米抗體、抗體前藥、結構域抗體或單抗體(unibody)。
換言之,示例性細胞結合劑可包括特異性結合於目標細胞之抗體、單鏈抗體、抗體片段、特異性結合於目標細胞之單株抗體、單鏈單株抗體、單株抗體片段、特異性結合於目標細胞之嵌合抗體、嵌合抗體片段、雙特異性抗體、特異性結合於目標細胞之結構域抗體、結構域抗體片段、干擾素(例如α、β、γ)、淋巴介質(例如IL-2、IL-3、IL-4及IL-6)、激素(例如胰島素、促甲狀腺素釋放激素(TRH)、促黑素細胞激素(MSH)及類固醇激素(例如雄激素及雌激素))、維生素(例如葉酸)、生長因子(例如EGF、TGF-α、FGF、VEGF)、群落刺激因子、營養物運送分子(例如轉鐵蛋白;參見O'Keefe等人(1985)
J. Biol. Chem. 260:932-937,其以引用之方式併入本文中)、生替素 (基於III型纖連蛋白(FN3)重複之共同序列的蛋白質骨架;參見美國專利公開案2010/0255056、2010/0216708及2011/0274623,其以引用之方式併入本文中)、錨蛋白重複蛋白(例如經設計之錨蛋白重複蛋白,稱為DARPin;參見美國專利公開案第2004/0132028號、第2009/0082274號、第2011/0118146號及第2011/0224100號,其以引用之方式併入本文中,且亦參見C. Zahnd等人,
Cancer Res.(2010) 70:1595-1605;Zahnd等人,
J. Biol. Chem.(2006) 281(46):35167-35175;及Binz, H.K., Amstutz, P.及Pluckthun, A.,
Nature Biotechnology(2005) 23:1257-1268,其以引用之方式併入本文中)、錨蛋白樣重複蛋白或合成肽(參見例如美國專利公開案第2007/0238667號;美國專利第7,101,675號;WO 2007/147213;及WO 2007/062466,以引用之方式併入本文中)、阿德奈汀 (一種纖連蛋白結構域骨架蛋白;參見美國專利公開案第2007/0082365號;第2008/0139791號,其以引用之方式併入本文中)、Avibody (包括雙功能抗體、三功能抗體及四功能抗體;參見美國公開案第2008/0152586號及第2012/0171115號)、雙重受體重靶向(DART)分子(P.A. Moore等人,
Blood, 2011; 117(17):4542-4551;Veri MC等人,
Arthritis Rheum, 2010年3月30日; 62(7):1933-43;Johnson S等人
, J. Mol. Biol.,2010年4月9日;399(3):436-49)、細胞穿透超荷蛋白(
Methods in Enzymol.502, 293-319 (2012)及其他細胞結合分子或物質。
在某些實施例中,細胞結合劑可為配位體,其結合於目標細胞上之部分,諸如細胞表面受體。舉例而言,配位體可為生長因子或其結合於生長因子受體之片段;或可為細胞因子或其結合於細胞因子受體之片段。在某些實施例中,生長因子受體或細胞因子受體為細胞表面受體。
在細胞結合劑為抗體或其抗原結合部分(包括抗體衍生物)或某些抗體模擬物之某些實施例中,CBA可結合於目標細胞上之配位體,諸如細胞表面配位體,包括細胞表面受體。
特異性示例性抗原或配位體可包括腎素;生長激素(例如人類生長激素及牛生長激素);生長激素釋放因子;副甲狀腺激素;促甲狀腺激素;脂蛋白;α-1-抗胰蛋白酶;胰島素A-鏈;胰島素B-鏈;胰島素原;促卵泡激素;降鈣素;促黃體生成激素;胰高血糖素;凝血因子(例如因子vmc、因子IX、組織因子及馮威裡氏因子(von Willebrands factor));抗凝血因子(例如蛋白質C);心房利鈉因子;肺臟表面活性劑;纖維蛋白溶酶原活化劑(例如尿激酶、人類尿液或組織型纖維蛋白溶酶原活化劑);鈴蟾素;凝血酶;造血生長因子;腫瘤壞死因子-α及腫瘤壞死因子-β;腦啡肽酶;RANTES (亦即活化調節之正常T細胞表現及分泌之因子(regulated on activation normally T-cell expressed and secreted));人類巨噬細胞炎性蛋白-1-α;血清白蛋白(人類血清白蛋白);穆勒氏抑制物質(Muellerian-inhibiting substance);鬆弛肽A-鏈;鬆弛肽B-鏈;鬆弛素原;小鼠促性腺素相關肽;微生物蛋白(β-內醯胺酶);DNA酶;IgE;細胞毒性T-淋巴細胞相關抗原(例如CTLA-4);抑制素;激活素;血管內皮生長因子;激素或生長因子受體;蛋白質A或D;類風濕因子;神經營養因子(例如骨骼衍生神經營養因子、神經營養素-3、神經營養素-4、神經營養素-5或神經營養素-6)、神經生長因子(例如NGF-β);血小板衍生生長因子;纖維母細胞生長因子(例如aFGF及bFGF);纖維母細胞生長因子受體2;表皮生長因子;轉型生長因子(例如TGF-α、TGF-β1、TGF-β2、TGF-β3、TGF-β4及TGF-β5);胰島素樣生長因子-I及胰島素樣生長因子-II;des(1-3)-IGF-I (腦IGF-I);胰島素樣生長因子結合蛋白;黑素轉鐵蛋白;CA6、CAK1、CALLA、CAECAM5、GD3;FLT3;PSMA;PSCA;MUC1;STEAP;CEA;TENB2;EphA受體、EphB受體;葉酸受體;FOLR1;間皮素;畸胎瘤衍生生長因子;α
vβ
6;整合素;VEGF;VEGFR;EGFR;FGFR3;LAMP1、p-鈣黏蛋白、轉鐵蛋白受體;IRTA1;IRTA2;IRTA3;IRTA4;IRTA5;CD蛋白(例如CD2、CD3、CD4、CD6、CD8、CD11、CD14、CD19、CD20、CD21、CD22、CD26、CD28、CD30、CD33、CD36、CD37、CD38、CD40、CD44、CD52、CD55、CD56、CD59、CD70、CD79、CD80、CD81、CD103、CD105、CD123、CD134、CD137、CD138及CD152)、一或多種腫瘤相關抗原或細胞表面受體(參見美國公開案第2008/0171040號或美國公開案第2008/0305044號,其以全文引用之方式併入本文中);紅血球生成素;骨生成誘導因子;免疫毒素;骨形態發生蛋白;干擾素(例如干擾素-α、干擾素-β及干擾素-γ);群落刺激因子(例如M-CSF、GM-CSF及G-CSF);白介素(例如IL-1至IL-10);超氧化物歧化酶;T細胞受體;表面膜蛋白;衰變加速因子;病毒抗原(例如HIV包膜之一部分);轉運蛋白、歸巢受體;地址素;調控蛋白;整合素(例如CD11a、CD11b、CD11c、CD18、ICAM、VLA-4及VCAM);腫瘤相關抗原(例如HER2、HER3及HER4受體);內皮素;c-Met;c-kit;1GF1R;PSGR;NGEP;PSMA;PSCA;TMEFF2;LGR5;B7H4;TROP-2、DLL-3、CDH6、AXL、SLITRK6、ENPP3、BCMA、組織因子、CD352及以上列舉之多肽中之任一者的片段。
如本文所用,術語「
抗體」包括免疫球蛋白(Ig)分子。在某些實施例中,抗體為全長抗體,其包含四條多肽鏈,亦即藉由二硫鍵相互連接之兩條重鏈(HC)及兩條輕鏈(LC)。各重鏈包含重鏈可變區(HCVR或VH)及重鏈恆定區(CH)。重鏈恆定區包含三個結構域:CH1、CH2及CH3。各輕鏈包含輕鏈可變區(LCVR或VL)及輕鏈恆定區,其包含一個結構域CL。VH及VL區可進一步再分成具有高變異性之區,稱為互補決定區(CDR)。此類區中散佈有較保守之構架區(FR)。各VH及VL由三個CDR及四個FR組成,自胺基端至羧基端按以下順序排列∶FR1、CDR1、FR2、CDR2、FR3、CDR3及FR4。
在某些實施例中,抗體為IgG、IgA、IgE、IgD或IgM。在某些實施例中,抗體為IgG1、IgG2、IgG3或IgG4;或IgA1或IgA2。
在某些實施例中,細胞結合劑為單株抗體之「抗原結合部分」,其與抗體(諸如美國專利第7,342,110號及第7,557,189號中所描述之huMy9-6或其相關抗體;美國專利第8557966號、第9133275號、第9598490號、第9657100號、第9670278號、第9670279號及第9670280號及WO2011106528中所描述之huMov19或其相關抗體,該等專利全部以引用之方式併入本文中)共同擁有對抗原結合而言重要之序列。
如本文所用,術語抗體之「
抗原結合部分」(或有時可互換地稱為「抗體片段」)包括抗體之保留特異性結合於抗原之能力的一或多個片段。已證實抗體之抗原結合功能可由全長抗體之某些片段來執行。術語抗體之「抗原結合部分」內所涵蓋之結合片段的實例包括(但不限於):(i)
Fab片段,一種由VL、VH、CL及CH1結構域組成之單價片段(例如由木瓜蛋白酶消化之抗體產生三個片段:兩個抗原結合Fab片段及一個不結合抗原之Fc片段);(ii)
F(ab')
2 片段,一種包含在鉸鏈區由二硫鍵鍵聯之兩個Fab片段的二價片段(例如由胃蛋白酶消化之抗體產生兩個片段:二價抗原結合F(ab')
2片段及不結合抗原之pFc'片段)及其相關
F(ab')單價單元;(iii)
Fd片段,其由VH及CH1結構域組成(亦即包括於Fab中之重鏈部分);(iv)
Fv片段,其由抗體之單個臂之VL及VH結構域組成,及相關
二硫鍵聯 Fv;(v)
dAb(結構域抗體)
或 sdAb(單域抗體)片段(Ward等人, Nature 341:544-546, 1989),其由VH結構域組成;及(vi)分離之互補決定區(
CDR)。在某些實施例中,抗原結合部分為
sdAb(單域抗體)。
在某些實施例中,抗原結合部分亦包括某些工程改造或重組衍生物(或「
衍生抗體」),其除了可能不存在於天然存在之抗體中的元素或序列之外亦包括抗體之保留特異性結合於抗原之能力的一或多個片段。
舉例而言,雖然Fv片段之兩個結構域VL及VH由單獨基因編碼,但其可使用標準重組方法藉由合成連接子連接,該合成連接子使其能夠成為VL及VH區配對以形成單價分子之單一蛋白質鏈(稱為單鏈Fv (
scFv);參見例如Bird等人Science 242:423-426, 1988;及Huston等人, Proc. Natl. Acad. Sci. USA 85:5879-5883, 1988)。
在本文所描述之所有實施例中,scFv之N-末端可為VH結構域(亦即N-VH-VL-C),或VL結構域(亦即N-VL-VH-C)。
可藉由鍵聯兩個scFv來對二價(或雙價)工程改造出單鏈可變片段(
di-scFv、
bi-scFv)。此舉產生具有兩個VH區及兩個VL區之單一肽鏈,從而產生串聯scFv (
tascFv)。可類似地藉由以頭尾相接方式鍵聯三個或更多個scFv產生更高程度之串聯重複序列,諸如tri-scFv。
在某些實施例中,可通過連接子肽使scFv鍵聯,該等連接子肽對於兩個可變區摺疊在一起而言太短(約五個胺基酸),從而迫使scFv二聚化,且形成
雙功能抗體(參見例如Holliger等人, Proc. Natl. Acad. Sci. USA 90:6444-6448, 1993;Poljak等人, Structure 2:1121-1123, 1994)。雙功能抗體可為雙特異性或單特異性的。雙功能抗體已顯示具有比對應scFv低高達40倍之解離常數,亦即對靶標具有高得多的親和力。
再更短之連接子(一個或兩個胺基酸)使得形成三聚體,或所謂的
三功能抗體或
三抗體。亦已類似地產生
四功能抗體。其對其靶標展現甚至比雙功能抗體更高之親和力。雙功能抗體、三功能抗體及四功能抗體有時統稱為「
AVIBODY
TM 」細胞結合劑(或簡稱為「AVIBODY」)。換言之,具有兩個、三個或四個靶標結合區(TBR)之AVIBODY通常稱為雙功能抗體、三功能抗體及四功能抗體。關於細節參見例如美國公開案第2008/0152586號及第2012/0171115號,該等公開案之全部教示以引用之方式併入本文中。
所有此等形式可由對兩個或更多個不同抗原具有特異性之可變片段構成,在此情況下其為雙特異性或多特異性抗體類型。舉例而言,某些雙特異性串聯di-scFv稱為雙特異性T細胞銜接器(
BiTE)。
在某些實施例中,串聯scFv或雙功能抗體/三功能抗體/四功能抗體中之各scFv可具有相同或不同的結合特異性,且各可獨立地具有N端VH或N端VL。
單鏈Fv (scFv)亦可融合至Fc部分,諸如人類IgG Fc部分以獲得IgG樣特性,然而其仍由單一基因編碼。由於在哺乳動物中瞬時製備此類
scFv-Fc蛋白可輕易實現毫克量,故此衍生抗體形式特別適合用於許多研究應用。
Fcab為自抗體之Fc恆定區工程改造的抗體片段。Fcab可表現為可溶性蛋白,或其可經工程改造回到全長抗體,諸如IgG,以形成
mAb2。
mAb2為具有Fcab代替正常Fc區之全長抗體。使用此等其他結合位點,mAb2雙特異性單株抗體可同時結合兩個不同靶標。
在某些實施例中,工程改造之抗體衍生物具有藉由移除被認為對功能而言不必要的結構域而產生的減小尺寸之抗原結合Ig衍生重組蛋白(「微型化」全尺寸mAb)。最佳實例之一為SMIP。
小模組化免疫藥物或
SMIP為主要由抗體之部分(免疫球蛋白)構建之人造蛋白質,且旨在用作藥物。SMIP具有與抗體類似之生物半衰期,但比抗體更小且因此可具有更佳之組織穿透特性。SMIP為單鏈蛋白質,其包含一個結合區、一個作為連接物之鉸鏈區及一個效應子結構域。結合區包含經修飾單鏈可變片段(scFv),且蛋白質之其餘部分可由抗體(諸如IgG1)之Fc (諸如CH2及CH3作為效應子結構域)及鉸鏈區構築。經基因修飾之細胞產生呈抗體樣二聚體形式之SMIP,其比真正的抗體小約30%。
此類經工程改造之微型化抗體之另一實例為「
單抗體」,其中鉸鏈區已自IgG4分子移除。IgG4分子為不穩定的且可使輕-重鏈異二聚體彼此轉換。鉸鏈區之缺失完全阻止重鏈-重鏈配對,留下高度特異性之單價輕/重異二聚體,同時保留Fc區以確保在活體內之穩定性及半衰期。
(
sdAb,包括但不限於彼等由Ablynx稱為
奈米抗體之單域抗體)為由單一單聚可變抗體結構域組成之抗體片段。如整個抗體一般,其能夠選擇性結合於特定抗原,但因其分子量僅為12-15 kDa而小得多。在某些實施例中,單域抗體係工程改造自重鏈抗體(hcIgG)。第一種此類sdAb係基於存在於駱駝中之稱為V
HH片段之hcIgG而工程改造的。在某些實施例中,單域抗體係使用V
NAR片段工程改造自IgNAR (「免疫球蛋白新抗原受體」,參見下文)。軟骨魚類(諸如鯊魚)具有此類重鏈IgNAR抗體。在某些實施例中,藉由將來自普通免疫球蛋白(IgG) (諸如來自人類或小鼠之彼等免疫球蛋白)之二聚體可變域分割成單體來工程改造出sdAb。在某些實施例中,奈米抗體係衍生自重鏈可變域。在某些實施例中,奈米抗體係衍生自輕鏈可變域。在某些實施例中,藉由針對目標抗原結合劑對單域重鏈序列(例如人類單域HC)之文庫進行篩選來獲得sdAb。
單一可變新抗原受體結構域抗體片段(
V
NAR 或
V
NAR 結構域)係衍生自軟骨魚類(例如鯊魚)免疫球蛋白新抗原受體抗體(
IgNAR)。作為最小之已知基於免疫球蛋白之蛋白質骨架之一,此類單域蛋白質展示有利之尺寸及隱藏之抗原決定基識別特性。成熟IgNAR抗體由一個可變新抗原受體(V
NAR)結構域及五個恆定新抗原受體(C
NAR)結構域之均二聚體組成。此分子為高度穩定的,且具有高效之結合特徵。其固有穩定性可能係歸因於以下兩者:(i)基礎Ig骨架,其與存在於鼠抗體中之習知抗體VH及VL結構域相比呈現大量帶電荷且親水之表面暴露殘基;及(ii)包括環間二硫橋之互補決定區(CDR)環中之穩定結構特徵,及環內氫鍵之模式。
微型抗體為包含scFv之經工程改造之抗體片段,該scFv鍵聯至CH結構域,諸如CH3γ1 (IgG1之CH3結構域)或CH4ε (IgE之CH4結構域)。舉例而言,已使對癌胚抗原(CEA)具特異性之scFv鍵聯至CH3γ1以形成微型抗體,其先前已經證實具有優良腫瘤靶向,並且在活體內快速清除(Hu等人,
Cancer Res.56:3055-3061, 1996)。scFv可具有N端VH或VL。該鍵聯可為短肽(例如二胺基酸連接子,諸如ValGlu),其產生非共價、無鉸鏈微型抗體。或者,該鍵聯可為IgG1鉸鏈及GlySer連接子肽,其產生共價、鉸鏈-微型抗體。
天然抗體為單特異性的,但為二價的,因為其表現兩個相同抗原結合域。相比之下,在某些實施例中,某些經工程改造之抗體衍生物為雙特異性或多特異性分子,具有兩個或更多個不同抗原結合域,其各自具有不同的靶標特異性。雙特異性抗體可藉由融合各自具有不同特異性之兩個產生抗體之細胞來產生。此等「四體瘤」產生多個分子種類,因為兩個不同輕鏈及兩個不同重鏈在四體瘤中以多個組態自由重組。自彼時起,已使用多種技術(參見上文)產生了雙特異性Fab、scFv及全尺寸mAb。
雙重可變域免疫球蛋白(
DVD-Ig)蛋白質為一類雙重特異性IgG,其同時靶向兩個抗原/抗原決定基(DiGiammarino等人,
Methods Mol. Biol.,899:145-56, 2012)。該分子以類似於習知IgG之組態含有Fc區及恆定區。然而,DVD-Ig蛋白質為獨特的,因為分子之各個臂含有兩個可變域(VD)。臂內之VD為串聯連接的且可具有不同結合特異性。
亦可藉由例如表現具有兩個不同Fab及Fc之雙特異性抗體來產生三特異性抗體衍生物分子。一個實例為小鼠IgG2a抗Ep-CAM、大鼠IgG2b抗CD3四體瘤,稱為BiUII,其被認為容許表現Ep-CAM之腫瘤細胞、表現CD3之T細胞及表現FCγRI之巨噬細胞共定位,因此加強免疫細胞之共刺激及抗腫瘤功能。
前抗體抗體前藥為完全重組、掩蔽之單株抗體,其在健康組織中保持惰性,但特定地在疾病微環境中為活化的(例如通過由在疾病微環境中富集或具特異性之蛋白酶進行蛋白酶裂解)。參見Desnoyers等人,
Sci. Transl. Med.,5:207, 144, 2013。類似遮蔽技術可用於本文所描述之抗體或其抗原結合部分中之任一者。
內抗體為已經修飾用於細胞內定位、在細胞內工作以結合於細胞內抗原之抗體。內抗體可保留在細胞質中,或可具有核定位信號,或可具有KDEL序列用於ER靶向。內抗體可為單鏈抗體(scFv)、經修飾具有超穩定性之免疫球蛋白VL結構域、經選擇對更具還原性之細胞內環境具抗性或與麥芽糖結合蛋白或其他穩定細胞內蛋白質表現為融合蛋白之抗體。此類最佳化改善內抗體之穩定性及結構,且可對本文所描述之抗體或其抗原結合部分中之任一者具有一般適用性。
本發明之抗原結合部分或衍生抗體與衍生/工程改造出它們之抗體相比可具有實質上相同或一致之(1)輕鏈及/或重鏈CDR3區;(2)輕鏈及/或重鏈CDR1、CDR2及CDR3區;或(3)輕鏈及/或重鏈區。此等區內之序列可含有保守胺基酸取代,包括CDR區內之取代。在某些實施例中,存在不超過1、2、3、4或5個保守取代。在一替代方案中,抗原結合部分或衍生抗體具有與衍生/工程改造出它們之抗體至少約90%、95%、99%或100%一致之輕鏈區及/或重鏈區。此等抗原結合部分或衍生抗體可與該抗體相比對目標抗原具有實質上相同之結合特異性及/或親和力。在某些實施例中,抗原結合部分或衍生抗體之K
d及/或
k 解離 值在本文所描述之抗體的10倍(更高或更低)、5倍(更高或更低)、3倍(更高或更低)或2倍(更高或更低)以內。
在某些實施例中,可自完全人類抗體、人類化抗體或嵌合抗體衍生/工程改造出抗原結合部分或衍生抗體,且可根據任何領域識別之方法來產生。
單株抗體技術允許製備呈特異性單株抗體形式之極具特異性之細胞結合劑。此項技術中特別熟知的為如下用於形成單株抗體的技術,該等單株抗體係藉由用諸如以下之相關抗原對小鼠、大鼠、倉鼠或任何其他哺乳動物進行免疫而產生:完整目標細胞、自目標細胞分離之抗原、全病毒、減毒全病毒及諸如病毒外殼蛋白之病毒蛋白。亦可使用經敏化之人類細胞。形成單株抗體之另一方法為使用scFv (單鏈可變區),尤其人類scFv之噬菌體文庫(參見例如Griffiths等人, 美國專利第5,885,793號及第5,969,108號;McCafferty等人, WO 92/01047;Liming等人, WO 99/06587)。此外,亦可使用美國專利第5,639,641號中所揭示之表面整修抗體,亦可使用嵌合抗體及人類化抗體。
細胞結合劑亦可為來源於噬菌體展示(參見例如Wang等人
, Proc. Natl. Acad. Sci. USA(2011) 108(17), 6909-6914)或肽文庫技術(參見例如Dane等人
, Mol. Cancer. Ther.(2009) 8(5):1312-1318)之肽。
在某些實施例中,本發明之CBA亦包括抗體模擬物,諸如DARPin、親和體、親和蛋白(affilin)、affitin、抗運載蛋白(anticalin)、高親和性聚合體(avimer)、Fynomer、庫尼茨(Kunitz)結構域肽、單體、奈米裝配體(nanofitin)、Bicycles
®肽(諸如US2014/0163201 (以引用之方式併入本文中)中所描述之彼等)及噴他林,諸如摘要3674, 2015年AACR第106屆年會; 2015年4月18-22日; Philadelphia, PA (以引用之方式併入本文中)中所描述之彼等。
如本文所用,術語「
DARPin」及「
( 經設計 ) 錨蛋白重複蛋白」可互換地用於指典型地展現優先(有時為特異性)靶標結合之某些經基因工程改造之抗體模擬蛋白。該靶標可為蛋白質、碳水化合物或其他化學實體,且結合親和力可能相當高。DARPin可衍生自含有天然錨蛋白重複序列之蛋白質,且較佳由此等蛋白質之至少三個、通常四個或五個錨蛋白重複基元(典型地各錨蛋白重複基元中約33個殘基)組成。在某些實施例中,DARPin含有約四個或五個重複序列,且分別可具有約14或18 kDa之分子量。可在DNA層面產生多樣性超過10
12個變異體之具有隨機化潛在靶標相互作用殘基之DARPin的文庫,用於使用諸如核糖體展示或信號識別粒子(SRP)噬菌體展示之多種技術來選擇以皮莫耳親和力及特異性結合所需靶標(例如充當受體促效劑或拮抗劑、反向促效劑、酶抑制劑或簡單目標蛋白質結合劑)之DARPin。關於DARPin製備參見例如美國專利公開案第2004/0132028號、第2009/0082274號、第2011/0118146號及第2011/0224100號、WO 02/20565及WO 06/083275 (其全部教示內容以引用之方式併入本文中),且亦參見C. Zahnd等人(2010)
Cancer Res.,70:1595-1605;Zahnd等人(2006)
J. Biol. Chem., 281(46):35167-35175;及Binz, H.K., Amstutz, P.及Pluckthun, A. (2005)
Nature Biotechnology, 23:1257-1268(全部以引用之方式併入本文中)。關於相關錨蛋白樣重複蛋白或合成肽亦參見美國專利公開案第2007/0238667號;美國專利第7,101,675號;WO 2007/147213;及WO 2007/062466 (其全部教示內容以引用之方式併入本文中)。
親和體分子為經工程改造以高親和力結合於大量目標蛋白質或肽之小蛋白質,因此模仿單株抗體。親和體由具有58個胺基酸之三個α螺旋組成且具有約6 kDa之莫耳質量。其已顯示可承受高溫(90℃)或酸性及鹼性條件(pH 2.5或pH 11),且已自原初文庫選擇獲得親和力降至亞萘莫耳範圍之結合劑,且已在親和力成熟之後獲得具有皮莫耳親和力之結合劑。在某些實施例中,親和體結合至弱親電子劑以共價結合於靶標。
單體(亦稱為
阿德奈汀),為能夠結合於抗原之經基因工程改造之抗體模擬蛋白。在某些實施例中,單體由94個胺基酸組成且具有約10 kDa之分子量。其係基於人類纖連蛋白之結構,更特定而言基於其第十個細胞外III型結構域,其具有類似於抗體可變域之結構,七個β摺疊形成桶狀且每一側之三個暴露之環對應於三個互補決定區。藉由對環BC (第二個與第三個β摺疊之間)及FG (第六個與第七個摺疊之間)進行修飾可定製對不同蛋白質具有特異性之單體。
三抗體為基於小鼠及人類軟骨基質蛋白(CMP)之C端捲曲螺旋區設計的自組裝抗體模擬物,其自組裝成平行三聚體複合物。其為藉由使特定靶標結合部分與來源於CMP之三聚結構域融合而形成的高度穩定之三聚體靶向配位體。所得融合蛋白可高效地自組裝成具有高穩定性之明確界定之平行均三聚體。三聚體靶向配位體之表面電漿子共振(SPR)分析展示與對應單體相比顯著增強之靶標結合強度。細胞結合研究證實此類三抗體對其相應受體具有優良結合強度。
生替素為另一抗體模擬物,其可使用基於共同FN3結構域序列之構架構建之文庫來獲得(Diem等人,
Protein Eng. Des. Sel., 2014)。此文庫在FN3結構域之C-鏈、CD-環、F-鏈及FG-環內採用多樣化之位置,且可針對特定靶標對高親和力生替素變異體加以選擇。
在一些實施例中,細胞結合劑為抗葉酸受體抗體。更特定而言,抗葉酸受體抗體為人類化抗體或其抗原結合片段,其特異性結合人類葉酸受體1 (亦稱為葉酸受體α (FR -α))。除非另外指出,否則如本文所用,術語「人類葉酸受體1」、「FOLR1」或「葉酸受體α (FR-α)」係指任何天然人類FOLR1。因此,所有此等術語均可指如本文中所指示之蛋白質或核酸序列。術語「FOLR1」涵蓋「全長」、「未加工之FOLR1」以及由細胞內之加工產生的任何形式之FOLR1。FOLR1抗體包含:(a)包含GYFMN (SEQ ID NO: 4)之重鏈CDR1、包含RIHPYDGDTFYNQXaa
1FXaa
2Xaa
3(SEQ ID NO: 5)之重鏈CDR2及包含YDGSRAMDY (SEQ ID NO: 6)之重鏈CDR3;及(b)包含KASQSVSFAGTSLMH (SEQ ID NO: 7)之輕鏈CDR1、包含RASNLEA (SEQ ID NO: 8)之輕鏈CDR2及包含QQSREYPYT (SEQ ID NO: 9)之輕鏈CDR3;其中Xaa
1係選自K、Q、H及R;Xaa
2係選自Q、H、N及R;且Xaa
3係選自G、E、T、S、A及V。較佳地,重鏈CDR2序列包含RIHPYDGDTFYNQKFQG (SEQ ID NO: 10)。
在另一實施例中,抗葉酸受體抗體為人類化抗體或其抗原結合片段,其特異性結合包含具有以下胺基酸序列之重鏈的人類葉酸受體1:QVQLVQSGAEVVKPGASVKISCKASGYTFT
GYFMNWVKQSPGQSLEWIG
RIHPYDGDTFYNQKFQGKATLTVDKSSNTAHMELLSLTSEDFAVYYCTR
YDGSRAMDYWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG (SEQ ID NO: 11)。在一些實施例中,重鏈胺基酸序列在SEQ ID NO:11之最後的甘胺酸之後具有C端離胺酸。
在另一實施例中,抗葉酸受體抗體為由質體DNA編碼之人類化抗體或其抗原結合片段,該質體DNA於2010年4月7日保藏在ATCC且具有ATCC保藏號PTA-10772及PTA-10773或10774。在一個實施例中,抗葉酸受體抗體包含由具有ATCC保藏號PTA-10772之質體DNA編碼之重鏈HC及由具有ATCC保藏號PTA-10773或10774之質體DNA編碼之輕鏈LC。在另一實施例中,抗葉酸受體抗體包含由具有ATCC保藏號PTA-10772之質體DNA編碼之重鏈HC及由具有ATCC保藏號PTA-10773之質體DNA編碼之輕鏈LC。在另一實施例中,抗葉酸受體抗體包含由具有ATCC保藏號PTA-10772之質體DNA編碼之重鏈HC及由具有ATCC保藏號PTA-10774之質體DNA編碼之輕鏈LC。
在另一實施例中,抗葉酸受體抗體為人類化抗體或其抗原結合片段,其特異性結合包含具有以下胺基酸序列之輕鏈的人類葉酸受體1:DIVLTQSPLSLAVSLGQPAIISC
KASQSVSFAGTSLMHWYHQKPGQQPRLLIY
RASNLEAGVPDRFSGSGSKTDFTLNISPVEAEDAATYYC
QQSREYPYTFGGGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 12);或DIVLTQSPLSLAVSLGQPAIISC
KASQSVSFAGTSLMHWYHQKPGQQPRLLIY
RASNLEAGVPDRFSGSGSKTDFTLTISPVEAEDAATYYC
QQSREYPYTFGGGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 13)。
在另一實施例中,抗葉酸受體抗體為人類化抗體或其抗原結合片段,其特異性結合包含具有SEQ ID NO: 11之胺基酸序列的重鏈及具有SEQ ID NO: 12或SEQ ID NO: 13之胺基酸序列的輕鏈的人類葉酸受體1。較佳地,抗體包含具有SEQ ID NO: 11之胺基酸序列的重鏈及具有SEQ ID NO: 13之胺基酸序列的輕鏈(hu FOLR1)。在一些實施例中,hu FOLR1 (huMov19)之重鏈序列在SEQ ID NO:11之最後的甘胺酸之後包含C端離胺酸。
在另一實施例中,抗葉酸受體抗體為人類化抗體或其抗原結合片段,其特異性結合人類葉酸受體1,且包含與以下序列至少約90%、95%、99%或100%一致之重鏈可變域:QVQLVQSGAEVVKPGASVKISCKASGYTFTGYFMNWVKQSPGQSLEWIGRIHPYDGDTFYNQKFQGKATLTVDKSSNTAHMELLSLTSEDFAVYYCTRYDGSRAMDYWGQGTTVTVSS (SEQ ID NO: 14),及與以下序列至少約90%、95%、99%或100%一致之輕鏈可變域:DIVLTQSPLSLAVSLGQPAIISCKASQSVSFAGTSLMHWYHQKPGQQPRLLIYRASNLEAGVPDRFSGSGSKTDFTLNISPVEAEDAATYYCQQSREYPYTFGGGTKLEIKR (SEQ ID NO: 15);或DIVLTQSPLSLAVSLGQPAIISCKASQSVSFAGTSLMHWYHQKPGQQPRLLIYRASNLEAGVPDRFSGSGSKTDFTLTISPVEAEDAATYYCQQSREYPYTFGGGTKLEIKR (SEQ ID NO: 16)。
在另一實施例中,抗葉酸受體抗體為huMov19或M9346A或M抗體(參見例如美國專利第8,709,432號、第8,557,966號、第9133275號、第9598490號、第9657100號、第9670278號、第9670279號及第9670280及WO2011106528,其全部以引用之方式併入本文中)。
在另一實施例中,細胞結合劑為抗EGFR抗體或其抗體片段。在一些實施例中,抗EGFR抗體為非拮抗劑抗體,包括例如以引用之方式併入本文中之WO2012058592中所描述之抗體。在另一實施例中,抗EGFR抗體為非功能性抗體,例如人類化ML66或EGFR-8。更特定而言,抗EGFR抗體為huML66。
在另一實施例中,抗EGFR抗體包含具有SEQ ID NO: 17之胺基酸序列的重鏈及具有SEQ ID NO: 18之胺基酸序列的輕鏈。如本文所用,加雙下劃線之序列表示重鏈或輕鏈序列之可變區(亦即重鏈可變區或HCVR及輕鏈可變區或LCVR),而粗體序列表示CDR區(亦即自重鏈或輕鏈序列之N端至C端分別為CDR1、CDR2及CDR3)。
抗體 | 全長重鏈/輕鏈胺基酸序列 |
huML66HC | QVQLQESGPGLVKPSETLSLTCTVSGLSL ASNSVSWIRQPPGKGLEWMG VIWNHG GTDYNPSIKS RLSISRDTSKSQVFLKMNSLTAADTAMYFCVR KGGIYFDYWGQGV LVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGV HTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKT HTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYV DGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIE KTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPEN NYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLS PG (SEQ ID NO:17) |
huML66LC | DTVLTQSPSLAVSPGERATISC RASESVSTLMHWYQQKPGQQPKLLIY LASHRESG VPARFSGSGSGTDFTLTIDPMEAEDTATYYC QQSRNDPWTFGQGTKLELKR TVAA PSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQD SKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO:18) |
在另一實施例中,抗EGFR抗體包含SEQ ID NO: 17之重鏈CDR1-CDR3及/或SEQ ID NO: 18之輕鏈CDR1-CDR3,且較佳特異性結合EGFR。
在另一實施例中,抗EGFR抗體包含與SEQ ID NO: 17至少約90%、95%、97%、99%或100%一致之重鏈可變區(HCVR)序列及/或與SEQ ID NO: 18至少約90%、95%、97%、99%或100%一致之輕鏈可變區(LCVR)序列,且較佳特異性結合EGFR。
在另一實施例中,抗EGFR抗體為以引用之方式併入本文中之8,790,649及WO 2012/058588中所描述之抗體。在一些實施例中,抗EGFR抗體為huEGFR-7R抗體。
在一些實施例中,抗EGFR抗體包含具有以下胺基酸序列之免疫球蛋白重鏈區:
QVQLVQSGAEVAKPGASVKLSCKASGYTF
TSYWMQWVKQRPGQGLECIG
TIYPGDGDTTYTQKFQGKATLTADKSSSTAYMQLSSLRSEDSAVYYCAR
YDAPGYAMDYWGQGTLVTVSS
ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG (SEQ ID NO:19)及具有以下胺基酸序列之免疫球蛋白輕鏈區:
DIQMTQSPSSLSASVGDRVTITC
RASQDINNYLAWYQHKPGKGPKLLIH
YTSTLHPGIPSRFSGSGSGRDYSFSISSLEPEDIATYYC
LQYDNLLYTFGQGTKLEIKR
TVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO:20),或具有以下胺基酸序列之免疫球蛋白輕鏈區:
DIQMTQSPSSLSASVGDRVTITC
KASQDINNYLAWYQHKPGKGPKLLIH
YTSTLHPGIPSRFSGSGSGRDYSFSISSLEPEDIATYYC
LQYDNLLYTFGQGTKLEIKR
TVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 21)。
在另一實施例中,抗EGFR抗體包含具有SEQ ID NO:19中所列之胺基酸序列的免疫球蛋白重鏈區及具有SEQ ID NO:20中所列之胺基酸序列的免疫球蛋白輕鏈區。
在另一實施例中,該抗EGFR抗體包含具有SEQ ID NO:19中所列之胺基酸序列的免疫球蛋白重鏈區及具有SEQ ID NO:21中所列之胺基酸序列的免疫球蛋白輕鏈區。
在另一實施例中,抗EGFR抗體包含SEQ ID NO: 19之重鏈CDR1-CDR3及/或SEQ ID NO: 20或21之輕鏈CDR1-CDR3,且較佳特異性結合EGFR。
在另一實施例中,抗EGFR抗體包含與SEQ ID NO: 19至少約90%、95%、97%、99%或100%一致之重鏈可變區(HCVR)序列及/或與SEQ ID NO: 20或21至少約90%、95%、97%、99%或100%一致之輕鏈可變區(LCVR)序列,且較佳特異性結合EGFR。
在另一實施例中,細胞結合劑為抗CD19抗體,諸如以引用之方式併入本文中之美國專利第8,435,528號及WO2004/103272中所描述之彼等抗CD19抗體。在一些實施例中,抗CD19抗體包含具有以下胺基酸序列之免疫球蛋白重鏈區:QVQLVQPGAEVVKPGASVKLSCKTSGYTFT
SNWMHWVKQAPGQGLEWIG
EIDPSDSYTNYNQNFQGKAKLTVDKSTSTAYMEVSSLRSDDTAVYYCAR
GSNPYYYAMDYWGQGTSVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO:22)及具有以下胺基酸序列之免疫球蛋白輕鏈區:EIVLTQSPAIMSASPGERVTMTC
SASSGVNYMHWYQQKPGTSPRRWIY
DTSKLASGVPARFSGSGSGTDYSLTISSMEPEDAATYYC
HQRGSYTFGGGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO:23)。
在另一實施例中,抗CD19抗體為huB4抗體。
在另一實施例中,抗CD19抗體包含SEQ ID NO: 22之重鏈CDR1-CDR3及/或SEQ ID NO: 23之輕鏈CDR1-CDR3,且較佳特異性結合CD19。
在另一實施例中,抗CD19抗體包含與SEQ ID NO: 22至少約90%、95%、97%、99%或100%一致之重鏈可變區(HCVR)序列及/或與SEQ ID NO: 23至少約90%、95%、97%、99%或100%一致之輕鏈可變區(LCVR)序列,且較佳特異性結合CD19。
在另一實施例中,細胞結合劑為抗Muc1抗體,諸如以引用之方式併入本文中之美國專利第7,834,155號、WO 2005/009369及WO 2007/024222中所描述之彼等抗Muc1抗體。在一些實施例中,抗Muc1抗體包含具有以下胺基酸序列之免疫球蛋白重鏈區:
QAQLVQSGAEVVKPGASVKMSCKASGYTFT
SYNMHWVKQTPGQGLEWIG
YIYPGNGATNYNQKFQGKATLTADTSSSTAYMQISSLTSEDSAVYFCAR
GDSVPFAYWGQGTLVTVSA
ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO:24)及具有以下胺基酸序列之免疫球蛋白輕鏈區:
EIVLTQSPATMSASPGERVTITC
SAHSSVSFMHWFQQKPGTSPKLWIY
STSSLASGVPARFGGSGSGTSYSLTISSMEAEDAATYYC
QQRSSFPLTFGAGTKLELKR
TVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO:25)。
在另一實施例中,抗Muc1抗體為huDS6抗體。
在另一實施例中,抗Muc1抗體包含SEQ ID NO: 24之重鏈CDR1-CDR3及/或SEQ ID NO: 25之輕鏈CDR1-CDR3,且較佳特異性結合Muc1。
在另一實施例中,抗Muc1抗體包含與SEQ ID NO: 24至少約90%、95%、97%、99%或100%一致之重鏈可變區(HCVR)序列及/或與SEQ ID NO: 25至少約90%、95%、97%、99%或100%一致之輕鏈可變區(LCVR)序列,且較佳特異性結合Muc1。
在另一實施例中,細胞結合劑為抗CD33抗體或其片段,諸如以引用之方式併入本文中之美國專利第7,557,189號、第7,342,110號、第8,119,787號及第8,337,855號及WO2004/043344中所描述之抗體或其片段。在另一實施例中,抗CD33抗體為huMy9-6抗體。
在一些實施例中,抗CD33抗體包含具有以下胺基酸序列之免疫球蛋白重鏈區:
QVQLQQPGAEVVKPGASVKMSCKASGYTFT
SYYIHWIKQTPGQGLEWVG
VIYPGNDDISYNQKFQGKATLTADKSSTTAYMQLSSLTSEDSAVYYCAR
EVRLRYFDVWGQGTTVTVSS
ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG (SEQ ID NO:26),及具有以下胺基酸序列之免疫球蛋白輕鏈區:
EIVLTQSPGSLAVSPGERVTMSC
KSSQSVFFSSSQKNYLAWYQQIPGQSPRLLIY
WASTRESGVPDRFTGSGSGTDFTLTISSVQPEDLAIYYC
HQYLSSRTFGQGTKLEIKR
TVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO:27)。
在另一實施例中,抗CD33抗體包含SEQ ID NO: 26之重鏈CDR1-CDR3及/或SEQ ID NO: 27之輕鏈CDR1-CDR3,且較佳特異性結合CD33。
在另一實施例中,抗CD33抗體包含與SEQ ID NO: 26至少約90%、95%、97%、99%或100%一致之重鏈可變區(HCVR)序列及/或與SEQ ID NO: 27至少約90%、95%、97%、99%或100%一致之輕鏈可變區(LCVR)序列,且較佳特異性結合CD33。
在另一實施例中,細胞結合劑為抗CD37抗體或其抗體片段,諸如以引用之方式併入本文中之美國專利第8,765,917號及WO 2011/112978中所描述之彼等抗CD37抗體或其抗體片段。在一些實施例中,抗CD37抗體為huCD37-3抗體。
在一些實施例中,抗CD37抗體包含具有以下胺基酸序列之免疫球蛋白輕鏈區:
DIQMTQSPSSLSVSVGERVTITC
RASENIRSNLAWYQQKPGKSPKLLVN
VATNLADGVPSRFSGSGSGTDYSLKINSLQPEDFGTYYC
QHYWGTTWTFGQGTKLEIKR
TVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO:28)及具有以下胺基酸序列之免疫球蛋白重鏈區:
QVQVQESGPGLVAPSQTLSITCTVSGFSLT
TSGVSWVRQPPGKGLEWLG
VIWGDGSTNYHPSLKSRLSIKKDHSKSQVFLKLNSLTAADTATYYCAK
GGYSLAHWGQGTLVTVSS
ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG (SEQ ID NO:29),或具有以下胺基酸序列之免疫球蛋白重鏈區:
QVQVQESGPGLVAPSQTLSITCTVSGFSLT
TSGVSWVRQPPGKGLEWLG
VIWGDGSTNYHSSLKSRLSIKKDHSKSQVFLKLNSLTAADTATYYCAK
GGYSLAHWGQGTLVTVSS
ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG (SEQ ID NO:30)。
在另一實施例中,抗CD37抗體包含具有SEQ ID NO:28中所列之胺基酸序列的免疫球蛋白輕鏈區及具有SEQ ID NO:29中所列之胺基酸序列的免疫球蛋白重鏈區。
在另一實施例中,抗CD37抗體包含具有SEQ ID NO:28中所列之胺基酸序列的免疫球蛋白輕鏈區及具有SEQ ID NO:30中所列之胺基酸序列的免疫球蛋白重鏈區。
在另一實施例中,抗CD37抗體包含SEQ ID NO: 29或30之重鏈CDR1-CDR3及/或SEQ ID NO: 28之輕鏈CDR1-CDR3,且較佳特異性結合CD37。
在另一實施例中,抗CD37抗體包含與SEQ ID NO: 29或30至少約90%、95%、97%、99%或100%一致之重鏈可變區(HCVR)序列及/或與SEQ ID NO: 28至少約90%、95%、97%、99%或100%一致之輕鏈可變區(LCVR)序列,且較佳特異性結合CD37。
在另一實施例中,抗CD37抗體包含具有以下胺基酸序列之免疫球蛋白輕鏈區:
EIVLTQSPATMSASPGERVTMTC
SATSSVTYMHWYQQKPGQSPKRWIY
DTSNLPYGVPARFSGSGSGTSYSLTISSMEAEDAATYYC
QQWSDNPPTFGQGTKLEIKR
TVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO:31)及具有以下胺基酸序列之免疫球蛋白重鏈區:
QVQLQESGPGLLKPSQSLSLTCTVSGYSIT
SGFAWHWIRQHPGNKLEWMG
YILYSGSTVYSPSLKSRISITRDTSKNHFFLQLNSVTAADTATYYCAR
GYYGYGAWFAYWGQGTLVTVSA
ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG (SEQ ID NO:32)。
在另一實施例中,抗CD37抗體包含SEQ ID NO: 32之重鏈CDR1-CDR3及/或SEQ ID NO: 31之輕鏈CDR1-CDR3,且較佳特異性結合CD37。
在另一實施例中,抗CD37抗體包含與SEQ ID NO: 32至少約90%、95%、97%、99%或100%一致之重鏈可變區(HCVR)序列及/或與SEQ ID NO: 31至少約90%、95%、97%、99%或100%一致之輕鏈可變區(LCVR)序列,且較佳特異性結合CD37。
在另一實施例中,抗CD37抗體為huCD37-50抗體。
在一個實施例中,細胞結合劑為抗CD123抗體或其抗體片段,諸如以引用之方式併入本文中之WO2017/004026中所描述之彼等抗CD123抗體或其抗體片段。
在一個實施例中,該抗CD123抗體或其抗體片段包含:a)具有SSIMH (SEQ ID NO:33)之胺基酸序列的重鏈可變區CDR1、具有YIKPYNDGTKYNEKFKG (SEQ ID NO:34)之胺基酸序列的重鏈可變區CDR2及具有EGGNDYYDTMDY (SEQ ID NO:35)之胺基酸序列的重鏈可變區CDR3;及b)具有RASQDINSYLS (SEQ ID NO:36)之胺基酸序列的輕鏈可變區CDR1、具有RVNRLVD (SEQ ID NO:37)之胺基酸序列的輕鏈可變區CDR2及具有LQYDAFPYT (SEQ ID NO:38)之胺基酸序列的輕鏈可變區CDR3。
在另一實施例中,抗CD123抗體或其抗體片段包含具有以下胺基酸序列之重鏈可變區:QXQLVQSGAEVKKPGASVKVSCKASGYIFTSSIMHWVRQAPGQGLEWIGYIKPYNDGTKYNEKFKGRATLTSDRSTSTAYMELSSLRSEDTAVYYCAREGGNDYYDTMDYWGQGTLVTVSS (SEQ ID NO:39)及具有以下胺基酸序列之輕鏈可變區:DIQMTQSPSSLSASVGDRVTITCRASQDINSYLSWFQQKPGKAPKTLIYRVNRLVDGVPSRFSGSGSGNDYTLTISSLQPEDFATYYCLQYDAFPYTFGQGTKVEIKR (SEQ ID NO:40)。在某些實施例中,自SEQ ID NO:39 N端之第二個殘基X (或Xaa)為Phe (F)。。在某些實施例中,SEQ ID NO:39中之X (或Xaa)為Val (V)。
在另一實施例中,抗CD123抗體或其抗體片段包含具有SEQ ID NO:39之胺基酸序列的重鏈可變區及具有以下胺基酸序列之輕鏈可變區:SIQMTQSPSSLSASVGDRVTITCRASQDINSYLSWFQQKPGKAPKTLIYRVNRLVDGVPSRFSGSGSGNDYTLTISSLQPEDFATYYCLQYDAFPYTFGQGTKVEIKR (SEQ ID NO:41)。
在另一實施例中,抗CD123抗體包含具有以下胺基酸序列之重鏈:QXQLVQSGAEVKKPGASVKVSCKASGYIFTSSIMHWVRQAPGQGLEWIGYIKPYNDGTKYNEKFKGRATLTSDRSTSTAYMELSSLRSEDTAVYYCAREGGNDYYDTMDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLCLSPG (SEQ ID NO:42)及具有以下胺基酸序列之輕鏈:DIQMTQSPSSLSASVGDRVTITCRASQDINSYLSWFQQKPGKAPKTLIYRVNRLVDGVPSRFSGSGSGNDYTLTISSLQPEDFATYYCLQYDAFPYTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO:43)。在一些實施例中,自SEQ ID NO: 42 N端之第二個殘基X (或Xaa)為Val。
在另一實施例中,抗CD123抗體包含具有以下胺基酸序列之重鏈:QXQLVQSGAEVKKPGASVKVSCKASGYIFTSSIMHWVRQAPGQGLEWIGYIKPYNDGTKYNEKFKGRATLTSDRSTSTAYMELSSLRSEDTAVYYCAREGGNDYYDTMDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG (SEQ ID NO:44)及具有SEQ ID NO:43之胺基酸序列的輕鏈。在一些實施例中,自SEQ ID NO: 44 N端之第二個殘基X (或Xaa)為Val。
在某些實施例中,本發明之細胞結合劑(例如抗體)具有N端絲胺酸,其可經氧化劑氧化以形成具有N端醛基之經氧化之細胞結合劑。
任何適合之氧化劑均可用於上文所描述之方法的步驟(a)中。在某些實施例中,氧化劑為過碘酸鹽。更特定而言,氧化劑為過碘酸鈉。
可使用相對於細胞結合劑過量之莫耳當量的氧化劑。在某些實施例中,可使用約2-100、5-80、10-50、1-10或5-10莫耳當量之氧化劑。在某些實施例中,可使用約10或約50當量之氧化劑。當使用大量氧化劑時,使用短反應時間來避免過氧化。舉例而言,當使用50當量之氧化劑時,氧化反應進行約5至約60分鐘。或者,當使用10當量之氧化劑時,反應進行約30分鐘至約24小時。在一些實施例中,使用5-10莫耳當量之氧化劑且氧化反應進行約5至約60分鐘(例如約10至約30分鐘、約20至約30分鐘)。
在某些實施例中,氧化反應不引起顯著之非靶向氧化。舉例而言,在用於產生具有N端醛基之經氧化細胞結合劑的N端絲胺酸氧化過程期間未氧化顯著程度之甲硫胺酸及/或聚醣(例如不到20%、不到10%、不到5%、不到3%、不到2%或不到1%)。
在某些實施例中,本發明之細胞結合劑(例如抗體)具有經重組工程改造之Cys殘基,諸如在抗體之EU/OU編號位置442處之Cys殘基。因此,術語「半胱胺酸工程改造之抗體」包括具有至少一個不正常存在於抗體輕鏈或重鏈之給定殘基處的Cys的抗體。此類Cys亦可稱為「經工程改造之Cys」,可使用任何習知分子生物學或重組DNA技術(例如藉由將目標殘基處之非Cys殘基之編碼序列用Cys之編碼序列置換)來進行工程改造。舉例而言,若原始殘基為編碼序列為5'-UCU-3'之Ser,則可使該編碼序列突變(例如藉由定點誘變)為5'-UGU-3',其編碼Cys。在某些實施例中,Cys工程改造之本發明抗體在重鏈中具有經工程改造之Cys。在某些實施例中,經工程改造之Cys位於重鏈之CH3結構域中或其附近。可將經工程改造之抗體重(或輕)鏈序列插入適合之重組表現載體中以產生具有經工程改造之Cys殘基替代原始Ser殘基之經工程改造之抗體。
化合物及結合物之細胞毒性
可評估本發明之細胞毒性化合物及細胞結合劑-藥物結合物在活體外抑制各種癌細胞株增殖之能力。舉例而言,可使用諸如人類絨毛膜癌瘤JEG-3細胞之細胞株來評估此等化合物及結合物之細胞毒性。可使所要評估之細胞暴露於該等化合物或結合物1-5天,且在直接分析中藉由已知方法量測細胞之存活分數。然後可由分析結果計算IC
50值。或者或此外,可使用活體外細胞株敏感度篩選,諸如由美國國家癌症協會(U.S. National Cancer Institute)描述之活體外細胞株敏感度篩選(參見Voskoglou-Nomikos等人, 2003, Clinical Cancer Res. 9: 42227-4239,其以引用之方式併入本文中)作為一種指導來確定可能對用本發明之化合物或結合物治療敏感之癌症類型。
本發明之抗體-細胞毒性劑結合物之活體外效能及靶標特異性的實例描述於實例6中。抗原陰性細胞株當暴露於相同結合物時仍然有活力。
組合物及使用方法
本發明包括一種包含本文所描述之新穎類美登素化合物、其衍生物或其結合物(及/或其溶劑合物、水合物及/或鹽)及載劑(醫藥學上可接受之載劑)的組合物(例如醫藥組合物)。本發明亦包括一種包含本文所描述之新穎類美登素化合物、其衍生物或其結合物(及/或其溶劑合物、水合物及/或鹽)及載劑(醫藥學上可接受之載劑)的組合物(例如醫藥組合物)。本發明組合物可用於在哺乳動物(例如人類)中抑制異常細胞生長或治療增殖性病症。
本發明包括一種在哺乳動物(例如人類)中抑制異常細胞生長或治療增殖性病症的方法,該方法包括向哺乳動物投與治療有效量之本文所描述之新穎類美登素化合物、其衍生物或其結合物(及/或其溶劑合物及鹽)或其組合物。
本發明亦提供治療方法,該等方法包括向需要治療之個體投與有效量之上文所描述之結合物中之任一者。
類似地,本發明提供一種在所選細胞群體中誘導細胞死亡之方法,該方法包括使目標細胞或含有目標細胞之組織與有效量之細胞毒性劑接觸,該細胞毒性劑包含本發明之細胞毒性化合物-細胞結合劑、其鹽或溶劑合物中之任一者。目標細胞為可與細胞結合劑結合之細胞。
適合之醫藥學上可接受之載劑、稀釋劑及賦形劑為熟知的,且可由一般熟習此項技術者根據臨床情況加以確定。
適合之載劑、稀釋劑及/或賦形劑之實例包括:(1)杜爾貝科氏磷酸鹽緩衝鹽水(Dulbecco's phosphate buffered saline),pH約7.4,含有約1 mg/mL至25 mg/mL人類血清白蛋白或不含人類血清白蛋白,(2) 0.9%生理鹽水(0.9% w/v NaCl),及(3) 5% (w/v)右旋糖;且亦可含有抗氧化劑,諸如色胺;及穩定劑,諸如吐溫20 (Tween 20)。
在所選細胞群體中誘導細胞死亡之方法可在活體外、活體內或離體實施。
活體外使用之實例包括在移植至同一患者中之前處理自體骨髓以殺死患病或惡性細胞:在移植之前處理骨髓以殺死勝任型T細胞且預防移植物抗宿主疾病(GVHD);處理細胞培養物以殺死除不表現目標抗原之所需變異體以外的所有細胞;或殺死表現不需要之抗原的變異體。
非臨床活體外使用之條件由一般熟習此項技術者容易地確定。
臨床離體使用之實例為在癌症治療中或在自體免疫疾病之治療中在自體移植之前自骨髓移除腫瘤細胞或淋巴樣細胞,或在移植之前自自體或異體骨髓或組織移除T細胞及其他淋巴樣細胞以預防GVHD。可如下進行治療。自患者或其他個體收穫骨髓且然後在約37℃下在含有血清之培養基中孵育約30分鐘至約48小時,培養基中添加了本發明之細胞毒性劑,濃度在約10 μM至1 pM範圍內。濃度及孵育時間之確切條件(亦即劑量)由一般熟習此項技術者容易地確定。在孵育之後,將骨髓細胞用含有血清之培養基洗滌且根據已知方法使其以靜脈內方式回到患者體內。在收穫骨髓之時間與再輸注經處理之細胞之間患者接受諸如一系列消融化學治療或全身放射治療之其他治療的情況下,使用標準醫療設備將經處理之骨髓細胞冷凍儲存於液氮中。
對於臨床活體內使用,將以溶液或凍乾粉末之形式供應本發明之細胞毒性劑,針對無菌性且針對內毒素含量對其進行測試。
在一些實施例中,本發明之化合物及結合物可用於治療癌症(例如腎癌、乳癌(例如三陰性乳癌(TNBC))、結腸癌、腦癌、前列腺癌、子宮內膜癌、子宮頸癌、腎臟癌症、胰腺癌、卵巢癌、頭頸癌、黑素瘤、結腸直腸癌、胃癌、鱗狀癌症、肺癌(例如非小細胞肺癌及小細胞肺癌)、睪丸癌、絨毛膜癌瘤、默克細胞癌瘤、肉瘤(例如骨肉瘤、軟骨肉瘤、脂肪肉瘤及平滑肌肉瘤)、膠質母細胞瘤、神經母細胞瘤、淋巴瘤(例如非霍奇金淋巴瘤(non-Hodgkin lymphoma))、脊髓發育不良症候群(MDS)、腹膜癌、輸卵管癌、子宮癌或白血病(例如急性骨髓性白血病(AML)、急性單核球性白血病、前髓細胞性白血病、嗜伊紅球性白血病、急性淋巴母細胞性白血病(例如B-ALL)、慢性淋巴球性白血病(CLL)及慢性骨髓性白血病(CML))。
類似物及衍生物
熟習細胞毒性劑技術者將容易理解,可以一種方式對本文所描述之細胞毒性劑中之每一者進行修飾,使得所得化合物仍保留起始化合物之特異性及/或活性。熟練技工亦將理解,此等化合物中有許多可用於替代本文所描述之細胞毒性劑。因此,本發明之細胞毒性劑包括本文所描述之化合物的類似物及衍生物。
將美登醇(5.0 g,8.85 mmol)溶解於無水DMF (125 mL)中,然後在冰浴中冷卻。然後在氬氣氛圍下在磁力攪拌下添加N-甲基丙胺酸之N-羧基酸酐(5.7 g、44.25 mmol)、無水DIPEA (7.70 mL,44.25 mmol)及三氟甲烷磺酸鋅(22.5 g,62 mmol)。移除冰浴且在攪拌下使反應物升溫。在16 h之後,添加去離子水(10 mL)。在30 min之後,在劇烈攪拌下添加飽和碳酸氫鈉水溶液:飽和氯化鈉水溶液之1:1溶液(190 mL)及乙酸乙酯(250 mL)。將混合物轉移至分液漏斗中且截留有機層。將水層用乙酸乙酯(100 mL)萃取,然後將有機層合併且用飽和氯化鈉水溶液(50 mL)洗滌。藉由在真空下旋轉蒸發而不加熱蒸發器浴槽將有機層濃縮至其體積之約1/4,不進行純化。藉由用反應中所用美登醇之毫莫耳數(1.77 mmol)除以給定DM-H儲備溶液(0.06 mmol/mL)之體積(150 mL)來估計溶液之濃度。立即分配儲備溶液之等分試樣,然後用於反應中或儲存於-80 C冷凍器中,然後在需要時解凍。
實例 2. 硫代 - 肽 - 類美登素之合成
如如由FMoc-L-Ala-L-Ala-L-Ala-NH-CH
2-OAc所例示製備FMoc-肽-NH-CH
2-OAc類型之化合物。
FMoc- 肽 -OAc 化合物
FMoc-L-Ala-L-Ala-L-Ala-NH-CH
2-OAc (9a)
:將FMoc-L-Ala-L-Ala-L-Ala-Gly-OH (500 mg,0.979 mmol)溶解於DMF (2 mL)中,在氬氣下在磁力攪拌下向其中添加乙酸銅(II) (17.8 mg,0.098 mmol)及乙酸(84 μL,1.47 mmol)。一旦固體溶解,即添加四乙酸鉛(434 mg,0.979 mmol),允許反應在60℃下進行20 min,然後在C18 30微米450 g管柱上純化,在125 mL/min之流速下用含有0.1%甲酸之去離子水及歷時26 min 5%至55%之乙腈線性梯度進行溶離。將含有純所需產物之級分冷凍且凍乾,得到178 mg (34%產率)之白色固體。HRMS (M + Na)
+計算值547.2163;實驗值547.2160。
1H NMR (400 MHz, DMSO-
d6) δ 1.20 (qd,
J= 7.5, 6.9, 4.2 Hz, 9H), 1.91 - 2.05 (m, 3H), 3.26 - 3.38 (m, 1H), 4.05 (q,
J= 7.3 Hz, 1H), 4.23 (td,
J= 11.9, 10.7, 6.4 Hz, 5H), 5.07(ddd,
J= 11.2, 6.9, 4.3 Hz, 2H), 7.32 (q,
J= 7.5 Hz, 2H), 7.41 (q,
J= 7.4 Hz, 2H), 7.52 (t,
J= 6.8 Hz, 1H), 7.71 (q,
J= 7.5, 7.0 Hz, 2H), 7.82 - 8.08 (m, 4H), 8.84 (q,
J= 7.1 Hz, 1H)。
FMoc-D-Ala-L-Ala-L-Ala-NH-CH
2-OAc (9b)
:HRMS (M+Na)
+計算值547.2163,實驗值547.2167。
1H NMR (400 MHz, DMSO-d6) δ 1.23 (dd,
J= 12.5, 7.4 Hz, 9H), 1.95 (s, 2H), 4.00 - 4.13 (m, 1H), 4.17 - 4.38 (m, 6H), 5.06 (q,
J= 8.8 Hz, 2H), 7.33 (t,
J= 7.3 Hz, 2H), 7.42 (t,
J= 7.4 Hz, 2H), 7.62 (d,
J= 6.8 Hz, 1H), 7.71 (t,
J= 8.6 Hz, 2H), 7.85 - 8.01 (m, 3H), 8.21 (d,
J= 7.0 Hz, 1H), 8.69 (d,
J= 6.9 Hz, 1H)。
FMoc-L-Ala-D-Ala-L-Ala-NH-CH
2-OAc (9c)
:HRMS (M+Na)
+計算值547.2163,實驗值547.2168。
1H NMR (400 MHz, DMSO-d6) δ 1.16 - 1.24 (m, 9H), 1.97 (s, 3H), 4.07 (q,
J= 7.0 Hz, 1H), 4.16 - 4.34 (m, 5H), 5.00 - 5.16 (m, 2H), 7.33 (td,
J= 7.4, 1.1 Hz, 2H), 7.42 (t,
J= 7.4 Hz, 2H), 7.58 (d,
J= 7.0 Hz, 1H), 7.72 (t,
J= 8.1 Hz, 2H), 7.90 (d,
J= 7.5 Hz, 2H), 8.03 (d,
J= 7.5 Hz, 1H), 8.14 (d,
J= 7.2 Hz, 1H), 8.85 (t,
J= 6.9 Hz, 1H)。
FMoc-L-Ala-L-Ala-D-Ala-NH-CH
2-OAc (9d)
:HRMS (M+Na)
+計算值547.2163,實驗值547.2167。
1H NMR (400 MHz, DMSO-d6) δ 1.18 - 1.25 (m, 9H), 1.97 (s, 3H), 3.96 - 4.15 (m, 1H), 4.17 - 4.36 (m, 5H), 5.09 (d,
J= 6.9 Hz, 2H), 7.34 (t,
J= 7.4 Hz, 2H), 7.42 (t,
J= 7.4 Hz, 2H), 7.57 (d,
J= 7.2 Hz, 1H), 7.71 (d,
J= 7.3 Hz, 2H), 7.90 (d,
J= 7.5 Hz, 2H), 8.07 (s, 2H), 8.86 (s, 1H)。
FMoc-L-Ala-D-Ala-NH-CH
2-OAc (9f)
:HRMS (M+Na)
+計算值476.1792,實驗值476.1786。
1H NMR (400 MHz, DMSO-d6) δ 1.13 (dd,
J= 7.1, 1.4 Hz, 6H), 1.89 (s, 3H), 3.99 (q,
J= 7.1 Hz, 1H), 4.10 - 4.29 (m, 4H), 4.95 - 5.08 (m, 2H), 7.26 (t,
J= 7.4, 1.3 Hz, 2H), 7.35 (t,
J= 7.4 Hz, 2H), 7.49 (d,
J= 7.2 Hz, 1H), 7.66 (t,
J= 7.6 Hz, 2H), 7.82 (d,
J= 7.5 Hz, 2H), 8.11 (d,
J= 7.7 Hz, 1H), 8.76 (t,
J= 7.0 Hz, 1H)。
FMoc-D-Ala-L-Ala-NH-CH
2-OAc (9g)
:HRMS (M+Na)
+計算值476.1792,實驗值476.1788。
1H NMR (400 MHz, DMSO-d6) δ 1.21 (dd,
J= 7.1, 1.4 Hz, 6H), 1.96 (s, 3H), 4.08 (t,
J= 7.1 Hz, 1H), 4.17 - 4.36 (m, 4H), 5.05 - 5.14 (m, 2H), 7.26 - 7.38 (m, 2H), 7.42 (t,
J= 7.4 Hz, 2H), 7.56 (d,
J= 7.3 Hz, 1H), 7.73 (t,
J= 7.6 Hz, 2H), 7.90 (d,
J= 7.6 Hz, 2H), 8.18 (d,
J= 7.8 Hz, 1H), 8.83 (t,
J= 6.9 Hz, 1H)。
FMoc-D-Ala-D-Ala-NH-CH
2-OAc (9h)
:HRMS (M+H)
+計算值455.4877,實驗值455.2051
1H NMR (400 MHz, DMSO-d6) δ 1.14 (dd,
J= 7.1, 3.3 Hz, 6H), 1.21 (d,
J= 7.2 Hz, 1H), 1.81 (s, 1H), 1.91 (s, 2H), 4.01 (q,
J= 7.7 Hz, 1H), 4.09 - 4.27 (m, 5H), 4.95 - 5.10 (m, 1H), 7.26 (td,
J= 7.4, 1.2 Hz, 3H), 7.35 (t,
J= 7.4 Hz, 3H), 7.45 (d,
J= 7.6 Hz, 1H), 7.65 (t,
J= 7.1 Hz, 3H), 7.82 (d,
J= 6.4 Hz, 2H), 7.96 (d,
J= 7.4 Hz, 1H), 8.78 (t,
J= 7.0 Hz, 1H)。
FMoc- 肽 -COOH 化合物
如藉由如由FMoc-L-Ala-L-Ala-L-Ala-NH-CH
2-S-(CH
2)
5-CO
2H所例示製備FMoc-肽-NH-CH
2-S-(CH
2)
n-CO
2H類型之化合物。
FMoc-L-Ala-L-Ala-L-Ala-NH-CH
2-S-(CH
2)
5-CO
2H (10a)
:將6-巰基己酸(287 μL,2.07 mmol)溶解於1:4 TFA:二氯甲烷(5 mL)之溶液中,然後添加至含有FMoc-L-Ala-L-Ala-L-Ala-NH-CH
2-OAc (178 mg,0.339 mmol)之小瓶中。允許反應在室溫下在氬氣氛圍下在磁力攪拌下進行20 min。將粗物質真空濃縮,再溶解於最小體積之DMF中且在C18 30微米30g管柱上純化,在35 mL/min下用含有0.1%甲酸之去離子水加上歷時13 min自5%至95%之乙腈線性梯度進行溶離。將含有純所需產物之級分冷凍且凍乾,得到200 mg (96%產率)之白色固體。HRMS (M + H )
+計算值613.2690;實驗值613.2686。
1H NMR (400 MHz, DMSO-
d6) δ 1.20 (dt,
J= 7.1, 4.9 Hz, 10H), 1.31 (tt,
J= 10.1, 6.0 Hz, 2H), 1.49 (dq,
J= 12.5, 7.4 Hz, 4H), 2.18 (t,
J= 7.3 Hz, 2H),4.05 (t,
J= 7.3 Hz, 1H), 4.16 - 4.30 (m, 7H), 7.33 (td,
J= 7.4, 1.2 Hz, 2H), 7.42 (td,
J= 7.3, 1.1 Hz, 2H), 7.54 (d,
J= 7.4 Hz, 1H), 7.72 (t,
J= 7.0 Hz, 2H), 7.89 (d,
J= 7.5 Hz, 2H), 7.94 - 8.07 (m, 2H), 8.44 (t,
J= 6.1 Hz, 1H)。
FMoc-D-Ala-L-Ala-L-Ala-NH-CH
2-S-(CH
2)
5-CO
2H (10b)
:HRMS (M+Na)
+計算值635.2510,實驗值635.2515。
1H NMR (400 MHz, DMSO-d6) δ 1.15 (d,
J= 6.8 Hz, 3H), 1.18 - 1.25 (m, 10H), 2.18 (q,
J= 7.5 Hz, 4H), 2.40 - 2.48 (m, 1H), 2.70 (t,
J= 7.2 Hz, 1H), 4.15 - 4.30 (m, 6H), 6.29 (s, 2H), 7.34 (q,
J= 7.3 Hz, 3H), 7.42 (t,
J= 7.4 Hz, 3H), 7.63 - 7.78 (m, 1H), 7.85 (d,
J= 7.3 Hz, 2H), 7.89 (d,
J= 7.5 Hz, 3H), 8.37 - 8.46 (m, 1H)。
FMoc-L-Ala-D-Ala-L-Ala-NH-CH
2-S-(CH
2)
5-CO
2H (10c)
:HRMS (M+Na)
+計算值635.2510,實驗值635.2514。
1H NMR (400 MHz, DMSO-d6) δ 1.18 - 1.23 (m, 10H), 1.34 (q,
J= 3.4 Hz, 5H), 2.24 (s, 2H), 2.44 (s, 2H), 4.05 (t,
J= 7.1 Hz, 1H), 4.16 - 4.35 (m, 8H), 7.33 (t,
J= 7.4 Hz, 2H), 7.42 (t,
J= 7.5 Hz, 2H), 7.58 (d,
J= 7.0 Hz, 1H), 7.71 (t,
J= 8.4 Hz, 2H), 7.90 (s, 1H), 7.98 (d,
J= 7.5 Hz, 1H), 8.15 (d,
J= 7.3 Hz, 1H), 8.39 (t,
J= 6.2 Hz, 1H), 11.98 (s, 1H)。
FMoc-L-Ala-L-Ala-D-Ala-NH-CH
2-S-(CH
2)
5-CO
2H (10d)
:HRMS (M+Na)
+計算值635.2510,實驗值635.2510。
1H NMR (400 MHz, DMSO-d6) δ 1.15 (d,
J= 6.9 Hz, 3H), 1.21 (d,
J= 7.1 Hz, 9H), 1.28 - 1.38 (m, 3H), 1.44 - 1.60 (m, 5H), 2.13 - 2.22 (m, 3H), 3.33 (q,
J= 6.9 Hz, 1H), 4.20 (s, 2H), 6.29 (s, 2H), 7.29 - 7.40 (m, 3H), 7.38 - 7.47 (m, 3H), 7.85 (d,
J= 7.5 Hz, 2H), 7.89 (d,
J= 7.5 Hz, 2H), 8.26 (d,
J= 7.6 Hz, 1H), 8.48 (d,
J= 6.2 Hz, 1H)。
FMoc-D-Ala-L-Ala-NH-CH
2-S-(CH
2)
5-CO
2H (10g)
:HRMS (M+H)
+計算值542.2319,實驗值542.2316。
1H NMR (400 MHz, DMSO-d6) δ 1.13 (dd,
J= 7.1, 1.7 Hz, 6H), 1.16 - 1.25 (m, 2H), 1.32 - 1.47 (m, 4H), 2.08 (t,
J= 7.3 Hz, 2H), 3.25 (s, 2H), 3.99 (p,
J= 7.0 Hz, 1H), 4.07 - 4.27 (m, 6H), 7.26 (t,
J= 7.4, 1.2 Hz, 2H), 7.35 (t,
J= 7.4 Hz, 2H), 7.52 (d,
J= 7.0 Hz, 1H), 7.65 (t,
J= 7.3 Hz, 2H), 7.82 (d,
J= 7.5 Hz, 2H), 8.08 (d,
J= 7.7 Hz, 1H), 8.27 (t,
J= 6.2 Hz, 1H), 11.82 (s, 1H)。
FMoc-L-Ala-D-Ala-NH-CH
2-S-(CH
2)
5-CO
2H (10f)
:HRMS (M+H)
+計算值542.2319,實驗值542.2321。
1H NMR (400 MHz, DMSO-d6) δ 1.13 (dd,
J= 7.1, 1.8 Hz, 7H), 1.17 - 1.26 (m, 2H), 1.32 - 1.48 (m, 5H), 2.08 (t,
J= 7.3 Hz, 2H), 3.99 (p,
J= 7.1 Hz, 1H), 4.07 - 4.26 (m, 7H), 7.26 (t,
J= 7.4 Hz, 2H), 7.35 (t,
J= 7.4 Hz, 2H), 7.53 (d,
J= 7.1 Hz, 1H), 7.65 (t,
J= 7.3 Hz, 2H), 7.82 (d,
J= 7.4 Hz, 2H), 8.10 (d,
J= 7.7 Hz, 1H), 8.28 (t,
J= 6.3 Hz, 1H)。
FMoc-D-Ala-D-Ala-NH-CH
2-S-(CH
2)
5-CO
2H (10h)
:(16.7 mg,0.031 mmol,70%產率)。HRMS (M+H)
+計算值542.2319,實驗值542.2318。
FMoc-L-Ala-D-Ala-L-Ala-NH-CH
2-S-(CH
2)
3-CO
2H(10j)
:HRMS (M+H)
+計算值585.2377,實驗值585.2367。
1H NMR (400 MHz, DMSO-d6) δ 1.14 - 1.26 (m, 9H), 1.75 (p,
J= 7.3 Hz, 2H), 2.27 (t,
J= 7.3 Hz, 2H), 2.54 (d,
J= 7.7 Hz, 2H), 3.97 - 4.10 (m, 1H), 4.13 - 4.34 (m, 7H), 7.33 (t,
J= 7.5 Hz, 2H), 7.42 (t,
J= 7.5 Hz, 2H), 7.57 (d,
J= 6.9 Hz, 1H), 7.71 (t,
J= 8.4 Hz, 2H), 7.89 (d,
J= 7.6 Hz, 2H), 7.97 (d,
J= 7.5 Hz, 1H), 8.14 (d,
J= 7.0 Hz, 1H), 8.41 (s, 1H), 12.06 (s, 1H)。
FMoc-D-Ala-L-Ala-NH-CH
2-S-(CH)
2-CO
2H (10i)
:HRMS (M+H)
+計算值500.1850,實驗值500.1843。
1H NMR (400 MHz, DMSO-
d6) δ 1.20 (dd,
J= 7.2, 1.9 Hz, 6H), 2.53 (d,
J= 7.1 Hz, 2H), 2.70 (t,
J= 7.1 Hz, 2H), 4.07 (q,
J= 7.0 Hz, 1H), 4.17 - 4.26 (m, 4H), 4.29 (d,
J= 6.8 Hz, 2H), 7.33 (t,
J= 7.4 Hz, 2H), 7.41 (t,
J= 7.5 Hz, 2H), 7.56 (d,
J= 7.1 Hz, 1H), 7.72 (t,
J= 7.7 Hz, 2H), 7.89 (d,
J= 7.5 Hz, 2H), 8.14 (d,
J= 7.6 Hz, 1H), 8.42 (t,
J= 6.3 Hz, 1H), 12.22 (s, 1H)。
將FMoc-L-丙胺酸(10g,32.1 mmol)及D-Ala-OtBu,HCl (7.00 g,38.5 mmol)溶解於CH2Cl2 (100 ml)中,用COMU (20.63 g,48.2 mmol)及DIPEA (11.22 ml,64.2 mmol)處理。允許反應在氬氣下在室溫下進行。在2小時之後,藉由UPLC顯示反應完成,用2-MeTHF (50ml)稀釋,依次用10%水性檸檬酸(2x 100mL)、水(100mL)以及鹽水(100mL)洗滌。將有機層經硫酸鎂乾燥,過濾並濃縮,得到粗FMoc-L-Ala-D-Ala-OtBu,假設100%產率。
步驟 2 : FMoc-L-Ala-D-Ala (
9c2)
將FMoc-LAla-DAla-OtBu (11.25g,25.7 mmol)用TFA:水 (95:5) (50ml)處理。允許反應在室溫下在氬氣氛圍下進行。在4小時之後,藉由UPLC顯示反應完成,用甲苯(25mL)稀釋並共蒸發3次,得到FMoc-L-Ala-D-Ala,假設100%產率。
步驟 3 : FMoc-L-Ala-Gly-OtBu(
9c3)
將Z-L-Ala-ONHS (10 g,31.2 mmol)及甘胺酸第三丁酯(6.28 g,37.5 mmol)溶解於CH2Cl2 (100 ml)中,用DIPEA (10.91 ml,62.4 mmol)處理。允許反應在氬氣下在室溫下進行。在2小時之後,UPLC顯示完成,將反應物用2-MeTHF (50mL)稀釋,用10%檸檬酸水溶液(100mL)、飽和碳酸氫鈉(2x100mL)、水(100mL)、鹽水(100mL)洗滌。將有機層經硫酸鎂乾燥,過濾並濃縮,得到Z-L-Ala-Gly-OtBu,假設100%產率。
步驟 4. L-Ala-Gly-OtBu (
9c4)
將Z-Ala-Gly-OtBu (10.05 g,29.9 mmol)溶解於95:5 MeOH:水(50 ml)中,轉移至氫化器燒瓶中,用Pd/C (1.272 g,11.95 mmol)處理。將氫化器燒瓶放置在振盪器上,在振盪燒瓶之同時藉由真空移除空氣。用氫氣填充燒瓶至30psi,將燒瓶振盪2分鐘且藉由真空移除氫氣。將此舉再重複2次。允許氫氣填充燒瓶至30psi且允許其振盪。在4 h之後,UPLC顯示完成,將反應物經矽藻土塞真空過濾,再溶解於2-MeTHF中,濃縮,得到LAla- Gly-OtBu,假設100%產率。
步驟 5 : FMoc-L-Ala-D-Ala-L-Ala-Gly-OtBu (
9c5)
將FMoc-LAla-D-ALa-OH (0.959 g,2.508 mmol)及L-Ala-Gly-OtBu (0.718 g,3.01 mmol)溶解於CH2Cl2 (10 ml)中,用COMU (1.181 g,2.76 mmol)及DIPEA (0.876 ml,5.02 mmol)處理。允許反應在氬氣下在室溫下進行。在2小時之後顯示反應完成。將反應物濃縮以移除CH2Cl2,再溶解於2mL DMF中且藉由C18 combiflash使用線性梯度純化,將產物合併,產生FMoc-L-Ala-D-Ala-L-Ala-Gly-OtBu (660mg,46%產率)。
步驟 6. FMoc-L-Ala-D-Ala-L-Ala-Gly-OH (
9c6)
將FMoc-LAla-DAla-LAla-GlyOtBu (200mg,0.353 mmol)用TFA:水(95:5) (2 ml)處理。允許反應在氬氣下在室溫下進行。在1 h之後,藉由UPLC顯示反應完成,用甲苯(1mL)稀釋並與甲苯共蒸發2次,得到FMoc-L-Ala-D-Ala-L-Ala-Gly-OH,假設100%產率。
步驟 7. FMoc-L-Ala-D-Ala-L-Ala-CH
2-OAc (
9c7)
將FMoc-L-Ala-D-Ala-L-Ala-Gly-OH (2.65 g,5.19 mmol)溶解於DMF (20mL)中,用乙酸銅(II) (0.094 g,0.519 mmol)及乙酸(0.446 ml,7.79 mmol)處理,在所有試劑溶解後,將反應物用四乙酸鉛(3.45 g,7.785 mmol)處理。允許反應在氬氣下在60℃下進行30分鐘。將粗反應物經由Combiflash Rf 200i純化,使用C18 450g管柱,流速為125mL/min,使用含有0.1%甲酸之去離子水及乙腈作為溶劑,使用如下梯度(時間(分鐘),乙腈百分比) (0,5) (8,50) (26,55)。所需產物具有11分鐘之滯留時間,立即將產物級分冷凍並凍乾,得到FMoc-L-Ala-D-Ala-L-Ala-CH2-OAc (843mg,1.607 mmol,31.0%產率)。HRMS (M+Na)
+計算值547.2163,實驗值547.2167。
1H NMR (400 MHz, DMSO-d6) δ 1.23 (dd, J = 12.5, 7.4 Hz, 9H), 1.95 (s, 2H), 4.00 - 4.13 (m, 1H), 4.17 - 4.38 (m, 6H), 5.06 (q, J = 8.8 Hz, 2H), 7.33 (t, J = 7.3 Hz, 2H), 7.42 (t, J = 7.4 Hz, 2H), 7.62 (d, J = 6.8 Hz, 1H), 7.71 (t, J = 8.6 Hz, 2H), 7.85 - 8.01 (m, 3H), 8.21 (d, J = 7.0 Hz, 1H), 8.69 (d, J = 6.9 Hz, 1H)。
FMoc- 肽 -May-NMA 化合物
如藉由如由FMoc-L-Ala-L-Ala-L-Ala-NH-CH
2-S-(CH
2)
5-CO-DM所例示製備FMoc-肽-NH-CH
2-S-(CH
2)
n-CO
2-DM類型之化合物。
FMoc-L-Ala-L-Ala-L-Ala-NH-CH
2-S-(CH
2)
5-CO-DM (11a)
:向DM-H儲備溶液(8.2 mL,0.49 mmol)中添加FMoc-L-Ala-L-Ala-L-Ala-NH-CH
2-S-(CH
2)
5-COOH (300 mg,0.49 mmol)、EDC (94 mg,0.490 mmol)及DIPEA (90 μL,0.49 mmol)。允許反應在室溫下在氬氣氛圍下在磁力攪拌下進行2 h。藉由在真空下旋轉蒸發將粗物質濃縮且將殘餘物溶解於最小體積之DMF中,然後在C18 30微米30 g管柱上純化,用含有0.1%甲酸之去離子水及歷時25 min自5%至50%之乙腈線性梯度進行溶離。將含有純所需產物之級分冷凍並凍乾,得到151 mg (37.2%產率)之白色固體。HRMS (M + Na)
+計算值1266.5170;實驗值1266.5141。
1H NMR (400 MHz, DMSO-
d6) δ 0.77 (s, 3H), 1.12 (d,
J= 6.4 Hz, 3H), 1.14 - 1.22 (m, 12H), 1.22 - 1.30 (m, 3H), 1.35 - 1.49 (m, 4H), 1.50 - 1.55 (m, 1H), 1.59 (s, 3H), 2.00 - 2.07 (m, 1H), 2.14 (ddd,
J= 15.6, 8.7, 5.9 Hz, 1H), 2.40 (dtd,
J= 17.0, 7.9, 7.0, 4.9 Hz, 3H), 2.69 (s, 3H), 2.79 (d,
J= 9.6 Hz, 1H), 3.08 (s, 3H), 3.20 (d,
J= 12.6 Hz, 1H), 3.24 (s, 3H), 3.43 (d,
J= 12.4 Hz, 2H), 3.48 (d,
J= 8.9 Hz, 1H), 3.92 (s, 3H), 4.08 (ddd,
J= 20.8, 10.8, 5.0 Hz, 3H), 4.14 - 4.24 (m, 4H), 4.26 (d,
J= 6.0 Hz, 3H), 4.52 (dd,
J= 12.0, 2.8 Hz, 1H), 5.34 (q,
J= 6.7 Hz, 1H), 5.56 (dd,
J= 14.7, 9.0 Hz, 1H), 5.91 (s, 1H), 6.50 - 6.66 (m, 3H), 6.88 (s, 1H), 7.17 (d,
J= 1.8 Hz, 1H), 7.33 (td,
J= 7.5, 1.2 Hz, 2H), 7.41 (t,
J= 7.4 Hz, 2H), 7.53 (d,
J= 7.4 Hz, 1H), 7.72 (t,
J= 7.0 Hz, 2H), 7.89 (d,
J= 7.5 Hz, 3H), 7.99 (d,
J= 7.3 Hz, 1H), 8.36 (t,
J= 6.3 Hz, 1H)。
FMoc-D-Ala-L-Ala-L-Ala-NH-CH
2-S-(CH
2)
5-CO-DM (11b)
:HRMS (M+Na)
+計算值1266.5170,實驗值1266.5164。
1H NMR (400 MHz, DMSO-d6) δ 0.78 (s, 3H), 1.14 (dd,
J= 14.6, 6.5 Hz, 6H), 1.22 (t,
J= 6.8 Hz, 10H), 1.33 - 1.57 (m, 4H), 1.59 (s, 3H), 2.04 (d,
J= 13.5 Hz, 1H), 2.27 - 2.44 (m, 1H), 2.69 (s, 3H), 2.80 (d,
J= 9.7 Hz, 1H), 3.08 (s, 3H), 3.14 - 3.28 (m, 5H), 3.37 - 3.55 (m, 3H), 3.92 (s, 3H), 3.98 - 4.16 (m, 3H), 4.20 (dd,
J= 15.6, 7.6 Hz, 7H), 4.52 (d,
J= 12.7 Hz, 1H), 5.34 (d,
J= 6.9 Hz, 1H), 5.57 (dd,
J= 14.7, 9.0 Hz, 1H), 5.92 (s, 1H), 6.46 - 6.72 (m, 4H), 6.88 (s, 1H), 7.17 (s, 1H), 7.33 (t,
J= 7.5 Hz, 3H), 7.41 (t,
J= 7.4 Hz, 3H), 7.60 - 7.75 (m, 4H), 7.80 - 7.93 (m, 4H), 8.12 (t, 1H), 8.29 (d,
J= 6.9 Hz, 1H)。
FMoc-L-Ala-D-Ala-L-Ala-NH-CH
2-S-(CH
2)
5-CO-DM (11c)
:HRMS (M+Na)
+計算值1266.5170,實驗值1266.5170。
1H NMR (400 MHz, DMSO-d6) δ 0.71 (s, 3H), 0.96 - 1.16 (m, 10H), 1.16 - 1.51 (m, 10H), 1.52 (s, 4H), 1.82 - 2.16 (m, 1H), 2.17 - 2.56 (m, 11H), 2.62 (d,
J= 5.8 Hz, 4H), 2.68 - 2.87 (m, 3H), 2.92 - 3.04 (m, 4H), 3.09 - 3.22 (m, 7H), 3.24 (d,
J= 7.4 Hz, 1H), 3.33 - 3.50 (m, 2H), 3.73 - 3.89 (m, 4H), 3.92 - 4.07 (m, 2H), 4.07 - 4.25 (m, 2H), 4.45 (dd,
J= 12.0, 2.8 Hz, 1H), 5.27 (q,
J= 6.7 Hz, 1H), 5.40 - 5.55 (m, 1H), 5.85 (s, 1H), 6.33 - 6.66 (m, 4H), 6.81 (s, 2H), 7.03 - 7.19 (m, 1H), 7.19 - 7.43 (m, 2H), 7.62 (d,
J= 11.6 Hz, 1H), 7.73 - 7.85 (m, 1H)。
FMoc-L-Ala-L-Ala-D-Ala-NH-CH
2-S-(CH
2)
5-CO-DM (11d)
:HRMS (M+Na)
+計算值1266.5170,實驗值1266.5158。
1H NMR (400 MHz, DMSO-d6) δ 0.78 (s, 3H), 1.06 - 1.33 (m, 16H), 1.44 (d,
J= 10.3 Hz, 11H), 1.59 (s, 3H), 1.99 - 2.22 (m, 3H), 2.35 - 2.45 (m, 2H), 2.55 (d,
J= 1.8 Hz, 1H), 2.69 (s, 3H), 2.80 (d, J = 9.6 Hz, 1H), 3.08 (s, 2H), 3.25 (s, 3H), 3.39 - 3.52 (m, 3H), 3.92 (s, 3H), 3.99 - 4.40 (m, 4H), 4.52 (d,
J= 11.1 Hz, 1H), 5.34 (d,
J= 6.8 Hz, 1H), 5.57 (dd,
J= 14.5, 9.2 Hz, 1H), 5.92 (s, 1H), 6.53 - 6.64 (m, 2H), 6.88 (s, 2H), 7.17 (d,
J= 1.9 Hz, 1H), 7.33 (t,
J= 7.3 Hz, 3H), 7.42 (t,
J= 7.4 Hz, 3H), 7.57 (d,
J= 7.4 Hz, 1H), 7.72 (s, 3H), 7.89 (d,
J= 7.6 Hz, 3H), 7.99 (d,
J= 7.6 Hz, 1H), 8.07 (s, 1H), 8.35 (s, 1H)。
FMoc-D-Ala-L-Ala-NH-CH
2-S-(CH
2)
5-CO-DM (11g)
:HRMS (M+H)
+計算值1173.4980,實驗值1173.4964。
1H NMR (400 MHz, DMSO-d6) δ 0.79 (s, 3H), 1.06 - 1.34 (m, 13H), 1.36 - 1.54 (m, 4H), 1.60 (s, 2H), 1.88 - 2.10 (m, 1H), 2.10 - 2.23 (m, 1H), 2.31 - 2.51 (m, 13H), 2.71 (s, 3H), 2.80 (d,
J= 9.6 Hz, 1H), 3.10 (s, 3H), 3.26 (s, 4H), 3.33 - 3.66 (m, 3H), 3.98 - 4.32 (m, 4H), 4.53 (dd,
J= 12.0, 2.8 Hz, 1H), 5.35 (q,
J= 6.7 Hz, 1H), 5.49 - 5.65 (m, 1H), 6.51 - 6.67 (m, 3H), 6.89 (s, 1H), 7.19 (d,
J= 1.8 Hz, 1H), 8.25 (s, 2H), 8.34 (d,
J= 7.1 Hz, 1H), 8.58 (t,
J= 6.3 Hz, 1H)。
FMoc-L-Ala-D-Ala-NH-CH
2-S-(CH
2)
5-CO-DM (11f)
:HRMS (M+H)
+計算值1173.4980,實驗值1173.4969。
FMoc-D-Ala-D-Ala-NH-CH
2-S-(CH
2)
5-CO-DM (11h)
:HRMS (M+Na)
+計算值1195.4907,實驗值1195.4799。
1H NMR (400 MHz, DMSO-
d 6) δ 0.71 (s, 3H), 1.00 - 1.22 (m, 13H), 1.28 - 1.45 (m, 2H), 1.52 (s, 3H), 1.91 - 2.14 (m, 1H), 2.26 (t,
J= 1.9 Hz, 5H), 2.48 (t,
J= 1.8 Hz, 2H), 2.62 (s, 3H), 2.66 - 2.77 (m, 2H), 3.01 (s, 2H), 3.10 - 3.21 (m, 5H), 3.28 - 3.47 (m, 2H), 3.86 (d,
J= 6.7 Hz, 4H), 3.93 - 4.25 (m, 10H), 4.37 - 4.54 (m, 1H), 5.27 (d,
J= 6.7 Hz, 1H), 5.40 - 5.56 (m, 1H), 5.85 (s, 1H), 6.31 - 6.66 (m, 3H), 6.81 (s, 1H), 7.11 (d,
J= 1.8 Hz, 1H), 7.26 (t,
J= 7.4 Hz, 2H), 7.35 (t,
J= 7.4 Hz, 2H), 7.45 (d,
J= 7.5 Hz, 1H), 7.65 (t,
J= 7.1 Hz, 2H), 7.82 (d,
J= 7.5 Hz, 2H), 7.89 (d,
J= 7.3 Hz, 1H)。
FMoc-L-Ala-D-Ala-L-Ala-NH-CH
2-S-(CH
2)
3-CO-DM (11j)
:HRMS (M+H)
+計算值1216.5038,實驗值1216.4999。
1H NMR (400 MHz, DMSO-d6) δ 0.78 (s, 3H), 0.95 - 1.29 (m, 16H), 1.37 (d,
J= 3.4 Hz, 1H), 1.46 (t,
J= 12.5 Hz, 2H), 1.59 (s, 3H), 1.62 - 1.90 (m, 1H), 1.99 - 2.07 (m, 1H), 2.08 (s, 2H), 2.18 - 2.43 (m, 1H), 2.50 - 2.59 (m, 1H), 2.69 (s, 3H), 2.73 - 2.83 (m, 1H), 3.10 (s, 2H), 3.25 (s, 3H), 3.38 - 3.55 (m, 2H), 3.91 (s, 3H), 3.99 - 4.13 (m, 4H), 4.12 - 4.35 (m, 7H), 4.52 (dd,
J= 12.0, 2.9 Hz, 1H), 5.34 (q,
J= 6.7 Hz, 1H), 5.48 - 5.65 (m, 1H), 5.92 (s, 1H), 6.48 - 6.70 (m, 3H), 6.88 (s, 1H), 7.17 (d,
J= 1.7 Hz, 1H), 7.33 (t,
J= 7.5 Hz, 2H), 7.41 (t,
J= 7.4 Hz, 2H), 7.58 (d,
J= 7.0 Hz, 1H), 7.71 (t,
J= 8.3 Hz, 2H), 7.89 (d,
J= 7.5 Hz, 3H), 7.95 (d,
J= 7.6 Hz, 1H), 8.15 (d,
J= 7.2 Hz, 1H), 8.29 - 8.38 (m, 1H), 8.41 (s, 1H)。
FMoc-D-Ala-L-Ala-NH-CH
2-S-(CH
2)
2-CO-DM (11i)
:HRMS (M+H)
+計算值1131.4510,實驗值1131.4507。
1H NMR (400 MHz, DMSO-
d6) δ 0.76 (s, 3H), 1.08 - 1.21 (m, 12H), 1.24 (d,
J= 13.9 Hz, 1H), 1.38 - 1.52 (m, 2H), 1.58 (s, 3H), 1.99 - 2.09 (m, 1H), 2.33 - 2.44 (m, 1H), 2.68 (s, 3H), 2.80 (dd,
J= 14.4, 8.6 Hz, 2H), 3.08 (s, 3H), 3.17 (d,
J= 12.5 Hz, 1H), 3.23 (s, 3H), 3.46 (t,
J= 10.3 Hz, 2H), 3.91 (s, 3H), 4.00 - 4.13 (m, 3H), 4.13 - 4.34 (m, 5H), 4.52 (dd,
J= 12.0, 2.9 Hz, 1H), 5.30 (q,
J= 6.8 Hz, 1H), 5.55 (dd,
J= 13.4, 9.1 Hz, 1H), 5.91 (s, 1H), 6.55 (dd,
J= 7.4, 5.7 Hz, 3H), 6.87 (s, 1H), 7.16 (d,
J= 1.8 Hz, 1H), 7.32 (tt,
J= 7.4, 1.5 Hz, 2H), 7.41 (tt,
J= 7.5, 1.5 Hz, 2H), 7.57 (d,
J= 7.0 Hz, 1H), 7.71 (dd,
J= 10.5, 7.5 Hz, 2H), 7.88 (d,
J= 7.5 Hz, 2H), 8.14 (d,
J= 7.6 Hz, 1H), 8.37 (t,
J= 6.3 Hz, 1H)。
胺基 - 肽 - 類美登素
如藉由如由H
2N-L-Ala-L-Ala-L-Ala-NH-CH
2-S-(CH
2)
5-CO-DM所例示製備H
2N-肽-NH-CH
2-S-(CH
2)
n-CO
2-DM類型之化合物。
H
2N-L-Ala-L-Ala-L-Ala-NH-CH
2-S-(CH
2)
5-CO-DM (12a)
:將FMoc-L-Ala-L-Ala-L-Ala-NH-CH
2-S-(CH
2)
5-CO-DM (151 mg,0.121 mmol)用20%嗎啉DMF溶液(2 mL)處理。允許反應在室溫下在氬氣下在磁力攪拌下進行1 h。將粗物質在C18 30微米150 g管柱上純化,用含有0.1%甲酸之去離子水及歷時26 min自5%至50%之乙腈線性梯度進行溶離。立即將含有所需產物之級分冷凍並凍乾,得到46 mg (37.1%產率)之無色油狀物。HRMS (M + H)
+計算值1022.4670;實驗值1022.4669。
1H NMR (400 MHz, DMSO-
d6) δ 0.78 (s, 3H), 1.12 (d,
J= 6.3 Hz, 3H), 1.13 - 1.21 (m, 10H), 1.21 - 1.31 (m, 3H), 1.37 - 1.50 (m, 4H), 1.51 - 1.57 (m, 1H), 1.59 (s, 3H), 2.04 (dd,
J= 14.4, 2.8 Hz, 1H), 2.15 (ddd,
J= 15.9, 8.7, 6.0 Hz, 1H), 2.38 (td,
J= 7.0, 3.6 Hz, 2H), 2.70 (s, 3H), 2.79 (d,
J= 9.6 Hz, 1H), 3.09 (s, 3H), 3.21 (d,
J= 12.5 Hz, 1H), 3.25 (s, 3H), 3.33-3.55 (m, 8H), 3.93 (s, 3H), 4.01 - 4.33 (m, 5H), 4.52 (dd,
J= 12.0, 2.8 Hz, 1H), 5.34 (q,
J= 6.7 Hz, 1H), 5.57 (dd,
J= 14.6, 9.0 Hz, 1H), 5.95 (s, 1H), 6.48 - 6.65 (m, 3H), 6.89 (s, 1H), 7.18 (d,
J= 1.8 Hz, 1H), 8.07 (d,
J= 7.5 Hz, 1H), 8.13 (s, 1H), 8.31 (s, 1H), 8.40 (t,
J= 6.3 Hz, 1H)。
H
2N-D-Ala-L-Ala-L-Ala-NH-CH
2-S-(CH
2)
5-CO-DM (12b)
:HRMS (M+H)
+計算值1022.4670,實驗值1022.4675。
1H NMR (400 MHz, DMSO-d6) δ 0.71 (s, 3H), 1.05 (dd,
J= 6.7, 3.1 Hz, 7H), 1.08 - 1.16 (m, 10H), 1.19 (t,
J= 8.1 Hz, 3H), 1.30 - 1.50 (m, 6H), 1.52 (s, 3H), 1.97 (d,
J= 13.3 Hz, 1H), 2.01 - 2.21 (m, 2H), 2.34 (s, 3H), 2.63 (s, 3H), 2.73 (d,
J= 9.8 Hz, 1H), 3.02 (s, 3H), 3.14 (d,
J= 12.5 Hz, 1H), 3.33 - 3.48 (m, 2H), 3.86 (s, 3H), 3.95 - 4.23 (m, 7H), 4.45 (dd,
J= 13.1 Hz, 1H), 5.27 (q,
J= 6.8 Hz, 1H), 5.41 - 5.58 (m, 1H), 5.85 (s, 1H), 6.39 - 6.63 (m, 4H), 6.81 (s, 1H), 7.12 (d,
J= 1.8 Hz, 1H), 8.02 (s, 1H), 8.13 (d,
J= 7.7 Hz, 1H), 8.26 (s, 1H), 8.36 (t,
J= 6.2 Hz, 1H)。
H
2N-L-Ala-D-Ala-L-Ala-NH-CH
2-S-(CH
2)
5-CO-DM (12c)
:HRMS (M+H)
+計算值1022.4670,實驗值1022.4680。
1H NMR (400 MHz, DMSO-d6) δ 0.71 (s, 3H), 1.01 - 1.26 (m, 19H), 1.25 - 1.50 (m, 6H), 1.52 (s, 3H), 1.97 (d,
J= 13.7 Hz, 1H), 2.02 - 2.22 (m, 1H), 2.35 (dd,
J= 17.2, 9.5 Hz, 2H), 2.47 (d,
J= 11.5 Hz, 1H), 2.63 (s, 4H), 2.73 (d, J = 9.6 Hz, 1H), 3.02 (s, 3H), 3.10 - 3.24 (m, 6H), 3.32 - 3.50 (m, 2H), 3.86 (s, 3H), 3.95 - 4.18 (m, 4H), 4.45 (dd,
J= 12.1, 2.6 Hz, 1H), 5.27 (q,
J= 6.9 Hz, 1H), 5.44 - 5.55 (m, 1H), 5.85 (s, 1H), 6.42 - 6.59 (m, 4H), 6.81 (s, 1H), 7.12 (d,
J= 1.7 Hz, 1H), 8.02 (s, 1H), 8.13 (d,
J= 7.7 Hz, 1H), 8.36 (t,
J= 6.3 Hz, 1H)。
H
2N-L-Ala-L-Ala-D-Ala-NH-CH
2-S-(CH
2)
5-CO-DM (12d)
:HRMS (M+H)
+計算值1022.4670,實驗值1022.4675。
1H NMR (400 MHz, DMSO-d6) δ 0.71 (s, 3H), 0.98 - 1.14 (m, 13H), 1.14 - 1.26 (m, 2H), 1.30 - 1.49 (m, 4H), 1.52 (s, 3H), 2.24 - 2.41 (m, 2H), 2.44 (d,
J= 1.8 Hz, 16H), 2.63 (s, 2H), 2.73 (d,
J= 9.6 Hz, 1H), 3.02 (s, 2H), 3.08 - 3.21 (m, 4H), 3.32 - 3.49 (m, 2H), 3.86 (s, 3H), 3.92 - 4.23 (m, 3H), 4.45 (d,
J= 11.8 Hz, 1H), 5.26 (t,
J= 6.7 Hz, 1H), 5.40 - 5.57 (m, 1H), 5.86 (s, 1H), 6.41 - 6.66 (m, 3H), 6.81 (s, 1H), 7.12 (d,
J= 1.7 Hz, 1H), 8.02 (s, 1H), 8.10 (d,
J= 7.7 Hz, 1H), 8.35 (t,
J= 6.3 Hz, 1H)。
H
2N-D-Ala-L-Ala-NH-CH
2-S-(CH
2)
5-CO-DM (12g)
:HRMS (M+H)
+計算值951.4299,實驗值951.4289。
1H NMR (400 MHz, DMSO-d6) δ 0.79 (s, 3H), 1.06 - 1.34 (m, 13H), 1.36 - 1.54 (m, 4H), 1.60 (s, 2H), 1.88 - 2.10 (m, 1H), 2.10 - 2.23 (m, 1H), 2.31 - 2.51 (m, 13H), 2.71 (s, 3H), 2.80 (d,
J= 9.6 Hz, 1H), 3.10 (s, 3H), 3.26 (s, 4H), 3.33 - 3.66 (m, 3H), 3.98 - 4.32 (m, 4H), 4.53 (dd,
J= 12.0, 2.8 Hz, 1H), 5.35 (q,
J= 6.7 Hz, 1H), 5.49 - 5.65 (m, 1H), 6.51 - 6.67 (m, 3H), 6.89 (s, 1H), 7.19 (d,
J= 1.8 Hz, 1H), 8.25 (s, 2H), 8.34 (d,
J= 7.1 Hz, 1H), 8.58 (t,
J= 6.3 Hz, 1H)。
H
2N-L-Ala-D-Ala-NH-CH
2-S-(CH
2)
5-CO-DM (12f)
:HRMS (M+H)
+計算值951.4226,實驗值951.1299。
1H NMR (400 MHz, DMSO-d6) δ 0.71 (s, 3H), 1.00 - 1.13 (m, 11H), 1.19 (t,
J= 8.9 Hz, 3H), 1.29 - 1.45 (m, 4H), 1.52 (s, 3H), 1.92 - 2.03 (m, 1H), 2.07 (dd,
J= 15.7, 8.7 Hz, 1H), 2.23 - 2.39 (m, 1H), 2.63 (s, 3H), 2.73 (d,
J= 9.7 Hz, 1H), 3.02 (s, 3H), 3.07 - 3.32 (m, 14H), 3.34 - 3.47 (m, 2H), 3.86 (s, 3H), 3.95 - 4.21 (m, 4H), 4.45 (dd,
J= 11.9, 2.8 Hz, 1H), 5.27 (q,
J= 6.8 Hz, 1H), 5.50 (dd,
J= 14.7, 9.0 Hz, 1H), 5.85 (s, 1H), 6.40 - 6.61 (m, 3H), 6.81 (s, 1H), 7.12 (d,
J= 1.8 Hz, 1H), 8.41 (t,
J= 6.1 Hz, 1H)。
H
2N-D-Ala-D-Ala-NH-CH
2-S-(CH
2)
5-CO-DM (12h)
:HRMS (M+H)
+計算值950.4226,實驗值951.4299。
1H NMR (400 MHz, DMSO-d6) δ 0.71 (s, 3H), 0.96 - 1.14 (m, 14H), 1.19 (t,
J= 8.9 Hz, 3H), 1.38 (q,
J= 10.5, 7.0 Hz, 5H), 1.52 (s, 3H), 1.88 - 2.02 (m, 1H), 2.02 - 2.18 (m, 1H), 2.22 - 2.41 (m, 2H), 2.48 (s, 1H), 2.63 (s, 3H), 2.73 (d,
J= 9.6 Hz, 1H), 3.02 (s, 3H), 3.08 - 3.22 (m, 4H), 3.34 - 3.48 (m, 2H), 3.86 (s, 4H), 3.95 - 4.23 (m, 5H), 4.45 (dd,
J= 11.9, 2.8 Hz, 1H), 5.27 (q,
J= 6.7 Hz, 1H), 5.41 - 5.60 (m, 1H), 5.85 (s, 1H), 6.40 - 6.65 (m, 4H), 6.81 (s, 1H), 7.12 (d,
J= 1.8 Hz, 1H), 8.44 (t,
J= 6.1 Hz, 1H)。
H
2N-L-Ala-D-Ala-L-Ala-NH-CH
2-S-(CH
2)
3-CO-DM (12j)
:HRMS (M+H)
+計算值994.4357,實驗值994.4330。
H
2N-D-Ala-L-Ala-NH-CH
2-S-(CH
2)
2-CO-DM (12i)
:HRMS (M+H)
+計算值909.3830,實驗值909.3826。
1H NMR (400 MHz, DMSO-
d6) δ 0.77 (s, 3H), 1.12 (d,
J= 6.7 Hz, 6H), 1.17 (dd,
J= 7.0, 5.2 Hz, 6H), 1.25 (d,
J= 13.3 Hz, 1H), 1.40 - 1.51 (m, 2H), 1.59 (s, 3H), 2.04 (dd,
J= 14.4, 2.9 Hz, 1H), 2.41 (ddt,
J= 18.6, 10.1, 5.4 Hz, 1H), 2.61 - 2.70 (m, 1H), 2.72 (s, 3H), 2.76 - 2.90 (m, 3H), 3.09 (s, 3H), 3.20 (d,
J= 12.4 Hz, 1H), 3.25 (s, 3H), 3.33 (q,
J= 6.9 Hz, 1H), 3.39 - 3.64 (m, 3H), 3.93 (s, 3H), 4.03 - 4.16 (m, 2H), 4.24 (dt,
J= 15.1, 7.6 Hz, 2H), 4.53 (dd,
J= 12.0, 2.9 Hz, 1H), 5.32 (q,
J= 6.8 Hz, 1H), 5.51 - 5.64 (m, 1H), 5.93 (s, 1H), 6.49 - 6.62 (m, 2H), 6.88 (s, 1H), 7.19 (d,
J= 1.8 Hz, 1H), 8.10 (s, 1H), 8.55 (t,
J= 6.3 Hz, 1H)。
SPDB- 肽 - 類美登素
如藉由如由SPDB-L-Ala-L-Ala-L-Ala-NH-CH
2-S-(CH
2)
5-CO-DM所例示製備SPDB-肽-NH-CH
2-S-(CH
2)
n-CO
2-DM類型之化合物。
SPDB-L-Ala-L-Ala-L-Ala-NH-CH
2-S-(CH
2)
5-CO-DM (13a)
:將H
2N-L-Ala-L-Ala-L-Ala-NH-CH
2-S-(CH
2)
5-CO-DM (46 mg,0.045 mmol)溶解於DMF (2 mL)中,向其中添加SPDB (14.7 mg,0.045 mmol)且在室溫下在磁力攪拌下在氬氣氛圍下反應1 h。將粗物質在C18 430微米30g管柱上純化,用含有0.1%甲酸之去離子水及歷時35 min自5%至95%之乙腈線性梯度進行溶離。將含有純所需產物之級分冷凍並凍乾,得到38 mg (68.5%產率)之白色固體。HRMS (M + H)
+計算值1233.4796;實驗值1233.4783。
1H NMR (400 MHz, DMSO-
d6) δ 0.78 (s, 3H), 1.12 (d,
J= 6.4 Hz, 3H), 1.14 - 1.21 (m, 10H), 1.22 - 1.30 (m, 3H), 1.44 (qd,
J= 10.2, 4.5 Hz, 5H), 1.50 - 1.56 (m, 1H), 1.59 (s, 3H), 1.84 (p,
J= 7.3 Hz, 2H), 2.04 (dd,
J= 14.4, 2.7 Hz, 1H), 2.15 (ddd,
J= 15.8, 8.6, 5.9 Hz, 2H), 2.24 (t,
J= 7.2 Hz, 2H), 2.39 (dtdd,
J= 18.1, 13.2, 8.1, 4.7 Hz, 3H), 2.70 (s, 3H), 2.76 - 2.86 (m, 3H), 3.09 (s, 3H), 3.21 (d,
J= 12.5 Hz, 1H), 3.25 (s, 3H), 3.43 (d,
J= 12.4 Hz, 1H), 3.48 (d,
J= 9.0 Hz, 1H), 3.92 (s, 3H), 4.13 (s, 2H), 4.19 (h,
J= 6.6 Hz, 4H), 4.52 (dd,
J= 12.1, 2.8 Hz, 1H), 5.34 (q,
J= 6.8 Hz, 1H), 5.56 (dd,
J= 14.7, 9.0 Hz, 1H), 5.92 (s, 1H), 6.49 - 6.66 (m, 3H), 6.85 - 6.97 (m, 2H), 7.18 (d,
J= 1.8 Hz, 1H), 7.23 (ddd,
J= 7.3, 4.8, 1.2 Hz, 1H), 7.76 (dt,
J= 8.1, 1.2 Hz, 1H), 7.78 - 7.91 (m, 2H), 8.00 (d,
J= 7.1 Hz, 1H), 8.09 (d,
J= 7.0 Hz, 1H), 8.33 (t,
J= 6.3 Hz, 1H), 8.44 (dt,
J= 4.7, 1.3 Hz, 1H), 8.50 (s, 1H)。
SPDB-D-Ala-L-Ala-L-Ala-NH-CH
2-S-(CH
2)
5-CO-DM (13b)
:HRMS (M+H)
+計算值1233.4796,實驗值1233.4799。
1H NMR (400 MHz, DMSO-d6) δ 0.71 (s, 3H), 1.01 - 1.22 (m, 13H), 1.27 - 1.45 (m, 2H), 1.52 (s, 3H), 1.91 - 2.16 (m, 1H), 2.26 (d,
J= 7.4 Hz, 7H), 2.26 (t,
J= 1.9 Hz, 4H), 2.48 (t,
J= 1.8 Hz, 2H), 2.57 - 2.65 (m, 3H), 2.65 - 2.77 (m, 2H), 3.01 (s, 2H), 3.13 (d,
J= 12.2 Hz, 1H), 3.18 (s, 3H), 3.32 - 3.47 (m, 2H), 3.86 (d,
J= 6.7 Hz, 4H), 3.93 - 4.11 (m, 3H), 4.18 (t,
J= 11.2 Hz, 7H), 4.39 - 4.50 (m, 1H), 5.27 (d,
J= 6.7 Hz, 1H), 5.50 (dd,
J= 14.7, 8.8 Hz, 1H), 5.85 (s, 1H), 6.37 - 6.61 (m, 3H), 6.81 (s, 1H), 7.11 (d,
J= 1.8 Hz, 1H), 7.26 (t,
J= 7.4 Hz, 2H), 7.35 (t,
J= 7.4 Hz, 2H), 7.45 (d,
J= 7.5 Hz, 1H), 7.65 (t,
J= 7.1 Hz, 2H), 7.82 (d,
J= 7.5 Hz, 2H), 7.89 (d,
J= 7.3 Hz, 1H)。
SPDB- L-Ala-D-Ala-L-Ala-NH-CH
2-S-(CH
2)
5-CO-DM (13c)
:HRMS (M+H)
+計算值1233.4796,實驗值1233.4795。
1H NMR (400 MHz, DMSO-d6) δ 0.71 (s, 3H), 1.02 - 1.25 (m, 18H), 1.29 - 1.50 (m, 6H), 1.52 (s, 3H), 1.70 - 1.87 (m, 2H), 1.87 - 2.14 (m, 2H), 2.13 - 2.22 (m, 2H), 2.27 - 2.40 (m, 3H), 2.63 (s, 3H), 2.69 - 2.84 (m, 4H), 3.02 (s, 3H), 3.14 (d,
J= 12.3 Hz, 1H), 3.18 (s, 3H), 3.32 - 3.45 (m, 2H), 3.85 (s, 3H), 3.95 - 4.07 (m, 2H), 4.07 - 4.19 (m, 4H), 4.45 (dd,
J= 11.9, 2.7 Hz, 1H), 5.27 (q,
J= 6.7 Hz, 1H), 5.44 - 5.55 (m, 1H), 5.85 (s, 1H), 6.42 - 6.59 (m, 3H), 6.81 (s, 1H), 7.11 (s, 1H), 7.13 - 7.19 (m, 1H), 7.68 (d,
J= 8.2, 2.7 Hz, 1H), 7.72 - 7.80 (m, 1H), 7.88 (t,
J= 6.6 Hz, 1H), 8.04 (d,
J= 6.4 Hz, 1H), 8.09 (d,
J= 7.4 Hz, 1H), 8.25 (t,
J= 6.3 Hz, 1H), 8.37 (dd,
J= 5.0, 1.9 Hz, 1H)。
SPDB- L-Ala-L-Ala-D-Ala-NH-CH
2-S-(CH
2)
5-CO-DM (13d)
:HRMS (M+H)
+計算值1233.4796,實驗值1233.4797。
1H NMR (400 MHz, DMSO-d6) δ 0.72 (d,
J= 3.3 Hz, 3H), 0.98 - 1.28 (m, 22H), 1.30 - 1.46 (m, 3H), 1.53 (s, 3H), 1.78 (q,
J= 7.1 Hz, 2H), 1.86 - 2.16 (m, 2H), 2.19 (q,
J= 7.4, 5.6 Hz, 2H), 2.26 - 2.41 (m, 2H), 2.41 - 2.55 (m, 4H), 2.64 (d,
J= 3.2 Hz, 2H), 2.81 - 2.92 (m, 1H), 3.02 (s, 2H), 3.14 (d,
J= 12.0 Hz, 1H), 3.26 (s, 1H), 3.31 - 3.48 (m, 2H), 3.86 (s, 3H), 3.97 - 4.30 (m, 7H), 4.46 (dd,
J= 11.8, 3.2 Hz, 1H), 5.24 - 5.36 (m, 1H), 5.45 - 5.62 (m, 1H), 5.86 (s, 1H), 6.40 - 6.65 (m, 3H), 6.82 (d,
J= 3.4 Hz, 1H), 7.11 (d,
J= 3.2 Hz, 1H), 7.18 (d,
J= 12.1, 6.1, 4.9 Hz, 2H), 7.69 (d,
J= 8.1 Hz, 1H), 7.75 (t,
J= 7.6 Hz, 2H), 7.89 (d,
J= 7.8, 3.2 Hz, 1H), 7.95 - 8.04 (m, 2H), 8.26 (d,
J= 6.1 Hz, 1H), 8.33 - 8.47 (m, 1H)。
SPDB-D-Ala-L-Ala-NH-CH
2-S-(CH
2)
5-CO-DM (13g)
:HRMS (M+H)
+計算值1162.4425,實驗值1162.4405。
1H NMR (400 MHz, DMSO-d6) δ 0.71 (s, 3H), 1.08 (dt,
J= 13.9, 6.9 Hz, 15H), 1.15 - 1.25 (m, 3H), 1.28 - 1.44 (m, 5H), 1.52 (s, 3H), 1.77 (p,
J= 7.2 Hz, 2H), 1.91 - 2.02 (m, 1H), 2.02 - 2.13 (m, 1H), 2.17 (t,
J= 7.2 Hz, 2H), 2.22 - 2.40 (m, 2H), 2.63 (s, 3H), 2.68 - 2.80 (m, 3H), 3.02 (s, 3H), 3.13 (d,
J= 12.3 Hz, 1H), 3.18 (s, 3H), 3.33 - 3.45 (m, 2H), 3.85 (s, 3H), 3.95 - 4.16 (m, 5H), 4.45 (dd,
J= 12.1, 2.8 Hz, 1H), 5.27 (q,
J= 6.7 Hz, 1H), 5.44 - 5.56 (m, 1H), 5.85 (s, 1H), 6.43 - 6.60 (m, 3H), 6.82 (s, 1H), 7.11 (d,
J= 1.8 Hz, 1H), 7.12 - 7.18 (m, 1H), 7.65 - 7.79 (m, 2H), 8.06 - 8.16 (m, 2H), 8.30 (t,
J= 6.3 Hz, 1H), 8.35 - 8.40 (m, 1H)。
SPDB-L-Ala-D-Ala-NH-CH
2-S-(CH
2)
5-CO-DM (13f)
:HRMS (M+H)
+計算值1162.4399,實驗值1162.455。
1H NMR (400 MHz, DMSO-d6) δ 0.71 (s, 3H), 1.02 - 1.13 (m, 12H), 1.14 - 1.25 (m, 3H), 1.31 - 1.44 (m, 5H), 1.52 (s, 3H), 1.77 (p,
J= 7.3 Hz, 2H), 1.97 (d,
J= 14.3, 2.7 Hz, 1H), 2.02 - 2.13 (m, 1H), 2.17 (t,
J= 7.2 Hz, 2H), 2.28 - 2.40 (m, 3H), 2.43 (m,
J= 3.2 Hz, 3H), 2.63 (s, 3H), 2.69 - 2.80 (m, 3H), 3.02 (s, 3H), 3.13 (d,
J= 12.4 Hz, 1H), 3.18 (s, 3H), 3.39 (dd,
J= 21.0, 10.7 Hz, 2H), 3.85 (s, 3H), 3.96 - 4.18 (m, 5H), 4.45 (dd,
J= 12.1, 2.8 Hz, 1H), 5.27 (q,
J= 6.7 Hz, 1H), 5.45 - 5.55 (m, 1H), 5.85 (s, 1H), 6.43 - 6.60 (m, 3H), 6.81 (s, 1H), 7.10 (d,
J= 1.8 Hz, 1H), 7.16 (t,
J= 7.2, 4.9 Hz, 1H), 7.68 (d,
J= 8.1 Hz, 1H), 7.71 - 7.79 (m, 1H), 8.02 - 8.15 (m, 2H), 8.28 (t,
J= 6.3 Hz, 1H), 8.37 (d,
J= 4.8, 1.7 Hz, 1H)。
SPDB-D-Ala-D-Ala-NH-CH
2-S-(CH
2)
5-CO-DM (13h)
:HRMS (M+H)
+計算值1162.4399,實驗值1162.455。
1H NMR (400 MHz, DMSO-d6) δ 0.71 (s, 3H), 1.02 - 1.16 (m, 13H), 1.14 - 1.25 (m, 3H), 1.28 - 1.49 (m, 5H), 1.52 (s, 3H), 1.77 (p,
J= 7.2 Hz, 2H), 1.92 - 2.14 (m, 2H), 2.17 (t,
J= 7.2 Hz, 2H), 2.23 - 2.40 (m, 2H), 2.46 - 2.54 (m, 1H), 2.63 (s, 3H), 2.65 - 2.85 (m, 4H), 3.02 (s, 3H), 3.03 - 3.16 (m, 2H), 3.18 (s, 3H), 3.28 - 3.45 (m, 2H), 3.85 (s, 3H), 3.95 - 4.20 (m, 5H), 4.45 (dd,
J= 12.1, 2.8 Hz, 1H), 5.27 (q,
J= 6.7 Hz, 1H), 5.44 - 5.55 (m, 1H), 5.82 - 5.88 (m, 1H), 6.42 - 6.59 (m, 3H), 6.81 (s, 1H), 7.11 (d,
J= 1.9 Hz, 1H), 7.14 - 7.20 (m, 1H), 7.67 - 7.72 (m, 1H), 7.72 - 7.80 (m, 1H), 7.88 (d, J = 7.6 Hz, 1H), 7.99 (d,
J= 7.1 Hz, 1H), 8.28 (t,
J= 6.3 Hz, 1H), 8.35 - 8.40 (m, 1H)。
SPDB-L-Ala-D-Ala-L-Ala-NH-CH
2-S-(CH
2)
3-CO-DM (13j)
:HRMS (M+H)
+計算值1203.4337,實驗值1203.4315。
1H NMR (400 MHz, DMSO-d6) δ 0.71 (s, 3H), 0.94 - 1.24 (m, 20H), 1.38 (s, 3H), 1.52 (s, 3H), 1.57 - 1.87 (m, 1H), 1.89 - 2.08 (m, 1H), 2.26 (t,
J= 15.1 Hz, 1H), 2.50 (d,
J= 5.2 Hz, 2H), 2.54 - 2.79 (m, 7H), 3.05 (d,
J= 3.8 Hz, 3H), 3.18 (s, 5H), 3.29 - 3.46 (m, 3H), 3.86 (d,
J= 6.1 Hz, 4H), 4.00 (s, 3H), 4.05 - 4.24 (m, 4H), 4.33 - 4.54 (m, 1H), 5.17 - 5.38 (m, 1H), 5.39 - 5.58 (m, 1H), 5.85 (s, 1H), 6.29 - 6.58 (m, 4H), 6.63 (s, 1H), 6.81 (s, 1H), 7.04 - 7.19 (m, 1H), 7.90 (s, 1H), 8.14 - 8.39 (m, 1H), 8.45 (s, 1H)。
SPDB-D-Ala-L-Ala-NH-CH
2-S-(CH
2)
2-CO-DM (13i)
:HRMS (M+H)
+計算值1120.3955,實驗值1120.3951。
1H NMR (400 MHz, DMSO-
d6) δ 0.74 - 0.82 (m, 3H), 1.10 - 1.22 (m, 13H), 1.25 (d,
J= 14.1 Hz, 1H), 1.46 (t,
J= 10.9 Hz, 2H), 1.56 - 1.63 (m, 3H), 1.85 (ddd,
J= 14.4, 9.0, 5.1 Hz, 2H), 2.00 (ddd,
J= 14.7, 9.3, 5.4 Hz, 9H), 2.24 (dt,
J= 10.8, 5.0 Hz, 2H), 2.72 (d,
J= 3.6 Hz, 2H), 2.94 (dq,
J= 10.7, 7.2, 5.7 Hz, 9H), 3.10 (d,
J= 3.7 Hz, 3H), 3.20 (d,
J= 3.4 Hz, 1H), 3.25 (d,
J= 3.6 Hz, 3H), 3.32 (d,
J= 3.7 Hz, 1H), 3.47 (td,
J= 10.7, 10.0, 3.8 Hz, 2H), 3.93 (t,
J= 4.6 Hz, 3H), 4.02 - 4.25 (m, 6H), 4.49 - 4.57 (m, 1H), 5.28 - 5.37 (m, 1H), 5.53 - 5.62 (m, 1H), 5.92 (d,
J= 3.6 Hz, 1H), 6.57 (q,
J= 5.4, 4.5 Hz, 3H), 6.85 - 6.93 (m, 1H), 7.17 (d,
J= 3.3 Hz, 1H), 7.25 (dq,
J= 8.0, 4.9 Hz, 6H), 7.72 - 7.87 (m, 11H), 8.16 (dt,
J= 15.4, 4.9 Hz, 2H), 8.45 (tt,
J= 9.9, 5.9 Hz, 6H)。
硫代 - 肽 - 類美登素
如藉由如由HS-(CH
2)
3CO-L-Ala-L-Ala-L-Ala-NH-CH
2-S-(CH
2)
5-CO-DM所例示製備HS-(CH
2)
3CO-肽-NH-CH
2-S-(CH
2)
n-CO
2-DM類型之化合物。
HS-(CH
2)
3CO-L-Ala-L-Ala-L-Ala-NH-CH
2-S-(CH
2)
5-CO-DM (14a)
:將SPDB-L-Ala-L-Ala-L-Ala-NH-CH
2-S-(CH
2)
5-CO-DM (38 mg,0.031 mmol)溶解於DMSO (1 mL)中,向其中添加DTT (19 mg,0.12 mmol)於100 mM磷酸鉀、2mM EDTA pH 7.5緩衝液(1mL)中之溶液。允許反應在室溫下在氬氣下在磁力攪拌下進行1 h。將粗反應在C18 30微米30g管柱上純化,用含有0.1%甲酸之去離子水及歷時35 min自5%至95%之乙腈線性梯度進行溶離。立即將含有所需產物之級分冷凍並凍乾,得到18.2 mg (52.5%產率)之白色固體。HRMS (M + H)+計算值1124.4809;實驗值1124.4798。
1H NMR (400 MHz, DMSO-
d6) δ 0.78 (s, 3H), 1.12 (d,
J= 6.4 Hz, 3H), 1.14 - 1.21 (m, 10H), 1.22 - 1.30 (m, 3H), 1.37 - 1.50 (m, 5H), 1.51 - 1.57 (m, 1H), 1.59 (s, 3H), 1.74 (p,
J= 7.2 Hz, 2H), 2.04 (dd,
J= 14.4, 2.8 Hz, 1H), 2.09 - 2.18 (m, 1H), 2.18 - 2.24 (m, 2H), 2.27 (t,
J= 7.6 Hz, 1H), 2.38 (td,
J= 7.1, 4.7 Hz, 2H), 2.44 (t,
J= 7.3 Hz, 2H), 2.70 (s, 3H), 2.79 (d,
J= 9.6 Hz, 1H), 3.09 (s, 3H), 3.21 (d,
J= 12.6 Hz, 1H), 3.25 (s, 3H), 3.43 (d,
J= 12.4 Hz, 1H), 3.49 (d,
J= 9.0 Hz, 1H), 3.93 (s, 3H), 4.08 (ddd,
J= 21.6, 11.4, 4.1 Hz, 2H), 4.13 - 4.28 (m, 4H), 4.52 (dd,
J= 12.1, 2.8 Hz, 1H), 5.34 (q,
J= 6.7 Hz, 1H), 5.56 (dd,
J= 14.7, 9.0 Hz, 1H), 5.91 (d,
J= 1.4 Hz, 1H), 6.48 - 6.66 (m, 3H), 6.88 (s, 1H), 7.18 (d,
J= 1.8 Hz, 1H), 7.86 (d,
J= 7.5 Hz, 1H), 7.96 (d,
J= 7.3 Hz, 1H), 8.05 (d,
J= 7.1 Hz, 1H), 8.33 (t,
J= 6.3 Hz, 1H)。
HS-(CH
2)
3CO-D-Ala-L-Ala-L-Ala-NH-CH
2-S-(CH
2)
5-CO-DM (14b)
:HRMS (M+Na)
+計算值1146.4629,實驗值1146.4591。
1H NMR (400 MHz, DMSO-d6) δ 0.71 (s, 3H), 1.03 - 1.25 (m, 19H), 1.30 - 1.45 (m, 6H), 1.52 (s, 4H), 1.65 (p,
J= 7.3 Hz, 2H), 1.91 - 2.02 (m, 1H), 2.02 - 2.13 (m, 1H), 2.12 - 2.19 (m, 4H), 2.29 - 2.39 (m, 4H), 2.63 (s, 3H), 2.73 (d,
J= 9.6 Hz, 1H), 3.02 (s, 3H), 3.14 (d,
J= 12.5 Hz, 1H), 3.33 - 3.47 (m, 2H), 3.86 (s, 3H), 4.01 (td,
J= 10.4, 9.7, 4.3 Hz, 2H), 4.04 - 4.16 (m, 5H), 4.45 (dd,
J= 12.0, 2.9 Hz, 1H), 5.27 (q,
J= 6.7 Hz, 1H), 5.43 - 5.56 (m, 1H), 5.85 (s, 1H), 6.38 - 6.61 (m, 4H), 6.81 (s, 1H), 7.11 (d,
J= 1.8 Hz, 1H), 7.82 (d,
J= 7.7 Hz, 1H), 7.97 (t,
J= 6.3 Hz, 1H), 8.10 (d,
J= 6.0 Hz, 1H), 8.25 (d,
J= 6.9 Hz, 1H)。
HS-(CH
2)
3CO-L-Ala-D-Ala-L-Ala-NH-CH
2-S-(CH
2)
5-CO-DM (14c)
:HRMS (M+Na)
+計算值1146.4629,實驗值1146.4553。
1H NMR (400 MHz, DMSO-d6) δ 0.71 (s, 3H), 0.99 - 1.26 (m, 21H), 1.31 - 1.45 (m, 5H), 1.52 (s, 3H), 1.67 (p,
J= 7.2 Hz, 2H), 1.89 - 2.02 (m, 1H), 2.02 - 2.24 (m, 4H), 2.25 - 2.46 (m, 3H), 2.63 (s, 3H), 2.73 (d,
J= 9.7 Hz, 1H), 3.02 (s, 3H), 3.18 (s, 3H), 3.32 - 3.51 (m, 2H), 3.86 (s, 3H), 3.96 - 4.18 (m, 7H), 4.45 (dd,
J= 12.0, 2.9 Hz, 1H), 5.27 (q, J = 6.8 Hz, 1H), 5.44 - 5.63 (m, 1H), 5.85 (s, 1H), 6.37 - 6.59 (m, 4H), 6.81 (s, 1H), 7.11 (d,
J= 1.8 Hz, 1H), 7.89 (d,
J= 7.7 Hz, 1H), 8.03 (d,
J= 6.5 Hz, 1H), 8.08 (d,
J= 7.3 Hz, 1H), 8.27 (t,
J= 6.3 Hz, 1H)。
HS-(CH
2)
3CO-L-Ala-L-Ala-D-Ala-NH-CH
2-S-(CH
2)
5-CO-DM (14d)
:HRMS (M+Na)
+計算值1146.4629,實驗值1146.4519。
1H NMR (400 MHz, DMSO-d6) δ 0.71 (s, 3H), 0.95 - 1.24 (m, 20H), 1.27 - 1.45 (m, 5H), 1.52 (s, 3H), 1.67 (p,
J= 7.3 Hz, 2H), 1.93 - 2.01 (m, 1H), 2.02 - 2.22 (m, 4H), 2.22 - 2.41 (m, 5H), 2.63 (s, 3H), 2.73 (d,
J= 9.6 Hz, 1H), 3.02 (s, 3H), 3.18 (s, 4H), 3.39 (dd,
J= 21.4, 10.7 Hz, 2H), 3.86 (s, 3H), 3.94 - 4.24 (m, 6H), 4.45 (dd,
J= 12.0, 2.8 Hz, 1H), 5.27 (q,
J= 6.7 Hz, 1H), 5.44 - 5.57 (m, 1H), 5.85 (s, 1H), 6.37 - 6.65 (m, 3H), 6.81 (s, 1H), 7.11 (d,
J= 1.8 Hz, 1H), 7.89 (d,
J= 7.6 Hz, 1H), 7.93 - 8.05 (m, 2H), 8.26 (t,
J= 6.4 Hz, 1H)。
HS-(CH
2)
3CO-D-Ala-L-Ala-NH-CH
2-S-(CH
2)
5-CO-DM (14g)
:HRMS (M+H)
+計算值1053.4438,實驗值1053.4426。
1H NMR (400 MHz, DMSO-d6) δ 0.71 (s, 3H), 1.01 - 1.15 (m, 13H), 1.15 - 1.27 (m, 3H), 1.31 - 1.44 (m, 5H), 1.53 (s, 3H), 1.67 (p,
J= 7.1 Hz, 2H), 1.93 - 2.03 (m, 1H), 2.03 - 2.23 (m, 4H), 2.22 - 2.41 (m, 5H), 2.63 (s, 3H), 2.73 (d,
J= 9.7 Hz, 1H), 3.02 (s, 3H), 3.14 (d,
J= 12.5 Hz, 1H), 3.18 (s, 3H), 3.32 - 3.46 (m, 2H), 3.86 (s, 3H), 3.92 - 4.20 (m, 6H), 4.45 (dd,
J= 11.9, 2.8 Hz, 1H), 5.27 (q,
J= 6.7 Hz, 1H), 5.42 - 5.58 (m, 1H), 5.85 (s, 1H), 6.42 - 6.60 (m, 3H), 6.81 (s, 1H), 7.12 (d,
J= 1.8 Hz, 1H), 8.05 (d,
J= 6.5 Hz, 1H), 8.10 (d,
J= 7.8 Hz, 1H), 8.30 (t,
J= 6.3 Hz, 1H)。
HS-(CH
2)
3CO-L-Ala-D-Ala-NH-CH
2-S-(CH
2)
5-CO-DM (14f)
:HRMS (M+H)
+計算值1053.4366,實驗值1053.4438。
1H NMR (400 MHz, DMSO-d6) δ 0.71 (s, 3H), 1.02 - 1.14 (m, 13H), 1.19 (t,
J= 9.7 Hz, 3H), 1.31 - 1.43 (m, 6H), 1.53 (s, 3H), 1.67 (p,
J= 7.3 Hz, 2H), 1.91 - 2.02 (m, 1H), 2.02 - 2.22 (m, 4H), 2.34 - 2.39 (m, 4H), 2.63 (s, 3H), 2.73 (d,
J= 9.5 Hz, 1H), 3.02 (s, 3H), 3.19 (d,
J= 4.2 Hz, 4H), 3.30 - 3.47 (m, 2H), 3.86 (s, 3H), 3.94 - 4.20 (m, 6H), 4.45 (d,
J= 11.8, 2.8 Hz, 1H), 5.27 (q,
J= 6.7 Hz, 1H), 5.44 - 5.56 (m, 1H), 5.85 (s, 1H), 6.40 - 6.61 (m, 3H), 6.81 (s, 1H), 7.12 (s, 1H), 8.03 (d,
J= 6.5 Hz, 1H), 8.08 (d,
J= 7.8 Hz, 1H), 8.29 (t,
J= 6.2 Hz, 1H)。
HS-(CH
2)
3CO-D-Ala-D-Ala-NH-CH
2-S-(CH
2)
5-CO-DM (14h)
:HRMS (M+H)
+計算值1053.4366,實驗值1053.4438。
1H NMR (400 MHz, DMSFO-d6) δ 0.71 (s, 3H), 1.02 - 1.15 (m, 13H), 1.14 - 1.24 (m, 3H), 1.30 - 1.45 (m, 5H), 1.53 (s, 3H), 1.67 (p, J = 7.1 Hz, 2H), 1.90 - 2.01 (m, 1H), 2.01 - 2.24 (m, 4H), 2.27 - 2.33 (m, 1H), 2.33 - 2.42 (m, 4H), 2.63 (s, 3H), 2.73 (d,
J= 9.7 Hz, 1H), 3.02 (s, 3H), 3.10 - 3.21 (m, 4H), 3.33 - 3.46 (m, 2H), 3.86 (s, 3H), 3.95 - 4.18 (m, 6H), 4.45 (dd,
J= 11.9, 2.8 Hz, 1H), 5.27 (q,
J= 6.7 Hz, 1H), 5.44 - 5.55 (m, 1H), 5.85 (s, 1H), 6.42 - 6.59 (m, 3H), 6.81 (s, 1H), 7.12 (d,
J= 1.8 Hz, 1H), 8.05 (d,
J= 6.5 Hz, 1H), 8.10 (d,
J= 7.8 Hz, 1H), 8.30 (t,
J= 6.3 Hz, 1H)。
HS-(CH
2)
3CO-L-Ala-D-Ala-L-Ala-NH-CH
2-S-(CH
2)
3-CO-DM (14j)
:HRMS (M+H)
+計算值1096.4496,實驗值1096.4464。1H NMR (400 MHz, DMSO-
d6) δ 0.78 (s, 3H), 1.02 - 1.31 (m, 19H), 1.35 - 1.55 (m, 2H), 1.60 (s, 3H), 1.74 (p,
J= 7.4 Hz, 3H), 1.78 - 1.93 (m, 1H), 2.14 - 2.33 (m, 4H), 2.41 - 2.49 (m, 2H), 2.71 (s, 3H), 2.80 (d,
J= 9.6 Hz, 1H), 3.12 (s, 3H), 3.22 (d,
J= 12.7 Hz, 1H), 3.26 (s, 3H), 3.47 (dd,
J= 21.3, 10.6 Hz, 2H), 3.93 (s, 4H), 4.03 - 4.13 (m, 3H), 4.13 - 4.25 (m, 3H), 4.52 (dd,
J= 12.0, 2.8 Hz, 1H), 5.35 (q,
J= 6.8 Hz, 1H), 5.50 - 5.64 (m, 1H), 5.92 (s, 1H), 6.47 - 6.69 (m, 4H), 6.88 (s, 1H), 7.18 (d,
J= 1.7 Hz, 1H), 7.94 (d,
J= 7.3 Hz, 1H), 8.09 (d,
J= 6.4 Hz, 1H), 8.15 (d,
J= 7.3 Hz, 1H), 8.32 (t,
J= 6.3 Hz, 1H)。
HS-(CH
2)
3CO-(CH
2)
3-CO-D-Ala-L-Ala-NH-CH
2-S-(CH
2)
2-CO-DM (14i)
:HRMS (M+H)
+計算值1011.3969,實驗值1011.3961。
1H NMR (400 MHz, DMSO-
d6) δ 0.77 (s, 3H), 1.12 (d,
J= 6.4 Hz, 3H), 1.17 (dd,
J= 7.0, 5.1 Hz, 9H), 1.25 (d,
J= 13.0 Hz, 1H), 1.40 - 1.51 (m, 2H), 1.59 (s, 3H), 1.74 (q,
J= 7.2 Hz, 2H), 2.00 - 2.08 (m, 1H), 2.23 (dt,
J= 16.8, 7.6 Hz, 3H), 2.43 (q,
J= 7.4 Hz, 2H), 2.62 - 2.69 (m, 1H), 2.72 (s, 3H), 2.76 - 2.88 (m, 2H), 3.10 (s, 3H), 3.20 (d,
J= 12.6 Hz, 1H), 3.25 (s, 3H), 3.31 (s, 3H), 3.39 - 3.54 (m, 2H), 3.93 (s, 3H), 4.01 - 4.26 (m, 5H), 4.53 (dd,
J= 12.0, 2.8 Hz, 1H), 5.32 (q,
J= 6.8 Hz, 1H), 5.49 - 5.63 (m, 1H), 5.92 (d,
J= 1.4 Hz, 1H), 6.48 - 6.62 (m, 3H), 6.88 (s, 1H), 7.18 (d,
J= 1.8 Hz, 1H), 8.10 (d,
J= 6.5 Hz, 1H), 8.16 (d,
J= 7.7 Hz, 1H), 8.41 (t,
J= 6.3 Hz, 1H)。
NHS-L-Ala-D-Ala-L-Ala-Imm-C6-May
如由HOOC-(CH
2)
3-CO-L-Ala-D-Ala-L-Ala-NH-CH
2-S-(CH
2)
5-CO-DM所例示製備HOOC-(CH
2)
3-CO-肽-NH-CH
2-S-(CH
2)
n-CO
2-DM類型之化合物。
-(CH
2)
3-CO-L-Ala-D-Ala-L-Ala-NH-CH
2-S-(CH
2)
5-CO-DM(19a)
:將L-Ala-D-Ala-L-Ala-NH-CH
2-S-(CH
2)
5-CO-DM (17.25 mg,0.017 mmol)用戊二酸酐(38.5 mg,0.337 mmol)處理且在室溫下在磁力攪拌下在氬氣下反應隔夜。將粗反應物藉由HPLC純化,使用XDB-C18 21.2 x 5 mm 5微米管柱,在20 ml/min下用含有0.1%甲酸之去離子水及歷時30 min自5%至95%之乙腈線性梯度進行溶離。立即將含有純所需產物之級分合併,冷凍並凍乾,得到3 mg (15%產率)之白色固體。HRMS (M+H)
+計算值1136.4987,實驗值1136.4954。
1H NMR (400 MHz, DMSO-d6) δ 0.71 (s, 3H), 0.92 - 1.27 (m, 20H), 1.26 - 1.48 (m, 5H), 1.52 (s, 3H), 1.63 (q,
J= 7.1 Hz, 2H), 1.83 - 2.20 (m, 7H), 2.23 - 2.41 (m, 5H), 2.63 (s, 4H), 2.73 (d,
J= 9.5 Hz, 1H), 3.02 (s, 3H), 3.36 - 3.50 (m, 2H), 3.86 (s, 3H), 3.91 - 4.24 (m, 7H), 4.45 (d,
J= 11.8 Hz, 1H), 5.27 (q,
J= 6.7 Hz, 1H), 5.41 - 5.57 (m, 1H), 5.86 (s, 1H), 6.32 - 6.66 (m, 3H), 6.81 (s, 1H), 7.12 (s, 1H), 8.06 (t,
J= 9.1 Hz, 2H), 8.35 (d,
J= 11.6 Hz, 1H), 8.62 (s, 1H)。
HOOC-(CH
2)
3-CO-D-Ala-L-Ala-NH-CH
2-S-(CH
2)
5-CO-DM (19g)
:HRMS (M+H)
+計算值1136.4987,實驗值1136.4962。
1H NMR (400 MHz, DMSO-d6) δ 0.71 (s, 3H), 0.97 - 1.14 (m, 13H), 1.14 - 1.26 (m, 3H), 1.28 - 1.45 (m, 5H), 1.52 (s, 3H), 1.62 (p,
J= 7.5 Hz, 2H), 1.93 - 2.00 (m, 1H), 2.08 (dt,
J= 13.1, 7.4 Hz, 6H), 2.25 - 2.41 (m, 3H), 2.63 (s, 3H), 2.73 (d,
J= 9.5 Hz, 1H), 3.02 (s, 3H), 3.18 (s, 3H), 3.31 - 3.48 (m, 2H), 3.86 (s, 3H), 3.93 - 4.19 (m, 6H), 4.45 (dd,
J= 12.0, 2.8 Hz, 1H), 5.27 (q,
J= 6.8 Hz, 1H), 5.43 - 5.58 (m, 1H), 5.85 (s, 1H), 6.40 - 6.61 (m, 3H), 6.81 (s, 1H), 7.11 (d,
J= 1.8 Hz, 1H), 8.03 (d,
J= 6.5 Hz, 1H), 8.13 (d,
J= 7.8 Hz, 1H), 8.34 (t,
J= 6.3 Hz, 1H), 11.94 (s, 1H)。
HOOC-(CH
2)
3-CO-L-Ala-D-Ala-L-Ala-NH-CH
2-S-(CH
2)
3-CO-DM (19i)
:HRMS (M+H)
+計算值1108.4674,實驗值1108.4634。
1H NMR (400 MHz, DMSO-d6) δ 0.78 (s, 3H), 1.04 - 1.32 (m, 16H), 1.45 (d,
J= 12.6 Hz, 2H), 1.60 (s, 3H), 1.69 (p,
J= 7.2 Hz, 3H), 1.77 - 1.95 (m, 1H), 1.99 - 2.07 (m, 1H), 2.11 - 2.20 (m, 4H), 2.20 - 2.39 (m, 1H), 2.55 (s, 1H), 2.71 (s, 3H), 2.80 (d,
J= 9.5 Hz, 1H), 3.12 (s, 3H), 3.40 (d,
J= 21.0 Hz, 8H), 3.49 (d,
J= 9.1 Hz, 1H), 3.93 (s, 3H), 4.02 - 4.27 (m, 6H), 4.48 - 4.61 (m, 1H), 5.34 (q, J = 6.6 Hz, 1H), 5.48 - 5.65 (m, 1H), 5.92 (s, 1H), 6.50 - 6.71 (m, 3H), 6.88 (s, 1H), 7.18 (s, 1H), 7.99 (d,
J= 7.6 Hz, 1H), 8.08 (d,
J= 6.5 Hz, 1H), 8.22 (d,
J= 7.4 Hz, 1H), 8.30 (s, 1H), 8.42 (s, 1H)。
如藉由如由NHS-OOC-(CH
2)
3-CO-D-Ala-L-Ala-NH-CH
2-S-(CH
2)
5-CO-DM所例示製備NHS-OOC-(CH
2)
3-CO-肽-NH-CH
2-S-(CH
2)
n-CO
2-DM類型之化合物。
NHS-OOC-(CH
2)
3-CO-D-Ala-L-Ala-NH-CH
2-S-(CH
2)
5-CO-DM (20g)
:將HOOC-(CH
2)
3-CO-D-Ala-L-Ala-NH-CH
2-S-(CH
2)
5-CO-DM (8 mg 7.5 μmol)溶解於DMSO (1 mL)中,用NHS (0.9 mg,7.51 μmol)及EDC (1.4 mg,7.51 μmol)處理。允許反應在室溫下在氬氣氛圍下在磁力攪拌下進行2小時。將粗物質經由HPLC純化,使用XDB-C18 21.2 x 5mm 5 μm管柱,在20 ml/min下用含有0.1%甲酸之去離子水及歷時30 min自5%至95%之乙腈線性梯度進行溶離。將含有所需產物之級分合併且立即冷凍,然後凍乾,得到6.5 mg (74%產率)之白色固體。
1H NMR (400 MHz, DMSO-d6) δ 0.71 (s, 3H), 1.00 - 1.14 (m, 13H), 1.14 - 1.25 (m, 3H), 1.29 - 1.46 (m, 5H), 1.52 (s, 3H), 1.75 (p,
J= 7.5 Hz, 2H), 1.92 - 2.12 (m, 2H), 2.16 (t,
J= 7.3 Hz, 2H), 2.22 - 2.39 (m, 3H), 2.62 (d,
J= 10.8 Hz, 5H), 2.73 (d,
J= 10.5 Hz, 5H), 3.02 (s, 3H), 3.18 (s, 3H), 3.32 - 3.47 (m, 2H), 3.86 (s, 3H), 3.95 - 4.19 (m, 6H), 4.45 (dd,
J= 12.0, 2.8 Hz, 1H), 5.27 (q,
J= 6.8 Hz, 1H), 5.42 - 5.57 (m, 1H), 5.82 - 5.87 (m, 1H), 6.41 - 6.60 (m, 4H), 6.81 (s, 1H), 7.11 (d,
J= 1.7 Hz, 1H), 8.05 (d,
J= 6.5 Hz, 1H), 8.10 (d,
J= 7.7 Hz, 1H), 8.20 (d, J = 4.8 Hz, 1H), 8.29 (t,
J= 6.3 Hz, 1H)。
NHS-OOC-(CH
2)
3-CO-L-Ala-D-Ala-L-Ala-NH-CH
2-S-(CH
2)
5-CO-DM (20g)
:HRMS (M+H)
+計算值1233.5151,實驗值1233.5135。
NHS-OOC-(CH
2)
3-CO-L-Ala-D-Ala-L-Ala-NH-CH
2-S-(CH
2)
3-CO-DM (20i)
:HRMS (M+H)
+計算值1205.4838,實驗值1205.4808。
如藉由如由H
2N-O-CH
2-CO-L-Ala-D-Ala-L-Ala-NH-CH
2-S-(CH
2)
5-CO-DM所例示製備H
2N-O-CH
2-CO-肽-NH-CH
2-S-(CH
2)
n-CO
2-DM類型之化合物。
H
2N-O-CH
2-CO-L-Ala-D-Ala-L-Ala-NH-CH
2-S-(CH
2)
5-CO-DM (22c):
將H
2N-L-Ala-D-Ala-L-Ala-CH
2-S-(CH
2)
5-CO-DM (23 mg,0.022 mmol)溶解於DMF (1 mL)中,用FMoc-胺基氧基乙酸(14.09 mg,0.045 mmol)及EDC (8.62 mg,0.045 mmol處理。允許反應在室溫下在氬氣氛圍下在磁力攪拌下進行3 h。該粗物質用20%嗎啉DMF溶液(1 mL)處理且允許反應進行2 h。將粗物質經由半製備型HPLC純化,使用XDB-C18 21.2 x 5mm 5 μm,在20 ml/min下用含有0.1%甲酸之去離子水及歷時30 min自5%至95%之乙腈線性梯度進行溶離。將含有所需產物之級分彙集起來且立即冷凍,然後凍乾,得到5.5 mg (22%產率)之白色固體。HRMS (M+H)
+計算值1095.4834,實驗值1095.4795。
1H NMR (400 MHz, DMSO-
d 6) δ 0.71 (s, 3H), 1.00 - 1.14 (m, 13H), 1.14 - 1.25 (m, 6H), 1.31 - 1.43 (m, 4H), 1.52 (s, 3H), 1.92 - 2.02 (m, 1H), 2.02 - 2.14 (m, 1H), 2.23 - 2.39 (m, 3H), 2.63 (s, 3H), 2.73 (d,
J= 9.6 Hz, 1H), 3.02 (s, 3H), 3.14 (d,
J= 12.5 Hz, 1H), 3.18 (s, 3H), 3.29 - 3.46 (m, 3H), 3.86 (s, 3H), 3.90 (d,
J= 2.0 Hz, 2H), 3.95 - 4.20 (m, 6H), 4.25 (p,
J= 7.7, 7.2 Hz, 1H), 4.45 (dd,
J= 12.0, 2.8 Hz, 1H), 5.27 (q,
J= 6.8 Hz, 1H), 5.44 - 5.58 (m, 1H), 5.85 (s, 1H), 6.30 (s, 2H), 6.43 - 6.60 (m, 3H), 6.81 (s, 1H), 7.12 (d,
J= 1.7 Hz, 1H), 7.82 (d,
J= 7.4 Hz, 1H), 7.97 (d,
J= 7.6 Hz, 1H), 8.10 (d,
J= 7.2 Hz, 1H), 8.29 (t,
J= 6.3 Hz, 1H)。
H
2N-O-CH
2CO-L-Ala-D-Ala-L-Ala-NH-CH
2-S-(CH
2)
3-CO-DM (22i)
:HRMS (M+H)
+計算值1067.4521,實驗值1067.4484。
1H NMR (400 MHz, DMSO-
d 6) δ 0.71 (s, 3H), 1.01 - 1.26 (m, 18H), 1.30 - 1.46 (m, 2H), 1.52 (s, 3H), 1.55 - 1.69 (m, 1H), 1.69 - 1.84 (m, 1H), 1.97 (d,
J= 14.4, 2.8 Hz, 1H), 2.15 - 2.31 (m, 1H), 2.56 - 2.61 (m, 1H), 2.63 (s, 3H), 2.73 (d,
J= 9.6 Hz, 1H), 3.04 (s, 3H), 3.14 (d,
J= 12.6 Hz, 1H), 3.18 (s, 3H), 3.36 (d,
J= 12.3 Hz, 1H), 3.42 (dd,
J= 9.1, 3.3 Hz, 1H), 3.85 (s, 3H), 3.90 (d,
J= 2.3 Hz, 2H), 3.95 - 4.05 (m, 3H), 4.06 - 4.17 (m, 2H), 4.15 - 4.35 (m, 2H), 4.45 (dd,
J= 12.0, 2.8 Hz, 1H), 5.27 (q,
J= 6.7 Hz, 1H), 5.44 - 5.56 (m, 1H), 5.85 (s, 1H), 6.30 (s, 2H), 6.42 - 6.61 (m, 3H), 6.81 (s, 1H), 7.11 (d,
J= 1.7 Hz, 1H), 7.82 (d,
J= 7.3 Hz, 1H), 7.96 (d,
J= 7.6 Hz, 1H), 8.11 (d,
J= 7.2 Hz, 1H), 8.22 - 8.40 (m, 1H)。
Mal-(CH
2)
3-CO-L-Ala-D-Ala-L-Ala-NH-CH
2-S-(CH
2)
5-CO-DM (23c)
:將H
2N-L-Ala-D-Ala-L-Ala-CH
2-S-(CH
2)
5-CO-DM (8 mg,7.82 μmol)溶解於DMF (2 mL)中,用3-順丁烯二醯亞胺基丙酸(1.32 mg,7.82 mol)、EDC (2.25 mg,0.012 mmol)及HOBt (1.198 mg,7.82 μmol)處理。允許反應在室溫下在氬氣氛圍下在磁力攪拌下進行2 h。將粗物質經由半製備型HPLC純化,使用XDB-C18 21.2x5mm 5 μm,在20 ml/min下用含有0.1%甲酸之去離子水及歷時30 min自5%至95%之乙腈線性梯度進行溶離。立即將含有所需產物之級分合併且冷凍,然後凍乾,得到1.8 mg (19.60%產率)之白色固體。HRMS (M+H)
+計算值1173.4940,實驗值1173.4931。
1H NMR (400 MHz, DMSO-d6) δ 0.71 (s, 3H), 1.02 - 1.14 (m, 15H), 1.16 - 1.25 (m, 3H), 1.30 - 1.44 (m, 5H), 1.52 (s, 3H), 1.92 - 2.03 (m, 1H), 2.03 - 2.17 (m, 1H), 2.23 - 2.39 (m, 4H), 2.63 (s, 3H), 2.73 (d,
J= 9.6 Hz, 1H), 3.02 (s, 3H), 3.18 (s, 4H), 3.33 - 3.46 (m, 2H), 3.52 (t,
J= 7.3 Hz, 2H), 3.86 (s, 3H), 3.95 - 4.17 (m, 7H), 4.45 (dd,
J= 12.0, 2.9 Hz, 1H), 5.27 (q,
J= 6.7 Hz, 1H), 5.44 - 5.56 (m, 1H), 5.85 (s, 1H), 6.39 - 6.64 (m, 3H), 6.81 (s, 1H), 6.86 (s, 1H), 6.92 (s, 2H), 7.11 (d,
J= 1.7 Hz, 1H), 7.89 (d,
J= 7.4 Hz, 1H), 8.10 (d, J = 7.3 Hz, 1H), 8.17 (d,
J= 6.7 Hz, 1H), 8.28 (t,
J= 6.3 Hz, 1H), 8.43 (s, 1H)。
Mal2-LAla-D-Ala-L-Ala-Imm-C6-May
Mal-C5-L-Ala-D-Ala-L-Ala-Imm-C6-May :L-Ala-D-Ala-L-Ala-CH
2-S-(CH
2)
5-CO-MayNMA (化合物I-1a) (25mg,0.024 mmol)與6-(2,5-二側氧基-2,5-二氫-1H-吡咯-1-基)己酸2,5-二側氧基吡咯啶-1-基酯(7.54 mg,0.024 mmol)之間的反應產生Mal-C5-L-Ala-D-Ala-L-Ala-Imm-C6-May (化合物I-2a) (20.8mg,0.017 mmol,70.0 %產率)。
LRMS (M+H)
+計算值1215.52,實驗值1216.4。
1H NMR (400 MHz, DMSO-
d6) δ 0.71 (s, 3H), 1.05 (d,
J= 6.4 Hz, 3H), 1.07 - 1.14 (m, 14H), 1.15 - 1.25 (m, 3H), 1.39 (t,
J= 9.2 Hz, 10H), 1.52 (s, 3H), 2.01 (t,
J= 7.6 Hz, 3H), 2.26 (t,
J= 1.9 Hz, 1H), 2.28 - 2.38 (m, 2H), 2.57 - 2.62 (m, 1H), 2.63 (s, 3H), 2.73 (d,
J= 9.6 Hz, 1H), 3.02 (s, 3H), 3.14 (d,
J= 12.5 Hz, 1H), 3.18 (s, 3H), 3.29 (t,
J= 7.1 Hz, 2H), 3.36 (d,
J= 12.5 Hz, 1H), 3.42 (d,
J= 9.0 Hz, 1H), 3.86 (s, 3H), 3.96 - 4.05 (m, 1H), 4.04 - 4.15 (m, 4H), 4.41 - 4.48 (m, 1H), 5.27 (q,
J= 6.7 Hz, 1H), 5.46 - 5.54 (m, 1H), 5.82 - 5.88 (m, 1H), 6.47 - 6.50 (m, 2H), 6.54 (t,
J= 11.4 Hz, 2H), 6.82 (s, 1H), 6.92 (s, 2H), 7.11 (d,
J= 1.8 Hz, 1H), 7.86 - 7.93 (m, 2H), 7.95 (s, 1H), 8.05 (d,
J= 7.4 Hz, 1H), 8.24 (t,
J= 6.2 Hz, 1H)。
Mal-(CH
2)
2-PEG
2-CO-L-Ala-D-Ala-L-ALa-NH-CH2-S-(CH2)5-CO-MayNMA
-(CH
2)
2-PEG
2-CO-L-Ala-D-Ala-L-ALa-NH-CH
2-S-(CH
2)
5-CO-MayNMA
: L-Ala-D-Ala-L-Ala-NH-CH
2-S-(CH
2)
5-CO-MayNMA (化合物I-1a) (25mg,0.024 mmol)與Mal-醯胺基-PEG
2-NHS (10.40 mg,0.024 mmol)之間的反應產生Mal-(CH2)
2-PEG
2-CO2-L-Ala-D-Ala-L-ALa-NH-CH
2-S-(CH
2)
5-CO-MayNMA (化合物I-3a) (14.1mg,10.58 μmol,43.3 %產率)。
LRMS (M+H)
+計算值1332.58,實驗值1332.95。
1H NMR (400 MHz, DMSO-
d6) δ 0.71 (s, 4H), 1.05 (d,
J= 6.3 Hz, 4H), 1.07 - 1.14 (m, 15H), 1.18 (d,
J= 9.0 Hz, 2H), 1.37 (d,
J= 11.8 Hz, 6H), 1.52 (s, 3H), 2.23 - 2.38 (m, 5H), 2.63 (s, 4H), 2.72 (d,
J= 9.7 Hz, 1H), 3.02 (s, 3H), 3.07 (q,
J= 5.7 Hz, 2H), 3.18 (s, 3H), 3.39 (s, 4H), 3.41 (d,
J= 9.9 Hz, 2H), 3.47 - 3.56 (m, 4H), 3.86 (s, 4H), 3.95 - 4.08 (m, 2H), 4.08 - 4.19 (m, 3H), 4.41 - 4.51 (m, 1H), 5.23 - 5.31 (m, 1H), 5.44 - 5.54 (m, 1H), 5.85 (s, 1H), 6.46 - 6.50 (m, 2H), 6.54 (t,
J= 11.3 Hz, 2H), 6.83 (s, 1H), 6.93 (s, 2H), 7.12 (s, 1H), 7.88 - 8.00 (m, 2H), 8.01 - 8.08 (m, 2H), 8.27 (t,
J= 6.2 Hz, 1H)。
Mal-(CH
2)
2-PEG
4-CO-L-Ala-D-Ala-L-ALa-NH-CH
2-S-(CH
2)
5-CO-MayNMA
Mal-(CH
2)
2-PEG
4-CO
2-L-Ala-D-Ala-L-ALa-NH-CH
2-S-(CH
2)
5-CO-MayNMA
:L-Ala-D-Ala-L-Ala-NH-CH
2-S-(CH
2)
5-CO-MayNMA (化合物I-1a) (25mg,0.024 mmol)與Mal-醯胺基-PEG4-NHS (12.55 mg,0.024 mmol)之間的反應產生Mal-(CH
2)
2-PEG
4-CO2-L-Ala-D-Ala-L-ALa-NH-CH
2-S-(CH
2)
5-CO-MayNMA Mal-PEG4-CO2-C6-LDL-DM (化合物I-3b) (22.3mg,0.016 mmol,64.2 %產率)。
LRMS (M+H)
+計算值1420.63,實驗值1420.06
1H NMR (400 MHz, DMSO-
d6) δ 0.71 (s, 4H), 1.05 (d,
J= 6.4 Hz, 3H), 1.07 - 1.16 (m, 14H), 1.19 (t,
J= 8.1 Hz, 2H), 1.31 - 1.50 (m, 2H), 1.52 (s, 4H), 1.98 (s, 1H), 2.02 - 2.17 (m, 2H), 2.20 - 2.40 (m, 7H), 2.63 (s, 4H), 2.73 (d,
J= 9.6 Hz, 1H), 3.02 (s, 3H), 3.05 - 3.12 (m, 2H), 3.18 (s, 3H), 3.28 - 3.36 (m, 1H), 3.37 - 3.45 (m, 15H), 3.47 - 3.57 (m, 4H), 3.86 (s, 4H), 3.94 - 4.08 (m, 2H), 4.12 (ddt,
J= 14.5, 7.3, 3.6 Hz, 4H), 4.41 - 4.49 (m, 1H), 5.27 (q,
J= 6.7 Hz, 1H), 5.45 - 5.55 (m, 1H), 5.86 (s, 1H), 6.42 - 6.60 (m, 4H), 6.83 (s, 1H), 6.94 (s, 1H), 7.12 (d,
J= 1.8 Hz, 1H), 7.89 - 8.00 (m, 2H), 8.00 - 8.09 (m, 2H), 8.26 (t,
J= 6.2 Hz, 1H)。
實例 3. 代謝產物之合成
DM-CO-(CH
2)
5-SH (24a)
:在室溫下在磁力攪拌下向DM-H儲備溶液(1.5 mL,0.100 mmol)中添加EDC (29 mg,0.150 mmol)及DIPEA (17.5 μL,0.100 mmol)持續10 min。然後添加6-巰基己酸(13.8 μL,0.100 mmol)。在30 min之後,將粗物質經由半製備型HPLC純化,使用XDB-C18 21.2x5mm 5 μm,在20 ml/min下用含有0.1%甲酸之去離子水及歷時30 min自5%至95%之乙腈線性梯度進行溶離。立即將含有所需產物之級分合併且冷凍,然後凍乾,得到12 mg (15%產率)之白色固體。HRMS (M+H)
+計算值780.3291,實驗值780.3281。
1H NMR (400 MHz, DMSO-d6) δ 0.79 (s, 3H), 1.06 - 1.21 (m, 5H), 1.21 - 1.57 (m, 6H), 1.60 (s, 2H), 2.00 - 2.12 (m, 2H), 2.12 - 2.27 (m, 2H), 2.27 - 2.37 (m, 2H), 2.50 (s, 4H), 2.70 (s, 3H), 2.74 - 2.91 (m, 2H), 2.91 - 3.09 (m, 1H), 3.10 (s, 2H), 3.19 - 3.24 (m, 2H), 3.26 (s, 3H), 3.39 - 3.53 (m, 2H), 3.94 (s, 3H), 4.03 - 4.11 (m, 1H), 4.52 (dd,
J= 12.0, 2.9 Hz, 1H), 5.35 (q,
J= 6.8 Hz, 1H), 5.52 - 5.62 (m, 1H), 5.93 (d,
J= 1.3 Hz, 1H), 6.49 - 6.67 (m, 3H), 6.89 (s, 1H), 7.20 (d,
J= 1.8 Hz, 1H)。
DM-CO-(CH
2)
5-SMe (25a)
:將DM-CO-(CH
2)
5-SH (12 mg,0.015 mmol)溶解於DMF (2 mL)中,用DIPEA (24 μL,0.139 mmol)及碘甲烷(2.88 μL,0.046 mmol)處理,允許反應在室溫下在氬氣下進行2 h。以流速20ml/min將粗物質經由XDB-C18 21.2 x 5 mm 5 μm管柱純化。在20 ml/min下使用含0.1%甲酸之去離子水及歷時30 min自5%至95%之乙腈線性梯度。立即將含有所需產物之級分合併,冷凍,然後凍乾,得到2 mg (16%產率)之白色固體。HRMS (M+H)
+計算值794.3448,實驗值794.3440。
1H NMR (400 MHz, DMSO-d6) δ 0.71 (s, 3H), 1.01 - 1.13 (m, 6H), 1.13 - 1.27 (m, 3H), 1.27 - 1.50 (m, 6H), 1.53 (s, 3H), 1.87 (s, 2H), 1.93 - 2.04 (m, 2H), 2.04 - 2.15 (m, 1H), 2.15 - 2.27 (m, 2H), 2.27 - 2.41 (m, 1H), 2.63 (s, 3H), 2.73 (d,
J= 9.6 Hz, 1H), 3.02 (s, 3H), 3.10 - 3.22 (m, 5H), 3.33 - 3.49 (m, 2H), 3.86 (s, 3H), 3.94 - 4.06 (m, 1H), 4.45 (dd,
J= 12.1, 2.8 Hz, 1H), 5.28 (q,
J= 6.7 Hz, 1H), 5.44 - 5.56 (m, 1H), 5.85 (s, 1H), 6.42 - 6.62 (m, 3H), 6.81 (s, 1H), 7.13 (d,
J= 1.7 Hz, 1H)。
DM-CO-(CH
2)
3-SSPy (26)
:DM-CO-(CH
2)
3-SSPy
(3267-50-R1) :在室溫下在磁力攪拌下將SPDB (30.1 mg,0.092 mmol)添加至DM-H儲備溶液(0.81 mL,0.046 mmol)中。在30 min之後,將溶液以流速20 ml/min在XDB-C18 21.2 x 5 mm 5 μm管柱上純化。在20 ml/min下使用含0.1%甲酸之去離子水及歷時30 min自5%至95%之乙腈線性梯度。立即將含有所需產物之級分合併,冷凍,然後凍乾,得到6 mg (15%產率)之白色固體。HRMS (M+H)
+計算值861.2964,實驗值861.2963。
1H NMR (400 MHz, DMSO-
d6) δ 0.70 (s, 3H), 1.02 - 1.12 (m, 7H), 1.13 - 1.21 (m, 1H), 1.31 - 1.45 (m, 3H), 1.52 (s, 3H), 1.70 - 1.90 (m, 2H), 1.96 (dd,
J= 14.2, 2.9 Hz, 1H), 2.19 - 2.31 (m, 1H), 2.62 (s, 3H), 2.68 - 2.81 (m, 4H), 3.00 (s, 2H), 3.18 (s, 4H), 3.34 (d,
J= 12.4 Hz, 1H), 3.41 (d,
J= 9.1 Hz, 1H), 3.87 (s, 3H), 4.00 (t,
J= 11.2 Hz, 1H), 4.44 (dd,
J= 12.0, 2.9 Hz, 1H), 5.25 (q,
J= 6.8 Hz, 1H), 5.41 - 5.52 (m, 1H), 5.85 (s, 1H), 6.43 - 6.53 (m, 3H), 6.81 (s, 1H), 7.09 (d,
J= 1.8 Hz, 1H), 7.12 - 7.19 (m, 1H), 7.50 - 7.61 (m, 1H), 7.66 - 7.76 (m, 1H), 8.31 - 8.39 (m, 1H)。
DM-CO-(CH
2)
3-SH (24b)
:將DM-CO-(CH
2)
3-SSPy (6 mg,6.96 μmol)添加至DTT (1.1 mg,6.96 μmol)於2:1 DMSO:磷酸鉀2 mM EDTA pH 7.5緩衝液(0.5 mL)中之溶液中且在室溫下磁力攪拌20 min。將粗溶液以流速20 ml/min在XDB-C18 21.2 x 5 mm 5 μm管柱上純化。在20 ml/min下使用含0.1%甲酸之去離子水及歷時30 min自5%至95%之線性梯度的乙腈。立即將含有所需產物之級分合併,冷凍,然後凍乾,得到5 mg (95%產率)之白色固體。HRMS (M+H)
+計算值752.2978,實驗值752.2962。
1H NMR (400 MHz, DMSO-d6) δ 0.71 (d,
J= 1.9 Hz, 3H), 1.08 (dd,
J= 18.6, 6.6 Hz, 7H), 1.18 (d,
J= 12.4 Hz, 2H), 1.27 - 1.49 (m, 3H), 1.52 (d,
J= 2.7 Hz, 4H), 1.55 - 1.68 (m, 1H), 1.77 (
J= 14.2, 8.5, 6.5 Hz, 1H), 1.91 - 2.05 (m, 1H), 2.15 (t,
J= 7.9 Hz, 1H), 2.38 (s, 2H), 2.44 - 2.60 (m, 1H), 2.64 (s, 2H), 2.66 - 2.84 (m, 1H), 3.03 (d,
J= 12.6 Hz, 3H), 3.09 - 3.18 (m, 1H), 3.18 (s, 3H), 3.36 (d,
J= 12.2 Hz, 1H), 3.42 (d,
J= 9.0 Hz, 1H), 3.86 (s, 2H), 3.93 - 4.08 (m, 1H), 4.45 (dd,
J= 12.0, 2.8 Hz, 1H), 5.27 (q, 1H), 5.42 - 5.58 (m, 1H), 5.85 (d,
J= 1.3 Hz, 1H), 6.40 - 6.61 (m, 4H), 6.81 (s, 1H), 7.12 (d,
J= 1.8 Hz, 1H)。
DM-CO-(CH
2)
3-SMe (25b)
:將DM-CO-(CH
2)
3-SH (5 mg,6.65 μmol)溶解於無水DMF (0.3 mL)中,在室溫下在磁力攪拌下向其中添加DIPEA (3.57 μL,0.020 mmol)及碘甲烷(1.2 μL,0.020 mmol)。在1 h之後,將粗溶液以流速20 ml/min在XDB-C18 21.2 x 5 mm 5 μm管柱上純化。在20 ml/min下使用含0.1%甲酸之去離子水及歷時30 min自5%至95%之線性梯度的乙腈。立即將含有所需產物之級分合併,冷凍,然後凍乾,得到1 mg (19%產率)之白色固體。HRMS (M+H)
+計算值766.3135,實驗值766.3121。
1H NMR (400 MHz, DMSO-d6) δ 0.71 (s, 3H), 1.08 (dd,
J= 18.1, 6.6 Hz, 7H), 1.18 (d,
J = 12.9 Hz, 1H), 1.30 - 1.47 (m, 2H), 1.53 (s, 3H), 1.56 - 1.68 (m, 1H), 1.68 - 1.78 (m, 1H), 1.78 (s, 3H), 1.91 - 2.05 (m, 1H), 2.18 - 2.31 (m, 1H), 2.33 - 2.41 (m, 2H), 2.63 (s, 3H), 2.73 (d,
J= 9.7 Hz, 1H), 3.05 (s, 3H), 3.18 (s, 4H), 3.33 - 3.48 (m, 2H), 3.86 (s, 3H), 4.00 (t,
J= 11.5 Hz, 1H), 4.45 (dd,
J= 12.1, 2.8 Hz, 1H), 5.28 (q,
J= 6.7 Hz, 1H), 5.43 - 5.57 (m, 1H), 5.85 (s, 1H), 6.41 - 6.62 (m, 3H), 6.81 (s, 1H), 7.12 (d,
J= 1.8 Hz, 1H), 8.47 (s, 1H)。
實例 4. ADC (16a-16i 、 17a-17i 、 18a-18i) 之製備 .
用於製備
ADC (16a-16i
、
17a-17i
、
18a-18i)
之類美登素溶液的製備
將磺基-GMBS及帶有硫醇之化合物(14a-14j)中之一者溶解於3:7 (50 mM丁二酸鈉,pH 5.0:DMA)之溶液中,各自分別得到1.5 mM及1.9 mM之濃度。將溶液在室溫下輕輕攪拌30 min,然後藉由在輕柔攪拌下將溶液放至0.5 mM N-乙基順丁烯二醯亞胺(NEM)中持續10 min來將過量硫醇驟冷。
ADC (16a-16i 、 17a-17i 、 18a-18i) 之製備
向抗體(2.5 mg/mL)於含有15體積%之N,N-二甲基乙醯胺(DMA),pH 8.0之60 mM EPPS中之溶液中添加6.5莫耳當量之類美登素溶液。在16 h之後,將反應混合物使用NAP-G25管柱純化,該NAP-G25管柱經預平衡且用10 mM丁二酸鈉,pH 5.5、250 mM甘胺酸、0.5%蔗糖及0.01%吐溫-20緩衝液進行操作。如先前由Widdison W.等人J Med Chem (2006) 49, 4392-408所描述對經純化之結合物進行分析,以測定類美登素/抗體比率(MAR)、聚集之結合物的百分比、游離類美登素含量及內毒素單位(EU)。在所有結合物中蛋白質聚集物含量低於3%,游離類美登素含量低於1%且內毒素含量低於0.2 EU/mg。
ADC 1a-1d及4a-4c用作比較物來評估本發明之結合物。如由Widdison W.等人, Bioconjugate Chem., (2015), 26, 2261-2278所描述製備ADC 1a-1d及4a-4c。
C242-sGMBS-LDL-DM (ADC 18c) 之製備
在結合之前,如下製備sGMBS-LDL-DM:在丁二酸鹽緩衝液pH 5.0存在下,將磺基-GMBS (圖4中之化合物15)於N-N-二甲基乙醯胺(DMA,SAFC)中之儲備溶液與LDL-DM (圖3中之化合物14c)於DMA中之儲備溶液混合,以獲得60/40有機/水溶液及1.5 mM磺基-GMBS及1.95 mM LDL-DM之最終濃度。將反應物在25℃下孵育10min。將粗sGMBS-LDL-DM混合物添加至一溶液中,該溶液於磷酸鹽緩衝鹽水(PBS) pH 7.4外加300 mM 4-(2-羥乙基)-1-哌嗪丙磺酸(EPPS) pH 8.0之5x溶液及15% DMA (v/v)中含有C242抗體,達到7.5 mol磺基-GMBS-LDL-DM比1 mol C242抗體之最終比率。將反應物在25℃下孵育隔夜。
使用NAP脫鹽管柱(GE Healthcare)將反應物純化至10 mM丁二酸鹽、250 mM甘胺酸、0.5%蔗糖、0.01% 吐溫20,pH 5.5調配物緩衝液中,且經具有0.22 μm PVDF膜之針筒過濾器過濾。
藉由UV-Vis發現經純化之結合物具有每莫耳抗體3.8 mol LDL-DM,藉由SEC發現95%之單體,且藉由HPLC Hisep管柱分析發現游離藥物低於1%。
C242-sGMBS-LDL-DM之SEC/MS圖譜顯示於圖20中。
ML66-sGMBS-LDL-DM (ADC 16c) 之製備
在結合之前,如下製備sGMBS-LDL-DM:在丁二酸鹽緩衝液pH 5.0存在下,將磺基-GMBS (圖4中之化合物15)於N-N-二甲基乙醯胺(DMA,SAFC)中之儲備溶液與LDL-DM (圖3中之化合物14c)於DMA中之儲備溶液混合,以獲得60/40有機/水溶液及1.5 mM磺基-GMBS及1.95 mM LDL-DM之最終濃度。將反應物在25℃下孵育10min。將粗sGMBS-LDL-DM混合物添加至一溶液中,該溶液於磷酸鹽緩衝鹽水(PBS) pH 7.4外加300 mM 4-(2-羥乙基)-1-哌嗪丙磺酸(EPPS) pH 8.0之5x溶液及15% DMA (v/v)中含有ML66抗體,達到8.0 mol磺基-GMBS-LDL-DM比1 mol ML66抗體之最終比率。將反應物在25℃下孵育隔夜。
使用NAP脫鹽管柱(GE Healthcare)將反應物純化至10 mM丁二酸鹽、250 mM甘胺酸、0.5%蔗糖、0.01% 吐溫20,pH 5.5調配物緩衝液中,且經具有0.22 μm PVDF膜之針筒過濾器過濾。
藉由UV-Vis發現經純化之結合物具有每莫耳抗體3.7 mol LDL-DM,藉由SEC發現98%之單體,且藉由HPLC Hisep管柱分析發現游離藥物低於1%。
C242-sGMBS-LDL-DM之SEC/MS圖譜顯示於圖21中。
M9346A-sGMBS-LDL-DM ( 結合物 17c) 之製備
在結合之前,如下製備sGMBS-LDL-DM (圖4中之化合物15):在丁二酸鹽緩衝液pH 5.0存在下,將磺基-GMBS於N-N-二甲基乙醯胺(DMA,SAFC)中之儲備溶液與LDL-DM (圖3中之化合物14c)於DMA中之儲備溶液混合,以獲得60/40有機/水溶液及3 mM磺基-GMBS及3.9 mM LDL-DM之最終濃度。將反應物在25℃下孵育2h。將粗sGMBS-LDL-DM混合物添加至一溶液中,該溶液於磷酸鹽緩衝鹽水(PBS) pH 7.4外加300 mM 4-(2-羥乙基)-1-哌嗪丙磺酸(EPPS) pH 8.5之5x溶液及10% DMA (v/v)中含有M9346A抗體,達到9.5 mol磺基-GMBS-LDL-DM比1 mol M9346A抗體之最終比率。將反應物在25℃下孵育隔夜。
使用NAP脫鹽管柱(GE Healthcare)將反應物純化至10 mM丁二酸鹽、250 mM甘胺酸、0.5%蔗糖、0.01% 吐溫20,pH 5.5調配物緩衝液中,且經具有0.22 μm PVDF膜之針筒過濾器過濾。
藉由UV-Vis發現經純化之結合物具有每莫耳抗體3.7 mol LDL-DM,藉由SEC發現99%之單體,且藉由SEC/逆相HPLC雙管柱分析發現游離藥物低於1%。
C242-sGMBS-LDL-DM之SEC/MS圖譜顯示於圖22中。
M9346A-C442-MalC5-LDL-DM (結合物26c)之製備
將含M9346A-C442 (在位置442處具有經工程改造之Cys的抗葉酸劑抗體)之磷酸鹽緩衝鹽水(PBS) pH 7.4 (Life Technologies)用50莫耳當量之三(2-羧乙基)膦(TCEP,Sigma-Aldrich)處理且在37℃下孵育1h。藉由NAP脫鹽管柱(GE Healthcare)移除TCEP,且將100莫耳當量之去氫抗壞血酸(Sigma-Aldrich)添加至於PBS pH 7.4、2 mM EDTA (Sigma-Aldrich)中之經純化之還原之M9346A-C442中,且在25℃下孵育90分鐘至4小時。
將經還原且再氧化之抗體溶液立即用於結合至MalC5-LDL-DM (上文所示之化合物I-2a)。
向經再氧化之M9346A-C442抗體中外加PBS pH 6.0、2 mM EDTA,且在含有10% N-N-二甲基乙醯胺(DMA,SAFC)及5當量之MalC5-LDL-DM的90%水溶液中進行結合。將反應物在25℃下孵育隔夜。
在反應後,使用NAP脫鹽管柱(GE Healthcare)將結合物純化至10 mM乙酸鹽、9%蔗糖、0.01%吐溫-20,pH 5.0調配物緩衝液中,且經具有0.22 μm PVDF膜之針筒過濾器過濾。
藉由UV-Vis發現經純化之結合物具有每莫耳抗體2 mol LDL-DM,藉由SEC發現97%之單體,且藉由SEC/逆相HPLC雙管柱分析發現游離藥物低於3%。
C242-sGMBS-LDL-DM之SEC/MS圖譜顯示於圖23中。
實例 5. 細胞結合分析
藉由間接免疫螢光分析使用流式細胞術評估裸抗體或ADC與抗原陽性細胞之結合。將細胞(每孔5 X 104個)塗鋪於圓底96孔板中,且在測試物品之連續稀釋液存在下在0.2 mL之補充有2% (v/v)正常山羊血清的α-MEM (Sigma, St., Louis, MO)中在4℃下孵育3 h。各樣品一式三份進行分析。對照孔不含測試物品。然後將細胞用0.2-mL冷(4℃)培養基洗滌且在4℃下用螢光素標記之山羊抗人類免疫球蛋白G (IgG)抗體染色1 h。將細胞再次用培養基洗滌,固定於1%甲醛/PBS溶液中,且使用FACS Calibur流式細胞儀(BD Biosciences, San Jose, CA)進行分析。
如圖7中所示,結合僅適度影響裸抗體之結合親和力。
實例 6. ADC 及代謝產物之活體外細胞毒性分析
在平底96孔井板中對各數據點一式三份進行分析。首先將測試物品在完全細胞培養基中使用5倍稀釋系列進行稀釋且添加100 μL至各孔中。最終濃度典型地在3 x 10
-8M至8 x 10
-14M範圍內。然後將目標細胞於100 μL完全培養基中以1,500至3,000個細胞/孔添加至測試物品中。將混合物在37℃下在濕潤之5% CO
2孵育器中孵育5天。藉由WST-8 (四唑鹽-8;2-(2-甲氧基-4-硝基苯基)-3-(4-硝基苯基)-5-(2,4-二磺基苯基)-2H-四唑鎓)基於比色分析使用細胞計數套組-8 (Dojindo Molecular Technologies, Inc., Rockville, MD)測定剩餘細胞之活力。在活細胞中用脫氫酶還原WST-8,得到黃色甲臢產物,其可溶於組織培養基。甲臢染料之量與活細胞之數目成正比。添加WST-8至最終體積為10%且將板在37℃下在濕潤之5% CO
2孵育器中再孵育4 h。然後使用微板讀板儀在450 nm之光學密度下量測WST-8訊號。藉由用各經處理樣品之值除以未經處理之對照的平均值來計算存活分數,且在半對數坐標圖中關於各處理對測試物品濃度進行作圖。使用GraphPad Prism v5程式(GraphPad Software, La Jolla, CA)使用非線性回歸(曲線擬合)確定IC
50值。
如圖8中所示,本發明之結合物對KB細胞高度有效,且活體外細胞毒性為抗原特異性的,因為添加裸抗體顯著降低結合物之細胞毒性。
將本發明之結合物的活體外細胞毒性與具有可裂解二硫化物連接子之Ab-sSPDB-DM4結合物及肽苯胺基類美登素結合物相比較(表1)。如表1中所示,與Ab-sSPDB-DM4結合物相比本發明之結合物總體上更具細胞毒性。此外,間隔子L
1基團中之烷基鏈之長度對於對抗原陽性細胞之細胞毒性幾乎沒有影響。
表 1.
IC 50(nM) | ||||||||
KB | Igrov-1 | Jeg-3 | SKOV-6 | |||||
ADC | + 阻斷 | ADC | + 阻斷 | ADC | + 阻斷 | ADC | + 阻斷 | |
1b | 0.5 | 3 | 2 | 8 | 5 | 9 | 3 | 7 |
4b | 0.2 | >50 | 0.3 | 20 | 0.2 | 10 | 0.9 | 10 |
17h | 0.4 | >50 | 30 | >50 | 0.5 | >50 | >10 | >50 |
17i | 0.3 | >50 | 50 | >50 | 0.7 | >50 | >10 | >50 |
17g | 0.3 | >50 | 3 | >50 | 0.5 | >50 | >10 | >50 |
17c | 0.3 | >50 | 7 | >50 | 0.6 | >50 | >10 | >50 |
亦針對CA922細胞測試了本發明之結合物的活體外細胞毒性。如圖14中所示,結合物之肽連接子中之D-Ala若直接附接至式(I)之結合物的-NH-CR
1R
2-S-部分中之自分解氮則對細胞毒性為有害的。
針對Colo720E、H1703、H1975及COLO704細胞測試了主要ADC代謝產物之活體外細胞毒性,且資料顯示於圖15及下表2中。資料表明增加代謝產物疏水性(L
1間隔子中之較長烷基鏈)會增加代謝產物細胞毒性。
表 2 主要 ADC 代謝產物對 H1703 、 H1975 及 COLO704 細胞之活體外細胞毒性
實例 7. 活體內功效研究
IC 50(M) | |||
代謝產物 | H1703細胞 | H1975細胞 | COLO704細胞 |
25a | 2.27 x 10 -12 | 8.93 x 10 -13 | 3.04 x 10 -12 |
25b | 5.92 x 10 -12 | 5.60 x 10 -12 | 6.88 x 10 -12 |
25c | 5.02 x 10 -11 | 4.78 x 10 -11 | 3.99 x 10 -11 |
3 | 3.70 x 10 -12 | 1.78 x 10 -12 | 5.06 x 10 -12 |
在帶有確定之異種移植物(H1703 250 mm
3)、HT-29 (100 mm
3)或NCI-H2110 (100 mm
3)之小鼠中評估ADC之活體內功效。在右側為雌性SCID小鼠皮下接種於不含血清之培養基/基質膠中之所需細胞類型。使腫瘤生長至規定尺寸。然後將動物隨機分成多個組(每組6個動物)。將對照小鼠用磷酸鹽緩衝鹽水處理。以研究中所指示之mg/kg水準給予小鼠ADC。在異種移植模型中之所有給藥係基於結合物之抗體組分的重量。所有處理係藉由尾部靜脈靜脈內注射來投與。使用卡尺每週兩次以三維形式量測腫瘤尺寸,腫瘤體積以mm
3表示,且使用等式V =½(長度×寬度×高度)來計算。體重亦每週量測兩次。
如圖10、11A、11B及12中所示,本發明之結合物在活體內小鼠模型中對H1703 (圖10)、HT-29 (圖11A及11B)、NCI-H2110 (圖12)異種移植腫瘤具高度活性。結合物17c與肽苯胺基類美登素結合物相比為良好耐受的(參見圖13)。
亦對具有不同肽連接子(亦即式(I)中之A)之本發明結合物進行小鼠耐受性研究。量測給予結合物之小鼠的體重。如圖18中所示,若肽連接子含有連續L-丙胺酸,則小鼠耐受性降低。
實例 8. 活體外旁觀者殺傷分析
如先前所描述使用相關圖中指定之抗原陽性細胞與抗原陰性細胞之比率進行旁觀者殺傷分析,其中在存在不同數目之抗原陽性細胞之情況下抗原陰性細胞之數目保持恆定。對抗原陰性細胞及抗原陽性細胞保持恆定之此分析如下進行變化:將3000個EGFR+ Ca9-22細胞與2000個EGFR-MCF7細胞混合,且將細胞混合物與0.66 nM之所指示ADC一起孵育4天。使用WST-8分析來定量活細胞。在相同分析中,亦評估ADC對Ca9-22或MCF7細胞之細胞毒性效能;所有ADC以類似水準殺死EGFR+ Ca9-22細胞,但對EGFR-MCF7細胞沒有影響,除非添加抗原陽性細胞。
在另一實驗中,將各種比率之FRα(+)/FRα(-)細胞混合於低附著U型底孔中且暴露於2nM之本發明結合物,該本發明結合物對FRα(-)細胞(Namalwa,接種之1000個細胞)不具毒性,但殺死所有FRα(+)細胞(JEG-3,150K FRα ABC)。在4天之後藉由細胞效價Glo分析(Promega)量測FRα(-)細胞之存活率。資料顯示於圖9C中。特定而言,將本發明結合物之旁觀者殺傷作用與肽苯胺類美登素結合物相比較,且資料顯示於下表3中。
表 3
結合物 | 殺死 100% FRα(-) 細胞所需之 Jeg-3 細胞數目 |
4b | 3000 |
17c | 1000 |
如圖9A、9B及9C中所示,與具有可裂解二硫化物連接子之Ab-sSPDB-DM4結合物及肽苯胺基類美登素結合物相比,本發明之結合物具有更高之旁觀者殺傷效應。此外,當其他因素保持恆定時,增加代謝產物疏水性會增加代謝產物細胞毒性,此使得對應結合物之旁觀者殺傷作用增加。另外,資料似乎表明,本發明之結合物在所釋放代謝產物之類型及釋放效率方面不同於Ab-sSPDB-DM4結合物及肽苯胺類美登素結合物。本發明之結合物的旁觀者殺傷效應大於肽苯胺基類美登素結合物,肽苯胺基類美登素結合物又大於Ab-sSPDB-DM4 (17g>4b>1b)。
如圖9D中所示,結合物之肽連接子中之D-Ala若直接附接至式(I)之結合物的-NH-CR
1R
2-S-部分中之自分解氮則對旁觀者殺傷作用為有害的。
實例 9. 活體外代謝研究
將表現FRα之KB細胞用飽和量之17c結合物處理24小時。將含有分解產物之培養基與5mM NEM一起孵育以為存在之任何游離硫醇加蓋,且然後由預結合之蛋白質A-抗類美登素抗體複合物捕獲。藉由丙酮萃取來釋放分解產物,且藉由UHPLC/HRMS進行分析。
偵測到之代謝產物及建議之裂解位點顯示於圖16中。在細胞培養基中鑑定之主要流出之分解產物為DM-SMe (25a)及DM-SH種類。
在另一實驗中,將結合物
18c(抗CanAg-LDL-DM)與COLO205細胞一起孵育,隨後藉由先前描述之方法進行細胞溶解及任何二硫鍵之還原且用N-乙基順丁烯二醯亞胺為所得硫醇加蓋(參見Erickson HK, Park PU, Widdison WC, Kovtun YV, Garrett LM, Hoffman K等人Antibody-maytansinoid conjugates are activated in targeted cancer cells by lysosomal degradation and linker-dependent intracellular processing. Cancer Res 2006;66(8):4426-33)。亦對未處理之對照進行,其中將未用結合物處理之COLO205細胞溶解,且還原二硫鍵,然後將所得硫醇用N-乙基順丁烯二醯亞胺加蓋。藉由UPLC/MS對兩種樣品進行分析,使用經設定用於Pos、Neg、DDA Top-10 MS/MS偵測之Thermo Q-Exactive質譜儀,其與配備有Waters UPLC BEH C8 1.8微米100 x 2.1 mm管柱之Dionex UltiMate 3000 UPLC串聯。將管柱室設定為30℃且將uv偵測器設定為252 nm。注射體積為40 μL。用含有0.1%甲酸之去離子水加上在0.35 mL/min之流速下歷時20 min 20%至100%之含有0.1%甲酸之乙腈的線性梯度繼之以含有0.1%甲酸之一股100%乙腈持續10 min對管柱進行溶離。如圖19中所示,頂部UPLC描記線屬於來自未暴露於任何結合物之COLO205細胞的經DTT及NEM處理之細胞溶解產物。底部UPLC描記線屬於來自用結合物18c處理之COLO205細胞的經DTT及NEM處理之細胞溶解產物。12.73 min滯留時間峰具有與在實驗室中製備之CH
3S(CH
2)
5CO-DM化合物(化合物25a)相同的滯留時間及質譜。
在類似實驗中,將100 nM之C242-sGMBS-LDL-DM (18c)添加至COLO205細胞培養物中且在37℃下孵育24h。將細胞及培養基分離且將分解產物以親和力捕獲進行萃取且用20%乙腈重構。藉由UHPLC/HRMS對分解產物進行分析。在細胞培養基中鑑定之主要分解產物種類包括DM-SMe、經氧化之DM-SMe及酸形式游離藥物(參見以下結構):
實例 10. 在 OV-90 卵巢模型中之活體內功效
使用類似於實例7中所描述之程序在帶有OV-90異種移植物之小鼠中評估本發明之結合物的活體內功效。
如圖17A及17B及表4中所示,本發明之結合物對具有與肽苯胺基類美登素結合物相比相對低之FRα表現水準(H-得分35)之異源卵巢腫瘤異種移植模型展現增強之活性。
表4.
實例 11. 小鼠耐受性研究
組 | Ab 劑量 (mg/kg) | % T/C | PR | CR | 結果 |
17c | 5 | 5 | 5/6 | 0/6 | 高度活性 |
2.5 | 5 | 5/6 | 0/6 | 高度活性 | |
1.25 | 24 | 0/6 | 0/6 | 活性 | |
4b | 5 | 11 | 2/6 | 0/6 | 活性 |
2.5 | 15 | 0/6 | 0/6 | 活性 | |
1.25 | 35 | 0/6 | 0/6 | 活性 |
a. 在雌性CD-1小鼠中測試了1200μg/kg huML66-GMBS-LAlaLAlaLAla-Immol-DM (16a)、huML66-GMBS-DAlaLAlaLAla-Immol-DM (16b)、huML66-GMBS-LAlaDAlaLAla-Immol-DM (16c)、huML66-GMBS-LAlaLAlaDAla-Immol-DM (16d)及huML66-sSPDB-DM4 (1a)之耐受性。
材料:
huML66-s-SPDB-DM4 (1a)DM1之濃度:84.35 μg/ml
抗體濃度:4.6 mg/ml
藥物與抗體之比率:3.4 DM/Ab
內毒素:0.46 EU/mg
單體:99.2%
游離藥物:未偵測到
組及處理:(2隻小鼠/組)
1. 媒劑對照
2. huML66-GMBS-LAlaLAlaLAla-Immol-DM (16a),1200μg/kg
3. huML66-GMBS-DAlaLAlaLAla-Immol-DM (16b),1200μg/kg
4. huML66-GMBS-LAlaDAlaLAla-Immol-DM (16c),1200μg/kg
5. huML66-GMBS-LAlaLAlaDAla-Immol-DM (16d),1200μg/kg
6. huML66-sSPDB-DM4 (1a),1200μg/kg
研究特定設計:
huML66-GMBS-LAlaLAlaLAla-Immol-DM (16a) | huML66-GMBS-DAlaLAlaLAla-Immol-DM (16b) |
DM1之濃度:83.39 μg/mL | DM1之濃度:60.36 μg/ml |
抗體濃度:4.3 mg/mL | 抗體濃度:3.4 mg/ml |
藥物與抗體之比率:3.8 DM/Ab | 藥物與抗體之比率:3.5 DM/Ab |
內毒素:0.37 EU/mg | 內毒素:0.29 EU/mg |
單體:99.0% | 單體:97.9% |
游離藥物:未偵測到 | 游離藥物:未偵測到 |
huML66-LAlaDAlaLAla-Immol-DM (16c) | huML66-LAlaLAlaDAla-Immol-DM (16d) |
DM1之濃度:70.27 μg/ml | DM1之濃度:69.52 μg/ml |
抗體濃度:3.6 mg/ml | 抗體濃度:3.7 mg/ml |
藥物與抗體之比率:3.8 DM/Ab | 藥物與抗體之比率:3.6 DM/Ab |
內毒素:0.27 EU/mg | 內毒素:0.33 EU/mg |
單體:98.7% | 單體: 98.1% |
游離藥物:未偵測到 | 游離藥物:未偵測到 |
根據體重將三十隻小鼠隨機化至6個組中(2個小鼠/組)。體重在24.4至27.5公克(26.2±0.96,平均值±SD)範圍內。根據毛皮上帶顏色之標記來鑑別各組中之小鼠。在到達後第15天開始處理。基於個別體重給予小鼠結合物。所有結合物或PBS之投與係使用裝配有27號½吋針頭之1.0 ml注射器經靜脈內進行。歸因於給定劑量,將處理分成2次注射,相隔2小時。小鼠每次注射不允許超過350 μl 。
量測給予結合物之小鼠的體重且顯示於圖24A及24B中。
b. 在雌性CD-1小鼠中測試1000 μg/kg及1250 μg/kg Mov19v1.6-GMBS-lAladAlalAla-Immol-DM (17c)及1250 μg/kg Mov19v1.6-GMBS-dAlalAla-PAB-DM1 (4b)之耐受性。
材料:
組及處理:(8隻小鼠/組)
1. 媒劑對照
2. Mov19v1.6-GMBS-lAladAlalAla-Immol-DM,1250μg/kg
3. Mov19v1.6-GMBS-lAladAlalAla-Immol-DM,1000μg/kg
4. Mov19v1.6-GMBS-dAlalAla-PAB-DM1,1250μg/kg
研究特定設計:根據體重將三十二隻小鼠隨機化至4個組中(8隻小鼠/組)。體重在23.4至27.3公克(25.5±1.02,平均值±SD)範圍內。藉由剪耳號(ear notching)來鑑別各組中之小鼠。在到達後第8天開始處理。基於個別體重給予小鼠結合物。所有結合物或PBS之投與係使用裝配有27號½吋針頭之1.0 ml注射器經靜脈內進行。歸因於給定劑量,將處理分成2次注射,相隔2小時。小鼠每次注射不允許超過350 μl。
Mov19v1.6-GMBS-lAladAlalAla-Immol-DM | Mov19v1.6-GMBS-dAlalAla-PAB-DM1 |
DM1之濃度:63.18 μg/mL | DM1之濃度:40.01 μg/ml |
抗體濃度:3.5 mg/ml | 抗體濃度:2.5 mg/ml |
藥物與抗體之比率:3.6 DM/Ab | 藥物與抗體之比率:3.5 DM/Ab |
內毒素:<0.14 EU/mg | 內毒素:0.67 EU/mg |
單體:98.7% | 單體:98.3% |
游離藥物:未偵測到 | 游離藥物:未偵測到 |
量測給予結合物之小鼠的體重且顯示於圖25A-25D中。
實例 12. 藥物動力學研究1. 結合物17c
在雌性CD-1小鼠中評估M-LDL-IMM-DM (結合物17c)及M-SPDB-DM4之藥物動力學。基於體重將小鼠隨機分配至每組六隻小鼠的2個組中。組A中之小鼠經由尾部靜脈接受10 mg/kg M-LDL-IMM-DM之單次靜脈內注射。組B中之小鼠經由尾部靜脈接受10 mg/kg M-SPDB-DM4之單次靜脈內注射。在2分鐘、6、24、48、72、168、336、504、672及840小時時收集血液。輪流對小鼠進行採血以確保在24小時時間內沒有小鼠被採血超過兩次。將血清與血液分離且將樣品冷凍在-80℃下直至藉由ELISA進行分析。對樣品進行總抗體及ADC ELISA,且濃度與時間曲線顯示於圖26中。總抗體ELISA定量帶有至少一個類美登素之抗體以及未附接類美登素之抗體。藉由用抗人類IgG抗體捕獲,然後使用酶標記之抗人類IgG抗體定量來測定濃度。ADC ELISA涉及使用抗類美登素抗體捕獲帶有至少一個附接類美登素之結合物,然後捕獲結合物之抗體組分且用酶標記之抗人類Fc抗體進行偵測。為了被偵測到,結合物必須含有至少一個共價鍵聯之類美登素。
使用非房室藥物動力學分析程式Phoenix WinNonlin專業版v 6.1 (Certara, Princeton, NJ)之標準算法得到PK參數且顯示於表5中。
表5
2. 結合物26c
ADC/ELISA | C Max (μ g/ml) | T 1/2 (h) | AUC 0-∞ (h*μ g/ml) | Cl (ml/h/kg) | V SS (ml/kg) |
17c Ab ELISA | 153.8 | 366.4 | 31,341 | 0.32 | 162 |
17c ADC ELISA | 188.1 | 261.2 | 24,454 | 0.41 | 145 |
M-SPDB-DM4 Ab ELISA | 173.4 | 305.5 | 24,256 | 0.41 | 184 |
M-SPDB-DM4 ADC ELISA | 224.4 | 142.4 | 15,535 | 0.64 | 112 |
為CD-1小鼠注射單次10 mg/kg劑量之26c或M9346A-C442-mal-SPDB-DM4。在注射後2分鐘、24小時及72小時時收集血液。使用葉酸受體α-Fc融合蛋白使用親和力捕獲自血漿純化ADC且藉由尺寸排阻層析法(SEC)及質譜法(MS)分析樣品。以相較於時間經校正之降解百分比形式對DM或DM4之損失進行量測且繪製於圖27中。如由在2分鐘(-0.2%相較於7.3%)及24小時時間點(5.2%相較於16.5%)觀測到之較少降解所證實,26c之活體內穩定性大於M9346A-C442-mal-SPDB-DM4。M9346A-C442-mal-SPDB-DM4之72小時樣品濃度太稀而不能得到經校正之降解百分比值。
圖1展示所測試之Ab-sSPDB-DM4結合物並與本發明之結合物相比較。
圖2展示所測試之肽苯胺基類美登素ADC並與本發明之結合物相比較。
圖3展示用於製備本發明之具有自分解肽連接子之代表性類美登素化合物的合成方案。
圖4展示用於製備本發明之代表性結合物的合成方案。
圖5展示用於製備本發明之具有自分解肽連接子之代表性類美登素化合物的合成方案。
圖6展示用於製備本發明結合物之S-甲基化代謝產物的合成方案。
圖7顯示本發明之代表性結合物對T47D細胞上之目標抗原的結合親和力。
圖8顯示本發明之代表性結合物對KB細胞之活體外細胞毒性。
圖9A、9B、9C及9D顯示本發明之代表性結合物的旁觀者殺傷效應。
圖10顯示本發明之代表性結合物在帶有250 mm
2之大EGFR受體陽性異種移植物之小鼠中的活體內抗腫瘤活性。
圖11A及11B顯示在5 mg/kg (圖11A)及2.5 mg/kg (圖11B)劑量下本發明之代表性結合物在帶有CanAg+ HT-29異種移植物之小鼠中的活體內抗腫瘤活性。
圖12顯示本發明之代表性結合物在帶有NCI-H2110葉酸受體陽性異種移植物之小鼠中的活體內抗腫瘤活性。以3 mg/kg劑量給予小鼠結合物17c或4b。
圖13顯示用本發明之代表性結合物處理之小鼠與用結合物4b處理之小鼠相比的體重變化。
圖14顯示本發明之代表性結合物與1a相比對CA922細胞之活體外細胞毒性。
圖15顯示25a、25b及25c之代謝產物與結合物Ab-sSPDB-DM4之代謝產物種類3相比的活體外細胞毒性。
圖16顯示由結合物17c之活體外代謝研究偵測到之代謝產物種類及建議之裂解位點。
圖17A及17B顯示本發明之代表性結合物在帶有具有異源FRα表現之OV-90卵巢異種移植物之小鼠中的活體內抗腫瘤活性。以1.25mg/kg、2.5 mg/kg或5 mg/kg劑量給予小鼠結合物17c或結合物4b。
圖18用本發明之具有不同肽連接子之代表性結合物處理之小鼠與用結合物1a處理之小鼠相比的體重變化。
圖19顯示來自未暴露於任何結合物(頂部)之COLO205細胞及暴露於結合物18c之COLO205細胞的經DTT及NEM處理之細胞溶解產物的UPLC描記線。
圖20顯示結合物18c之SEC/MS圖譜。
圖21顯示結合物16c之SEC/MS圖譜。
圖22顯示結合物17c之SEC/MS圖譜。
圖23顯示結合物26c之SEC/MS圖譜。
圖24A顯示給予1200 μg/kg huML66-GMBS-Ala3-Immol-DM (結合物16a、16b、16c及16d)或huML66-s-SPDB-DM4 (結合物1a)之CD-1小鼠的體重(平均值±SD,g)。
圖24B顯示給予1200 μg/kg huML66-GMBS-Ala3-Immol-DM (結合物16a、16b、16c及16d)或huML66-s-SPDB-DM4 (結合物1a)之CD-1小鼠的體重變化(平均值±SD,g)。
圖25A顯示給予1000或1250 μg/kg Mov19v1.6-GMBS-lAladAlalAla-Immol-DM (結合物17c)或1250 μg/kg Mov19v1.6-GMBS-dAlalAla-PAB-DM1 (結合物4b)之CD-1小鼠的體重(平均值±SD,g)。
圖25B顯示給予1000或1250 μg/kg Mov19v1.6-GMBS-lAladAlalAla-Immol-DM (結合物17c)或1250 μg/kg Mov19v1.6-GMBS-dAlalAla-PAB-DM1 (結合物4b)之CD-1小鼠的體重變化(平均值±SD,g)。
圖25C顯示給予1000或1250 μg/kg Mov19v1.6-GMBS-lAladAlalAla-Immol-DM (結合物17c)或1250 μg/kg Mov19v1.6-GMBS-dAlalAla-PAB-DM1 (結合物4b)之個別CD-1小鼠的體重變化。
圖25D顯示給予1000或1250 μg/kg Mov19v1.6-GMBS-lAladAlalAla-Immol-DM (結合物17c)或1250 μg/kg Mov19v1.6-GMBS-dAlalAla-PAB-DM1 (結合物4b)之CD-1小鼠的個別體重。
圖26顯示結合物17c及M-SPDB-DM4結合物在小鼠中之藥物動力學型態。
圖27顯示結合物26c及M9346A-C442-mal-SPDB-DM4之相較於時間之經校正降解百分比。
<![CDATA[<110> 美商伊繆諾金公司(IMMUNOGEN, INC.)]]> <![CDATA[<120> 具有自分解肽連接子之類美登素衍生物及其結合物]]> <![CDATA[<130> 107106660]]> <![CDATA[<140> ]]> <![CDATA[<141> ]]> <![CDATA[<150> 62/480,209]]> <![CDATA[<151> 2017-03-31]]> <![CDATA[<150> 62/465,118]]> <![CDATA[<151> 2017-02-28]]> <![CDATA[<160> 44 ]]> <![CDATA[<170> PatentIn 版本 3.5]]> <![CDATA[<210> 1]]> <![CDATA[<211> 4]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人工序列描述:合成肽]]> <![CDATA[<400> 1]]> Ala Leu Ala Leu 1 <![CDATA[<210> 2]]> <![CDATA[<211> 4]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人工序列描述:合成肽]]> <![CDATA[<220>]]> <![CDATA[<221> MOD_RES]]> <![CDATA[<222> (1)..(1)]]> <![CDATA[<223> Beta-Ala]]> <![CDATA[<400> 2]]> Ala Leu Ala Leu 1 <![CDATA[<210> 3]]> <![CDATA[<211> 4]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人工序列描述:合成肽]]> <![CDATA[<400> 3]]> Gly Phe Leu Gly 1 <![CDATA[<210> 4]]> <![CDATA[<211> 5]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人工序列描述:合成肽]]> <![CDATA[<400> 4]]> Gly Tyr Phe Met Asn 1 5 <![CDATA[<210> 5]]> <![CDATA[<211> 17]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人工序列描述:合成肽]]> <![CDATA[<220>]]> <![CDATA[<221> MOD_RES]]> <![CDATA[<222> (14)..(14)]]> <![CDATA[<223> Lys, Gln, His or Arg ]]> <![CDATA[<220>]]> <![CDATA[<221> MOD_RES]]> <![CDATA[<222> (16)..(16)]]> <![CDATA[<223> Gln, His, Asn or Arg ]]> <![CDATA[<220>]]> <![CDATA[<221> MOD_RES]]> <![CDATA[<222> (17)..(17)]]> <![CDATA[<223> Gly, Glu, Thr, Ser, Ala or Val]]> <![CDATA[<400> 5]]> Arg Ile His Pro Tyr Asp Gly Asp Thr Phe Tyr Asn Gln Xaa Phe Xaa 1 5 10 15 Xaa <![CDATA[<210> 6]]> <![CDATA[<211> 9]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人工序列描述:合成肽]]> <![CDATA[<400> 6]]> Tyr Asp Gly Ser Arg Ala Met Asp Tyr 1 5 <![CDATA[<210> 7]]> <![CDATA[<211> 15]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人工序列描述:合成肽]]> <![CDATA[<400> 7]]> Lys Ala Ser Gln Ser Val Ser Phe Ala Gly Thr Ser Leu Met His 1 5 10 15 <![CDATA[<210> 8]]> <![CDATA[<211> 7]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人工序列描述:合成肽]]> <![CDATA[<400> 8]]> Arg Ala Ser Asn Leu Glu Ala 1 5 <![CDATA[<210> 9]]> <![CDATA[<211> 9]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人工序列描述:合成肽]]> <![CDATA[<400> 9]]> Gln Gln Ser Arg Glu Tyr Pro Tyr Thr 1 5 <![CDATA[<210> 10]]> <![CDATA[<211> 17]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人工序列描述:合成肽]]> <![CDATA[<400> 10]]> Arg Ile His Pro Tyr Asp Gly Asp Thr Phe Tyr Asn Gln Lys Phe Gln 1 5 10 15 Gly <![CDATA[<210> 11]]> <![CDATA[<211> 447]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人工序列描述:合成肽]]> <![CDATA[<400> 11]]> Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Val Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr 20 25 30 Phe Met Asn Trp Val Lys Gln Ser Pro Gly Gln Ser Leu Glu Trp Ile 35 40 45 Gly Arg Ile His Pro Tyr Asp Gly Asp Thr Phe Tyr Asn Gln Lys Phe 50 55 60 Gln Gly Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Asn Thr Ala His 65 70 75 80 Met Glu Leu Leu Ser Leu Thr Ser Glu Asp Phe Ala Val Tyr Tyr Cys 85 90 95 Thr Arg Tyr Asp Gly Ser Arg Ala Met Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro 115 120 125 Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly 130 135 140 Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn 145 150 155 160 Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln 165 170 175 Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser 180 185 190 Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser 195 200 205 Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr 210 215 220 His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser 225 230 235 240 Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg 245 250 255 Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro 260 265 270 Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala 275 280 285 Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val 290 295 300 Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr 305 310 315 320 Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr 325 330 335 Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu 340 345 350 Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys 355 360 365 Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser 370 375 380 Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp 385 390 395 400 Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser 405 410 415 Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala 420 425 430 Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly 435 440 445 <![CDATA[<210> 12]]> <![CDATA[<211> 218]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人工序列描述:合成肽]]> <![CDATA[<400> 12]]> Asp Ile Val Leu Thr Gln Ser Pro Leu Ser Leu Ala Val Ser Leu Gly 1 5 10 15 Gln Pro Ala Ile Ile Ser Cys Lys Ala Ser Gln Ser Val Ser Phe Ala 20 25 30 Gly Thr Ser Leu Met His Trp Tyr His Gln Lys Pro Gly Gln Gln Pro 35 40 45 Arg Leu Leu Ile Tyr Arg Ala Ser Asn Leu Glu Ala Gly Val Pro Asp 50 55 60 Arg Phe Ser Gly Ser Gly Ser Lys Thr Asp Phe Thr Leu Asn Ile Ser 65 70 75 80 Pro Val Glu Ala Glu Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Ser Arg 85 90 95 Glu Tyr Pro Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg 100 105 110 Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln 115 120 125 Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr 130 135 140 Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser 145 150 155 160 Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr 165 170 175 Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys 180 185 190 His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro 195 200 205 Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 210 215 <![CDATA[<210> 13]]> <![CDATA[<211> 218]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人工序列描述:合成肽]]> <![CDATA[<400> 13]]> Asp Ile Val Leu Thr Gln Ser Pro Leu Ser Leu Ala Val Ser Leu Gly 1 5 10 15 Gln Pro Ala Ile Ile Ser Cys Lys Ala Ser Gln Ser Val Ser Phe Ala 20 25 30 Gly Thr Ser Leu Met His Trp Tyr His Gln Lys Pro Gly Gln Gln Pro 35 40 45 Arg Leu Leu Ile Tyr Arg Ala Ser Asn Leu Glu Ala Gly Val Pro Asp 50 55 60 Arg Phe Ser Gly Ser Gly Ser Lys Thr Asp Phe Thr Leu Thr Ile Ser 65 70 75 80 Pro Val Glu Ala Glu Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Ser Arg 85 90 95 Glu Tyr Pro Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg 100 105 110 Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln 115 120 125 Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr 130 135 140 Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser 145 150 155 160 Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr 165 170 175 Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys 180 185 190 His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro 195 200 205 Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 210 215 <![CDATA[<210> 14]]> <![CDATA[<211> 118]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人工序列描述:合成肽]]> <![CDATA[<400> 14]]> Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Val Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr 20 25 30 Phe Met Asn Trp Val Lys Gln Ser Pro Gly Gln Ser Leu Glu Trp Ile 35 40 45 Gly Arg Ile His Pro Tyr Asp Gly Asp Thr Phe Tyr Asn Gln Lys Phe 50 55 60 Gln Gly Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Asn Thr Ala His 65 70 75 80 Met Glu Leu Leu Ser Leu Thr Ser Glu Asp Phe Ala Val Tyr Tyr Cys 85 90 95 Thr Arg Tyr Asp Gly Ser Arg Ala Met Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Thr Val Thr Val Ser Ser 115 <![CDATA[<210> 15]]> <![CDATA[<211> 112]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人工序列描述:合成肽]]> <![CDATA[<400> 15]]> Asp Ile Val Leu Thr Gln Ser Pro Leu Ser Leu Ala Val Ser Leu Gly 1 5 10 15 Gln Pro Ala Ile Ile Ser Cys Lys Ala Ser Gln Ser Val Ser Phe Ala 20 25 30 Gly Thr Ser Leu Met His Trp Tyr His Gln Lys Pro Gly Gln Gln Pro 35 40 45 Arg Leu Leu Ile Tyr Arg Ala Ser Asn Leu Glu Ala Gly Val Pro Asp 50 55 60 Arg Phe Ser Gly Ser Gly Ser Lys Thr Asp Phe Thr Leu Asn Ile Ser 65 70 75 80 Pro Val Glu Ala Glu Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Ser Arg 85 90 95 Glu Tyr Pro Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg 100 105 110 <![CDATA[<210> 16]]> <![CDATA[<211> 112]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人工序列描述:合成肽]]> <![CDATA[<400> 16]]> Asp Ile Val Leu Thr Gln Ser Pro Leu Ser Leu Ala Val Ser Leu Gly 1 5 10 15 Gln Pro Ala Ile Ile Ser Cys Lys Ala Ser Gln Ser Val Ser Phe Ala 20 25 30 Gly Thr Ser Leu Met His Trp Tyr His Gln Lys Pro Gly Gln Gln Pro 35 40 45 Arg Leu Leu Ile Tyr Arg Ala Ser Asn Leu Glu Ala Gly Val Pro Asp 50 55 60 Arg Phe Ser Gly Ser Gly Ser Lys Thr Asp Phe Thr Leu Thr Ile Ser 65 70 75 80 Pro Val Glu Ala Glu Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Ser Arg 85 90 95 Glu Tyr Pro Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg 100 105 110 <![CDATA[<210> 17]]> <![CDATA[<211> 445]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人工序列描述:合成肽]]> <![CDATA[<400> 17]]> Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu 1 5 10 15 Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Leu Ser Leu Ala Ser Asn 20 25 30 Ser Val Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Met 35 40 45 Gly Val Ile Trp Asn His Gly Gly Thr Asp Tyr Asn Pro Ser Ile Lys 50 55 60 Ser Arg Leu Ser Ile Ser Arg Asp Thr Ser Lys Ser Gln Val Phe Leu 65 70 75 80 Lys Met Asn Ser Leu Thr Ala Ala Asp Thr Ala Met Tyr Phe Cys Val 85 90 95 Arg Lys Gly Gly Ile Tyr Phe Asp Tyr Trp Gly Gln Gly Val Leu Val 100 105 110 Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala 115 120 125 Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu 130 135 140 Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly 145 150 155 160 Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser 165 170 175 Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu 180 185 190 Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr 195 200 205 Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr 210 215 220 Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe 225 230 235 240 Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro 245 250 255 Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val 260 265 270 Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr 275 280 285 Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val 290 295 300 Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys 305 310 315 320 Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser 325 330 335 Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro 340 345 350 Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val 355 360 365 Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly 370 375 380 Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp 385 390 395 400 Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp 405 410 415 Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His 420 425 430 Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly 435 440 445 <![CDATA[<210> 18]]> <![CDATA[<211> 213]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人工序列描述:合成肽]]> <![CDATA[<400> 18]]> Asp Thr Val Leu Thr Gln Ser Pro Ser Leu Ala Val Ser Pro Gly Glu 1 5 10 15 Arg Ala Thr Ile Ser Cys Arg Ala Ser Glu Ser Val Ser Thr Leu Met 20 25 30 His Trp Tyr Gln Gln Lys Pro Gly Gln Gln Pro Lys Leu Leu Ile Tyr 35 40 45 Leu Ala Ser His Arg Glu Ser Gly Val Pro Ala Arg Phe Ser Gly Ser 50 55 60 Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Asp Pro Met Glu Ala Glu 65 70 75 80 Asp Thr Ala Thr Tyr Tyr Cys Gln Gln Ser Arg Asn Asp Pro Trp Thr 85 90 95 Phe Gly Gln Gly Thr Lys Leu Glu Leu Lys Arg Thr Val Ala Ala Pro 100 105 110 Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr 115 120 125 Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys 130 135 140 Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu 145 150 155 160 Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser 165 170 175 Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala 180 185 190 Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe 195 200 205 Asn Arg Gly Glu Cys 210 <![CDATA[<210> 19]]> <![CDATA[<211> 448]]> <![CDATA[<212> PRT]]> <![CDATA[<213>]]> 人工序列 <![CDATA[<220>]]> <![CDATA[<223> 人工序列描述:合成肽]]> <![CDATA[<400> 19]]> Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Ala Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Trp Met Gln Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Cys Ile 35 40 45 Gly Thr Ile Tyr Pro Gly Asp Gly Asp Thr Thr Tyr Thr Gln Lys Phe 50 55 60 Gln Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Gln Leu Ser Ser Leu Arg Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Tyr Asp Ala Pro Gly Tyr Ala Met Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe 115 120 125 Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu 130 135 140 Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp 145 150 155 160 Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu 165 170 175 Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser 180 185 190 Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro 195 200 205 Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys 210 215 220 Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro 225 230 235 240 Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser 245 250 255 Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp 260 265 270 Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn 275 280 285 Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val 290 295 300 Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu 305 310 315 320 Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys 325 330 335 Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr 340 345 350 Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr 355 360 365 Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu 370 375 380 Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu 385 390 395 400 Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys 405 410 415 Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu 420 425 430 Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly 435 440 445 <![CDATA[<210> 20]]> <![CDATA[<211> 214]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人工序列描述:合成肽]]> <![CDATA[<400> 20]]> Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Ile Asn Asn Tyr 20 25 30 Leu Ala Trp Tyr Gln His Lys Pro Gly Lys Gly Pro Lys Leu Leu Ile 35 40 45 His Tyr Thr Ser Thr Leu His Pro Gly Ile Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Arg Asp Tyr Ser Phe Ser Ile Ser Ser Leu Glu Pro 65 70 75 80 Glu Asp Ile Ala Thr Tyr Tyr Cys Leu Gln Tyr Asp Asn Leu Leu Tyr 85 90 95 Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala Ala 100 105 110 Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125 Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140 Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln 145 150 155 160 Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175 Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190 Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205 Phe Asn Arg Gly Glu Cys 210 <![CDATA[<210> 21]]> <![CDATA[<211> 214]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人工序列描述:合成肽]]> <![CDATA[<400> 21]]> Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asp Ile Asn Asn Tyr 20 25 30 Leu Ala Trp Tyr Gln His Lys Pro Gly Lys Gly Pro Lys Leu Leu Ile 35 40 45 His Tyr Thr Ser Thr Leu His Pro Gly Ile Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Arg Asp Tyr Ser Phe Ser Ile Ser Ser Leu Glu Pro 65 70 75 80 Glu Asp Ile Ala Thr Tyr Tyr Cys Leu Gln Tyr Asp Asn Leu Leu Tyr 85 90 95 Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala Ala 100 105 110 Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125 Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140 Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln 145 150 155 160 Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175 Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190 Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205 Phe Asn Arg Gly Glu Cys 210 <![CDATA[<210> 22]]> <![CDATA[<211> 450]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223>]]> 人工序列描述:合成肽 <![CDATA[<400> 22]]> Gln Val Gln Leu Val Gln Pro Gly Ala Glu Val Val Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Leu Ser Cys Lys Thr Ser Gly Tyr Thr Phe Thr Ser Asn 20 25 30 Trp Met His Trp Val Lys Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Glu Ile Asp Pro Ser Asp Ser Tyr Thr Asn Tyr Asn Gln Asn Phe 50 55 60 Gln Gly Lys Ala Lys Leu Thr Val Asp Lys Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Val Ser Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Gly Ser Asn Pro Tyr Tyr Tyr Ala Met Asp Tyr Trp Gly Gln 100 105 110 Gly Thr Ser Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val 115 120 125 Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala 130 135 140 Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser 145 150 155 160 Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val 165 170 175 Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro 180 185 190 Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys 195 200 205 Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp 210 215 220 Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly 225 230 235 240 Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile 245 250 255 Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu 260 265 270 Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His 275 280 285 Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg 290 295 300 Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys 305 310 315 320 Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu 325 330 335 Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr 340 345 350 Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu 355 360 365 Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp 370 375 380 Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val 385 390 395 400 Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp 405 410 415 Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His 420 425 430 Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro 435 440 445 Gly Lys 450 <![CDATA[<210> 23]]> <![CDATA[<211> 211]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人工序列描述:合成肽]]> <![CDATA[<400> 23]]> Glu Ile Val Leu Thr Gln Ser Pro Ala Ile Met Ser Ala Ser Pro Gly 1 5 10 15 Glu Arg Val Thr Met Thr Cys Ser Ala Ser Ser Gly Val Asn Tyr Met 20 25 30 His Trp Tyr Gln Gln Lys Pro Gly Thr Ser Pro Arg Arg Trp Ile Tyr 35 40 45 Asp Thr Ser Lys Leu Ala Ser Gly Val Pro Ala Arg Phe Ser Gly Ser 50 55 60 Gly Ser Gly Thr Asp Tyr Ser Leu Thr Ile Ser Ser Met Glu Pro Glu 65 70 75 80 Asp Ala Ala Thr Tyr Tyr Cys His Gln Arg Gly Ser Tyr Thr Phe Gly 85 90 95 Gly Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala Ala Pro Ser Val 100 105 110 Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser 115 120 125 Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln 130 135 140 Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val 145 150 155 160 Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu 165 170 175 Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu 180 185 190 Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg 195 200 205 Gly Glu Cys 210 <![CDATA[<210> 24]]> <![CDATA[<211> 447]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人工序列描述:合成肽]]> <![CDATA[<400> 24]]> Gln Ala Gln Leu Val Gln Ser Gly Ala Glu Val Val Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Asn Met His Trp Val Lys Gln Thr Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Tyr Ile Tyr Pro Gly Asn Gly Ala Thr Asn Tyr Asn Gln Lys Phe 50 55 60 Gln Gly Lys Ala Thr Leu Thr Ala Asp Thr Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Gln Ile Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys 85 90 95 Ala Arg Gly Asp Ser Val Pro Phe Ala Tyr Trp Gly Gln Gly Thr Leu 100 105 110 Val Thr Val Ser Ala Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu 115 120 125 Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys 130 135 140 Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser 145 150 155 160 Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser 165 170 175 Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser 180 185 190 Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn 195 200 205 Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His 210 215 220 Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val 225 230 235 240 Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr 245 250 255 Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu 260 265 270 Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys 275 280 285 Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser 290 295 300 Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys 305 310 315 320 Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile 325 330 335 Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro 340 345 350 Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu 355 360 365 Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn 370 375 380 Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser 385 390 395 400 Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg 405 410 415 Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu 420 425 430 His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 435 440 445 <![CDATA[<210> 25]]> <![CDATA[<211> 213]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人工序列描述:合成肽]]> <![CDATA[<400> 25]]> Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Met Ser Ala Ser Pro Gly 1 5 10 15 Glu Arg Val Thr Ile Thr Cys Ser Ala His Ser Ser Val Ser Phe Met 20 25 30 His Trp Phe Gln Gln Lys Pro Gly Thr Ser Pro Lys Leu Trp Ile Tyr 35 40 45 Ser Thr Ser Ser Leu Ala Ser Gly Val Pro Ala Arg Phe Gly Gly Ser 50 55 60 Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Ser Met Glu Ala Glu 65 70 75 80 Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Arg Ser Ser Phe Pro Leu Thr 85 90 95 Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg Thr Val Ala Ala Pro 100 105 110 Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr 115 120 125 Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys 130 135 140 Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu 145 150 155 160 Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser 165 170 175 Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala 180 185 190 Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe 195 200 205 Asn Arg Gly Glu Cys 210 <![CDATA[<210> 26]]> <![CDATA[<211> 447]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人工序列描述:合成肽]]> <![CDATA[<400> 26]]> Gln Val Gln Leu Gln Gln Pro Gly Ala Glu Val Val Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Tyr Ile His Trp Ile Lys Gln Thr Pro Gly Gln Gly Leu Glu Trp Val 35 40 45 Gly Val Ile Tyr Pro Gly Asn Asp Asp Ile Ser Tyr Asn Gln Lys Phe 50 55 60 Gln Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Thr Thr Ala Tyr 65 70 75 80 Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Glu Val Arg Leu Arg Tyr Phe Asp Val Trp Gly Gln Gly Thr 100 105 110 Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro 115 120 125 Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly 130 135 140 Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn 145 150 155 160 Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln 165 170 175 Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser 180 185 190 Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser 195 200 205 Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr 210 215 220 His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser 225 230 235 240 Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg 245 250 255 Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro 260 265 270 Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala 275 280 285 Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val 290 295 300 Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr 305 310 315 320 Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr 325 330 335 Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu 340 345 350 Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys 355 360 365 Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser 370 375 380 Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp 385 390 395 400 Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser 405 410 415 Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala 420 425 430 Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly 435 440 445 <![CDATA[<210> 27]]> <![CDATA[<211> 219]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人工序列描述:合成肽]]> <![CDATA[<400> 27]]> Glu Ile Val Leu Thr Gln Ser Pro Gly Ser Leu Ala Val Ser Pro Gly 1 5 10 15 Glu Arg Val Thr Met Ser Cys Lys Ser Ser Gln Ser Val Phe Phe Ser 20 25 30 Ser Ser Gln Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Ile Pro Gly Gln 35 40 45 Ser Pro Arg Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val 50 55 60 Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 65 70 75 80 Ile Ser Ser Val Gln Pro Glu Asp Leu Ala Ile Tyr Tyr Cys His Gln 85 90 95 Tyr Leu Ser Ser Arg Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys 100 105 110 Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu 115 120 125 Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe 130 135 140 Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln 145 150 155 160 Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser 165 170 175 Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu 180 185 190 Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser 195 200 205 Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 210 215 <![CDATA[<210> 28]]> <![CDATA[<211> 214]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人工序列描述:合成肽]]> <![CDATA[<400> 28]]> Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Val Ser Val Gly 1 5 10 15 Glu Arg Val Thr Ile Thr Cys Arg Ala Ser Glu Asn Ile Arg Ser Asn 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ser Pro Lys Leu Leu Val 35 40 45 Asn Val Ala Thr Asn Leu Ala Asp Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Tyr Ser Leu Lys Ile Asn Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Gly Thr Tyr Tyr Cys Gln His Tyr Trp Gly Thr Thr Trp 85 90 95 Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala Ala 100 105 110 Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125 Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140 Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln 145 150 155 160 Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175 Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190 Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205 Phe Asn Arg Gly Glu Cys 210 <![CDATA[<210> 29]]> <![CDATA[<211> 444]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人工序列描述:合成肽]]> <![CDATA[<400> 29]]> Gln Val Gln Val Gln Glu Ser Gly Pro Gly Leu Val Ala Pro Ser Gln 1 5 10 15 Thr Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Thr Ser 20 25 30 Gly Val Ser Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Leu 35 40 45 Gly Val Ile Trp Gly Asp Gly Ser Thr Asn Tyr His Pro Ser Leu Lys 50 55 60 Ser Arg Leu Ser Ile Lys Lys Asp His Ser Lys Ser Gln Val Phe Leu 65 70 75 80 Lys Leu Asn Ser Leu Thr Ala Ala Asp Thr Ala Thr Tyr Tyr Cys Ala 85 90 95 Lys Gly Gly Tyr Ser Leu Ala His Trp Gly Gln Gly Thr Leu Val Thr 100 105 110 Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro 115 120 125 Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val 130 135 140 Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala 145 150 155 160 Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly 165 170 175 Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly 180 185 190 Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys 195 200 205 Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys 210 215 220 Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu 225 230 235 240 Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu 245 250 255 Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys 260 265 270 Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys 275 280 285 Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu 290 295 300 Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys 305 310 315 320 Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys 325 330 335 Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser 340 345 350 Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys 355 360 365 Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln 370 375 380 Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly 385 390 395 400 Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln 405 410 415 Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn 420 425 430 His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly 435 440 <![CDATA[<210> 30]]> <![CDATA[<211> 444]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人工序列描述:合成肽]]> <![CDATA[<400> 30]]> Gln Val Gln Val Gln Glu Ser Gly Pro Gly Leu Val Ala Pro Ser Gln 1 5 10 15 Thr Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Thr Ser 20 25 30 Gly Val Ser Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Leu 35 40 45 Gly Val Ile Trp Gly Asp Gly Ser Thr Asn Tyr His Ser Ser Leu Lys 50 55 60 Ser Arg Leu Ser Ile Lys Lys Asp His Ser Lys Ser Gln Val Phe Leu 65 70 75 80 Lys Leu Asn Ser Leu Thr Ala Ala Asp Thr Ala Thr Tyr Tyr Cys Ala 85 90 95 Lys Gly Gly Tyr Ser Leu Ala His Trp Gly Gln Gly Thr Leu Val Thr 100 105 110 Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro 115 120 125 Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val 130 135 140 Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala 145 150 155 160 Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly 165 170 175 Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly 180 185 190 Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys 195 200 205 Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys 210 215 220 Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu 225 230 235 240 Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu 245 250 255 Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys 260 265 270 Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys 275 280 285 Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu 290 295 300 Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys 305 310 315 320 Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys 325 330 335 Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser 340 345 350 Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys 355 360 365 Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln 370 375 380 Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly 385 390 395 400 Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln 405 410 415 Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn 420 425 430 His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly 435 440 <![CDATA[<210> 31]]> <![CDATA[<211> 213]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人工序列描述:合成肽]]> <![CDATA[<400> 31]]> Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Met Ser Ala Ser Pro Gly 1 5 10 15 Glu Arg Val Thr Met Thr Cys Ser Ala Thr Ser Ser Val Thr Tyr Met 20 25 30 His Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Lys Arg Trp Ile Tyr 35 40 45 Asp Thr Ser Asn Leu Pro Tyr Gly Val Pro Ala Arg Phe Ser Gly Ser 50 55 60 Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Ser Met Glu Ala Glu 65 70 75 80 Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Asp Asn Pro Pro Thr 85 90 95 Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala Ala Pro 100 105 110 Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr 115 120 125 Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys 130 135 140 Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu 145 150 155 160 Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser 165 170 175 Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala 180 185 190 Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe 195 200 205 Asn Arg Gly Glu Cys 210 <![CDATA[<210> 32]]> <![CDATA[<211> 449]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人工序列描述:合成肽]]> <![CDATA[<400> 32]]> Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Leu Lys Pro Ser Gln 1 5 10 15 Ser Leu Ser Leu Thr Cys Thr Val Ser Gly Tyr Ser Ile Thr Ser Gly 20 25 30 Phe Ala Trp His Trp Ile Arg Gln His Pro Gly Asn Lys Leu Glu Trp 35 40 45 Met Gly Tyr Ile Leu Tyr Ser Gly Ser Thr Val Tyr Ser Pro Ser Leu 50 55 60 Lys Ser Arg Ile Ser Ile Thr Arg Asp Thr Ser Lys Asn His Phe Phe 65 70 75 80 Leu Gln Leu Asn Ser Val Thr Ala Ala Asp Thr Ala Thr Tyr Tyr Cys 85 90 95 Ala Arg Gly Tyr Tyr Gly Tyr Gly Ala Trp Phe Ala Tyr Trp Gly Gln 100 105 110 Gly Thr Leu Val Thr Val Ser Ala Ala Ser Thr Lys Gly Pro Ser Val 115 120 125 Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala 130 135 140 Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser 145 150 155 160 Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val 165 170 175 Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro 180 185 190 Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys 195 200 205 Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp 210 215 220 Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly 225 230 235 240 Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile 245 250 255 Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu 260 265 270 Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His 275 280 285 Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg 290 295 300 Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys 305 310 315 320 Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu 325 330 335 Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr 340 345 350 Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu 355 360 365 Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp 370 375 380 Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val 385 390 395 400 Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp 405 410 415 Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His 420 425 430 Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro 435 440 445 Gly <![CDATA[<210> 33]]> <![CDATA[<211> 5]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人工序列描述:合成肽]]> <![CDATA[<400> 33]]> Ser Ser Ile Met His 1 5 <![CDATA[<210> 34]]> <![CDATA[<211> 17]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人工序列描述:合成肽]]> <![CDATA[<400> 34]]> Tyr Ile Lys Pro Tyr Asn Asp Gly Thr Lys Tyr Asn Glu Lys Phe Lys 1 5 10 15 Gly <![CDATA[<210> 35]]> <![CDATA[<211> 12]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人工序列描述:合成肽]]> <![CDATA[<400> 35]]> Glu Gly Gly Asn Asp Tyr Tyr Asp Thr Met Asp Tyr 1 5 10 <![CDATA[<210> 36]]> <![CDATA[<211> 11]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人工序列描述:合成肽]]> <![CDATA[<400> 36]]> Arg Ala Ser Gln Asp Ile Asn Ser Tyr Leu Ser 1 5 10 <![CDATA[<210> 37]]> <![CDATA[<211> 7]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人工序列描述:合成肽]]> <![CDATA[<400> 37]]> Arg Val Asn Arg Leu Val Asp 1 5 <![CDATA[<210> 38]]> <![CDATA[<211> 9]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人工序列描述:合成肽]]> <![CDATA[<400> 38]]> Leu Gln Tyr Asp Ala Phe Pro Tyr Thr 1 5 <![CDATA[<210> 39]]> <![CDATA[<211> 121]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人工序列描述:合成肽]]> <![CDATA[<220>]]> <![CDATA[<221> MOD_RES]]> <![CDATA[<222> (2)..(2)]]> <![CDATA[<223> 任何胺基酸]]> <![CDATA[<220> ]]> <![CDATA[<223> 取代及較佳實施態樣的詳細描述請參申請時說明書]]> <![CDATA[<400> 39]]> Gln Xaa Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ile Phe Thr Ser Ser 20 25 30 Ile Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Tyr Ile Lys Pro Tyr Asn Asp Gly Thr Lys Tyr Asn Glu Lys Phe 50 55 60 Lys Gly Arg Ala Thr Leu Thr Ser Asp Arg Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Glu Gly Gly Asn Asp Tyr Tyr Asp Thr Met Asp Tyr Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <![CDATA[<210> 40]]> <![CDATA[<211> 108]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人工序列描述:合成肽]]> <![CDATA[<400> 40]]> Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Ile Asn Ser Tyr 20 25 30 Leu Ser Trp Phe Gln Gln Lys Pro Gly Lys Ala Pro Lys Thr Leu Ile 35 40 45 Tyr Arg Val Asn Arg Leu Val Asp Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Asn Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln Tyr Asp Ala Phe Pro Tyr 85 90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg 100 105 <![CDATA[<210> 41]]> <![CDATA[<211> 108]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人工序列描述:合成肽]]> <![CDATA[<400> 41]]> Ser Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Ile Asn Ser Tyr 20 25 30 Leu Ser Trp Phe Gln Gln Lys Pro Gly Lys Ala Pro Lys Thr Leu Ile 35 40 45 Tyr Arg Val Asn Arg Leu Val Asp Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Asn Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln Tyr Asp Ala Phe Pro Tyr 85 90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg 100 105 <![CDATA[<210> 42]]> <![CDATA[<211> 450]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人工序列描述:合成肽]]> <![CDATA[<220>]]> <![CDATA[<221> MOD_RES]]> <![CDATA[<222> (2)..(2)]]> <![CDATA[<223> 任何胺基酸]]> <![CDATA[<220> ]]> <![CDATA[<223> 取代及較佳實施態樣的詳細描述請參申請時說明書]]> <![CDATA[<400> 42]]> Gln Xaa Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ile Phe Thr Ser Ser 20 25 30 Ile Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Tyr Ile Lys Pro Tyr Asn Asp Gly Thr Lys Tyr Asn Glu Lys Phe 50 55 60 Lys Gly Arg Ala Thr Leu Thr Ser Asp Arg Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Glu Gly Gly Asn Asp Tyr Tyr Asp Thr Met Asp Tyr Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys 210 215 220 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 225 230 235 240 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 245 250 255 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 260 265 270 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 275 280 285 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 290 295 300 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 305 310 315 320 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 325 330 335 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 340 345 350 Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser 355 360 365 Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 370 375 380 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 385 390 395 400 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 405 410 415 Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 420 425 430 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Cys Leu Ser 435 440 445 Pro Gly 450 <![CDATA[<210> 43]]> <![CDATA[<211> 214]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人工序列描述:合成多肽]]> <![CDATA[<400> 43]]> Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Ile Asn Ser Tyr 20 25 30 Leu Ser Trp Phe Gln Gln Lys Pro Gly Lys Ala Pro Lys Thr Leu Ile 35 40 45 Tyr Arg Val Asn Arg Leu Val Asp Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Asn Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln Tyr Asp Ala Phe Pro Tyr 85 90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala 100 105 110 Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125 Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140 Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln 145 150 155 160 Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175 Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190 Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205 Phe Asn Arg Gly Glu Cys 210 <![CDATA[<210> 44]]> <![CDATA[<211> 450]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人工序列描述:合成多肽]]> <![CDATA[<220>]]> <![CDATA[<221> MOD_RES]]> <![CDATA[<222> (2)..(2)]]> <![CDATA[<223> 任何胺基酸]]> <![CDATA[<220> ]]> <![CDATA[<223> 取代及較佳實施態樣的詳細描述請參申請時說明書]]> <![CDATA[<400> 44]]> Gln Xaa Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ile Phe Thr Ser Ser 20 25 30 Ile Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Tyr Ile Lys Pro Tyr Asn Asp Gly Thr Lys Tyr Asn Glu Lys Phe 50 55 60 Lys Gly Arg Ala Thr Leu Thr Ser Asp Arg Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Glu Gly Gly Asn Asp Tyr Tyr Asp Thr Met Asp Tyr Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys 210 215 220 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 225 230 235 240 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 245 250 255 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 260 265 270 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 275 280 285 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 290 295 300 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 305 310 315 320 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 325 330 335 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 340 345 350 Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser 355 360 365 Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 370 375 380 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 385 390 395 400 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 405 410 415 Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 420 425 430 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 435 440 445 Pro Gly 450
Claims (22)
- 一種細胞結合劑-細胞毒性劑結合物,其由下式表示: (I) 或其醫藥學上可接受之鹽,其中: CB為細胞結合劑; L 2由以下結構式表示 (L2a); (L2b); (L2c);或 (L2e); 其中: R x、R y、R x'及R y'在每次出現時獨立地為H、-OH、鹵素、-O-(C 1-4烷基)、-SO 3H、-NR 40R 41R 42 +或視情況經-OH、鹵素、-SO 3H或NR 40R 41R 42 +取代之C 1-4烷基,其中R 40、R 41及R 42各獨立地為H或C 1-4烷基; l及k各獨立地為1至10之整數; s1指示連接至該細胞結合劑CB之位點且s3指示連接至該A基團之位點; A為胺基酸殘基或包含2至20個胺基酸殘基之肽; R 1及R 2各獨立地為H或C 1-3烷基; L 1為間隔子; D-L 1-SH為細胞毒性劑;且 q為1至20之整數。
- 如請求項1之結合物,其中R 1及R 2中之一者為H,且另一者為Me,或R 1與R 2均為H。
- 如請求項1之結合物,其中L 1為-L 1'-C(=O)-;且L 1'為伸烷基或伸環烷基,其中L 1中之該-C(=O)-部分連接至D。
- 如請求項3之結合物,其中L 1為-CR 3R 4-(CH 2) 1-8-C(=O)-;R 3及R 4各獨立地為H或Me。
- 如請求項1之結合物,其中R x、R y、R x '及R y '全部為H;且l及k各獨立地為2至6之整數。
- 如請求項1之結合物,其中A為可由在腫瘤組織中表現之蛋白酶裂解之肽。
- 如請求項1之結合物,其中A係選自由以下組成之群:Gly-Gly-Gly、Ala-Val、Val-Ala、D-Val-Ala、Val-Cit、D-Val-Cit、Val-Lys、Phe-Lys、Lys-Lys、Ala-Lys、Phe-Cit、Leu-Cit、Ile-Cit、Phe-Ala、Phe-N 9-甲苯磺醯基-Arg、Phe-N 9-硝基-Arg、Phe-Phe-Lys、D-Phe-Phe-Lys、Gly-Phe-Lys、Leu-Ala-Leu、Ile-Ala-Leu、Val-Ala-Val、Ala-Ala-Ala、D-Ala-Ala-Ala、Ala-D-Ala-Ala、Ala-Ala-D-Ala、Ala-Leu-Ala-Leu (SEQ ID NO: 1)、β-Ala-Leu-Ala-Leu (SEQ ID NO: 2)、Gly-Phe-Leu-Gly (SEQ ID NO: 3)、Val-Arg、Arg-Arg、Val-D-Cit、Val-D-Lys、Val-D-Arg、D-Val-Cit、D-Val-Lys、D-Val-Arg、D-Val-D-Cit、D-Val-D-Lys、D-Val-D-Arg、D-Arg-D-Arg、Ala-Ala、Ala-D-Ala、D-Ala-Ala、D-Ala-D-Ala、Ala-Met、Gln-Val、Asn-Ala、Gln-Phe、Gln-Ala、D-Ala-Pro及D-Ala-tBu-Gly,其中各肽中之第一個胺基酸連接至L 2基團且各肽中之最後一個胺基酸連接至-NH-CR 1R 2-S-L 1-D。
- 如請求項1之結合物,其中該細胞結合劑為抗體或其抗原結合片段、單鏈抗體、特異性結合於目標細胞之單鏈抗體片段、單株抗體、單鏈單株抗體或特異性結合於目標細胞之單株抗體片段、嵌合抗體、特異性結合於目標細胞之嵌合抗體片段、結構域抗體、特異性結合於目標細胞之結構域抗體片段、抗體前藥、奈米抗體、淋巴介質、激素、維生素、生長因子、群落刺激因子、營養物運送分子、Bicycles ®肽或噴他林。
- 如請求項12之結合物,其中該細胞結合劑為抗體或其抗原結合片段、表面整修抗體或其表面整修抗體片段、單株抗體或其單株抗體片段、人類化抗體或其人類化抗體片段、嵌合抗體或其嵌合抗體片段。
- 如請求項12之結合物,其中該細胞結合劑為抗葉酸受體抗體或其抗體片段、抗EGFR抗體或其抗體片段、抗CD33抗體或其抗體片段、抗CD19抗體或其抗體片段、抗Muc1抗體或其抗體片段或抗CD37抗體或其抗體片段或抗CD123抗體或其抗體片段。
- 如請求項15之結合物,其中該抗葉酸受體抗體包含 (i) (a)具有SEQ ID NO: 4之胺基酸序列的重鏈CDR1;具有SEQ ID NO: 5之胺基酸序列的重鏈CDR2;及具有SEQ ID NO: 6之胺基酸序列的重鏈CDR3;及(b)具有SEQ ID NO: 7之胺基酸序列的輕鏈CDR1;具有SEQ ID NO: 10之胺基酸序列的輕鏈CDR2;及具有SEQ ID NO: 9之胺基酸序列的輕鏈CDR3; (ii) 具有SEQ ID NO: 14之胺基酸序列的重鏈可變域,及具有SEQ ID NO: 15或SEQ ID NO: 16之胺基酸序列的輕鏈可變域; (iii) 具有SEQ ID NO: 11之胺基酸序列的重鏈,及具有SEQ ID NO: 12或SEQ ID NO: 13之胺基酸序列的輕鏈;或 (iv) 由具有ATCC保藏號PTA-10772之質體DNA編碼之重鏈及由具有ATCC保藏號PTA-10774之質體DNA編碼之輕鏈。
- 一種醫藥組合物,其包含如請求項1至16中任一項之結合物及醫藥學上可接受之載劑。
- 一種如請求項1至16中任一項之結合物之用途,其係用於製備在哺乳動物中抑制異常細胞生長或治療增殖性病症之醫藥品。
- 如請求項21之用途,其中該用途係用於治療癌症,且其中: (i) 該癌症係選自腎癌、乳癌(例如三陰性乳癌(TNBC))、結腸癌、腦癌、前列腺癌、子宮內膜癌、子宮頸癌、腎臟癌症、胰腺癌、卵巢癌(例如上皮卵巢癌)、頭頸癌、黑素瘤、結腸直腸癌、胃癌、鱗狀癌症、肺癌(例如非小細胞肺癌及小細胞肺癌)、睪丸癌、絨毛膜癌瘤、默克細胞癌瘤、肉瘤(例如骨肉瘤、軟骨肉瘤、脂肪肉瘤及平滑肌肉瘤)、膠質母細胞瘤、神經母細胞瘤、淋巴瘤(例如非霍奇金淋巴瘤)、脊髓發育不良症候群(MDS)、腹膜癌、輸卵管癌、子宮癌或白血病(例如急性骨髓性白血病(AML)、急性單核球性白血病、前髓細胞白血病、嗜伊紅球性白血病、急性淋巴母細胞性白血病(例如B-ALL)、慢性淋巴球性白血病(CLL)或慢性骨髓性白血病(CML)); (ii) 該癌症為乳癌、卵巢癌或腎癌;或 (iii) 該癌症為子宮頸癌、卵巢癌、子宮癌、子宮內膜癌或輸卵管癌。
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2018
- 2018-02-27 RU RU2019129839A patent/RU2765098C2/ru active
- 2018-02-27 RU RU2022101392A patent/RU2022101392A/ru unknown
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2021
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RU2019129839A3 (zh) | 2021-06-24 |
MA47815A (fr) | 2020-01-08 |
JP7106560B2 (ja) | 2022-07-26 |
EP3589328A1 (en) | 2020-01-08 |
SG10202109376YA (en) | 2021-10-28 |
US20180296694A1 (en) | 2018-10-18 |
RU2765098C2 (ru) | 2022-01-25 |
IL298414A (en) | 2023-01-01 |
IL290698A (en) | 2022-04-01 |
CA3054608A1 (en) | 2018-09-07 |
TW201838657A (zh) | 2018-11-01 |
TWI781145B (zh) | 2022-10-21 |
CN116785451A (zh) | 2023-09-22 |
RU2019129839A (ru) | 2021-03-30 |
JP2020510656A (ja) | 2020-04-09 |
JP2022137200A (ja) | 2022-09-21 |
IL290698B2 (en) | 2023-04-01 |
SG11201907693VA (en) | 2019-09-27 |
US11135308B2 (en) | 2021-10-05 |
AU2018229277A1 (en) | 2019-10-10 |
CN116785450A (zh) | 2023-09-22 |
US20200197531A1 (en) | 2020-06-25 |
RU2022101392A (ru) | 2022-03-02 |
CN110366431B (zh) | 2023-07-18 |
IL268921B (en) | 2022-03-01 |
CN110366431A (zh) | 2019-10-22 |
IL290698B (en) | 2022-12-01 |
KR20190122766A (ko) | 2019-10-30 |
US10792372B2 (en) | 2020-10-06 |
WO2018160539A1 (en) | 2018-09-07 |
US20220111067A1 (en) | 2022-04-14 |
IL268921A (en) | 2019-10-31 |
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