TW201441248A - 毒傘肽(amatoxin)衍生物 - Google Patents
毒傘肽(amatoxin)衍生物 Download PDFInfo
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- TW201441248A TW201441248A TW103107305A TW103107305A TW201441248A TW 201441248 A TW201441248 A TW 201441248A TW 103107305 A TW103107305 A TW 103107305A TW 103107305 A TW103107305 A TW 103107305A TW 201441248 A TW201441248 A TW 201441248A
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Abstract
本發明係關於腫瘤療法。在一態樣中,本發明係關於藉由某些鏈接連結之毒傘肽(amatoxin)及靶結合部分(例如抗體)之偶聯物,其可用於治療癌症及其他病症及疾病。在另一態樣中,本發明係關於包括該等偶聯物之醫藥組合物。
Description
本發明係關於腫瘤療法。在一態樣中,本發明係關於藉由某些鏈接連結之毒傘肽(amatoxin)及靶結合部分(例如抗體)之偶聯物,其可用於治療癌症及其他病症及疾病。在另一態樣中,本發明係關於包括該等偶聯物之醫藥組合物。
毒傘肽係由8個胺基酸構成之環狀肽。其可(例如)自毒鵝膏(Amanita phalloides)蘑菇分離或以合成方式製備。具體而言,毒傘肽抑制哺乳動物細胞的DNA依賴性RNA聚合酶II,且由此亦抑制受影響細胞之轉錄及蛋白質生物合成。細胞中之轉錄抑制導致生長及增殖停止。儘管並不共價結合,瓢菌素及RNA聚合酶II之間之複合極其緊密(KD=3nM)。瓢菌素與酶之分離係極緩慢過程,由此使得不可能恢復受影響細胞。在轉錄抑制持續過長時,細胞將發生程式性細胞死亡(細胞凋亡)。
在1981年已探究使用毒傘肽作為用於腫瘤療法之細胞毒性部分,其中使用附接至Trp之吲哚環之連接體(胺基酸4;參見圖1)經由重氮化來使抗Thy 1.2抗體偶合至α-瓢菌素(Davis & Preston,Science 1981,213,1385-1388)。Davis及Preston將附接位點鑑別為7’位。Morris及Venton亦證實,7’位處之取代得到維持細胞毒性活性之衍生物(Morris及Venton,Int.J.Peptide Protein Res 1983,21 419-430)。
專利申請案EP 1 859 811 A1(公開於2007年11月28日)闡述β-瓢菌素之毒傘肽胺基酸1之γ C原子直接偶合(亦即並無連接體結構)至白蛋白或單株抗體HEA125、OKT3或PA-1之偶聯物。另外,展示該等偶聯物對於乳癌細胞(MCF-7)、伯基特氏淋巴瘤細胞(Burkitt’s lymphoma cell)(Raji)及T淋巴瘤細胞(Jurkat)之增殖之抑制效應。建議使用連接體,包含含有諸如醯胺、酯、醚、硫醚、二硫化物、脲、硫脲、烴部分及諸如此類等要素之連接體,但實際上並未展示該等構築體,且並未提供更多細節(例如毒傘肽上之附接位點)。
專利申請案WO 2010/115629及WO 2010/115630(皆公開於2010年10月14日)闡述如下偶聯物:其中抗體(例如抗EpCAM抗體,例如人類化huHEA125)經由(i)毒傘肽胺基酸1之γ C原子、(ii)毒傘肽胺基酸4之6’C原子或(iii)經由毒傘肽胺基酸3之δ C原子(在每一情形下皆直接經由抗體與毒傘肽之間之連接體)偶合至毒傘肽。所建議連接體包括諸如酯、醚、胺基甲酸酯、肽鍵及諸如此類等要素。另外,展示該等偶聯物對於乳癌細胞(細胞系MCF-7)、胰臟癌瘤(細胞系Capan-1)、結腸癌(細胞系Colo205)及膽管上皮癌(細胞系OZ)之增殖之抑制效應。
毒傘肽之結構活性關係綜述於Wieland(T.Wieland,Peptides of Poisonous Amanita Mushrooms,Springer series in molecular biology,Springer Verlag New York,1986)中。人們認為胺基酸2(羥基脯胺酸)之羥基及胺基酸3(二羥基-異白胺酸)之γ-羥基對於活性必不可少,而胺基酸1(天門冬胺酸鹽或天門冬胺酸)、胺基酸4(6-羥基-色胺酸)處之官能基及胺基酸3之δ-羥基對於化學改質較為耐受。此指示,後面位置係用於連接體附接之較佳位點,而前面位點之改質應加以避免。
已知毒傘肽在偶合至大生物分子載劑(例如抗體分子)時相對無毒,且其僅在生物分子載劑裂解之後施加其細胞毒性活性。鑒於毒傘肽尤其對於肝細胞之毒性,最重要的為,用於靶定腫瘤療法之毒傘肽
偶聯物在投與至血漿中之後保持高度穩定,且毒傘肽之釋放發生於在靶細胞中內在化之後。在此背景下,偶聯物穩定性之微小改良可對於用於治療方式之毒傘肽偶聯物之治療窗及安全性具有顯著影響。
本發明目標係提供在血漿中穩定之其他靶結合部分-毒傘肽偶聯物,從而最小化對於非靶細胞之有害副效應。
本發明係基於以下意外發現:經由兩個結合至毒傘肽胺基酸3之γ及δ C原子之氧原子形成環可改良靶結合部分-毒傘肽偶聯物之耐受性,且並不干擾該等毒傘肽與其靶(哺乳動物細胞之DNA依賴性RNA聚合酶II)之相互作用。迄今為止,結合至毒傘肽胺基酸3之γ C原子之羥基之存在已視為對於毒傘肽及毒傘肽偶聯物的效能必不可少。Wieland(T.Wieland,Peptides of Poisonous Amanita Mushrooms,Springer Series in Molecular Biology,Springer Verlag New York,1986;Wieland T,Rempel D,Gebert U,Buku A,Boehringer H.Über die Inhaltsstoffe des grünen Knollenblätterpilzes.XXXII.Chromatographische Auftrennung der Gesamtgifte und Isolierung der neuen Nebentoxine Amanin und Phallisin sowie des ungiftigen Amanullins.Liebigs Ann Chem.1967;704:226-236)報導天然存在之毒傘肽(例如缺乏γ-羥基之一羥鵝膏毒肽醯胺)具有顯著減小之毒性。
在第一態樣中,本發明係關於式I毒傘肽:
其中:R1係選自C=O、C=S、C=NR6及CR7R8;R2係選自S=O、SO2及S;R3係選自NHR5及OR5;R4係選自H、OR5及OC1-6-烷基;R6係選自C1-6-伸烷基-R5、伸環烷基-R5、伸雜環烷基-R5、伸芳基-R5及伸雜芳基-R5;R7及R8獨立地選自H、C1-6-伸烷基-R5、伸環烷基-R5、伸雜環烷基-R5、伸芳基-R5及伸雜芳基-R5;其中:(i)每一R5係H;(ii)R5中之一者係-Ln-X,其中L係連接體,n係選自0及1,且X係可與靶向部分偶合之化學部分,且其中剩餘R5係H;或
(iii)R5中之一者係-Ln-X*-Y,其中L係連接體,n係選自0及1,Y係靶向部分,且X*係源自X與Y之官能基之偶合之化學部分,且其中剩餘R5係H。
在另一態樣中,本發明係關於用作醫藥之本發明毒傘肽。
在另一態樣中,本發明係關於用於治療患者之癌症之本發明毒傘肽,特定而已,其中癌症係選自由以下組成之群:乳癌、胃腸癌(例如結腸直腸癌)、胰臟癌、膽管上皮癌、肝細胞癌瘤、骨肉瘤、肺癌、前列腺癌、鱗狀細胞癌瘤、卵巢癌、睪丸癌瘤、膀胱癌瘤、胃癌、頭頸癌、子宮頸癌瘤、腎癌、神經膠質瘤、皮膚癌(例如惡性黑素瘤)、甲狀腺癌、白血病及惡性淋巴瘤。
在另一態樣中,本發明係關於一種醫藥組合物,其包括本發明毒傘肽且進一步包括一或多種醫藥上可接受之稀釋劑、載劑、賦形劑、填充劑、黏合劑、潤滑劑、助流劑、崩解劑、吸附劑及/或防腐劑。
在另一態樣中,本發明係關於合成本發明毒傘肽之方法,其包括使以下物質進行反應之步驟:式II毒傘肽
其中:R2係選自S=O、SO2及S;R3係選自NHR5及OR5;R4係選自H、OR5及OC1-6-烷基;R6係選自C1-6-伸烷基-R5、伸環烷基-R5、伸雜環烷基-R5、伸芳基-R5及伸雜芳基-R5;R7及R8獨立地選自H、C1-6-伸烷基-R5、伸環烷基-R5、伸雜環烷基-R5、伸芳基-R5及伸雜芳基-R5;其中R5中之一者係-Ln-X,其中L係連接體,n係選自0及1,且X係可與靶向部分偶合之化學部分,且其中剩餘R5係H;(i)N,N’-二琥珀醯亞胺基碳酸酯(DSC);(ii)硫代羰基化試劑,尤其係硫光氣、1,1'-硫代羰基二咪唑或1,1'-硫代羰基二-2(1H)-吡啶酮;(iii)亞胺基羰基化試劑,尤其係二氯異腈或異硫氰酸苯基酯;或(iv)醛、酮或非環狀縮醛。
圖1展示不同毒傘肽之結構式。粗體型數字(1至8)指定形成毒傘肽之8個胺基酸之標準編號。亦展示胺基酸1、3及4中之原子之標準稱謂(分別為希臘字母α至γ、希臘字母α至δ及數字1’至7’)。
圖2展示在BrdU分析中於培育72h之後不同毒傘肽-曲妥珠單抗(Trastuzumab)(商標名為Herceptin®)偶聯物對SK-OV-3(卵巢癌)細胞之細胞毒性活性。
圖3展示在BrdU分析中於培育72h之後不同毒傘肽-曲妥珠單抗偶聯物對SK-OV-3(卵巢癌)細胞之細胞毒性活性。
圖4展示在BrdU分析中於培育72h之後不同毒傘肽-曲妥珠單抗偶聯物對SKBR-3(乳癌)細胞之細胞毒性活性。
圖5展示在BrdU分析中於培育72h之後不同毒傘肽-曲妥珠單抗偶
聯物對JIMT-1(乳癌)細胞之細胞毒性活性。
圖6展示兩種不同毒傘肽-曲妥珠單抗偶聯物在JIMT-1乳癌異種移植物模型中之活體內效能。
圖7展示兩種不同毒傘肽-曲妥珠單抗偶聯物在雌性NMRI nu/nu小鼠中之活體內耐受性。
藉由參照本發明之下列詳細說明及其中所包含之實例可更易於理解本發明。
在第一態樣中,本發明係關於式I毒傘肽:
其中:R1係選自C=O、C=S、C=NR6及CR7R8;R2係選自S=O、SO2及S;R3係選自NHR5及OR5;R4係選自H、OR5及OC1-6-烷基;
R6係選自C1-6-伸烷基-R5、伸環烷基-R5、伸雜環烷基-R5、伸芳基-R5及伸雜芳基-R5;R7及R8獨立地選自H、C1-6-伸烷基-R5、伸環烷基-R5、伸雜環烷基-R5、伸芳基-R5及伸雜芳基-R5;其中:(i)每一R5係H;(ii)R5中之一者係-Ln-X,其中L係連接體,n係選自0及1,且X係可與靶向部分偶合之化學部分,且其中剩餘R5係H;或(iii)R5中之一者係-Ln-X*-Y,其中L係連接體,n係選自0及1,Y係靶向部分,且X*係源自X與Y之官能基之偶合之化學部分,且其中剩餘R5係H。
本文所用之術語「靶結合部分」係指可特異性結合至靶分子或靶表位之任一分子或分子部分。在本申請案之上下文中,較佳靶結合部分係(i)抗體或其抗原結合片段;(ii)抗體樣蛋白;及(iii)核酸適體。適用於本發明之「靶結合部分」通常具有40 000Da(40kDa)或更高之分子質量。
如本文中所使用,若第一化合物(例如抗體)對第二化合物(例如抗原,例如靶蛋白)具有以下解離常數KD,則該第一化合物可視為「特異性結合」至該第二化合物:100μM或更小、較佳地50μM或更小、較佳地30μM或更小、較佳地20μM或更小、較佳地10μM或更小、較佳地5μM或更小、更佳地1μM或更小、更佳地900nM或更小、更佳地800nM或更小、更佳地700nM或更小、更佳地600nM或更小、更佳地500nM或更小、更佳地400nM或更小、更佳地300nM或更小、更佳地200nM或更小、甚至更佳地100nM或更小、甚至更佳地90nM或更小、甚至更佳地80nM或更小、甚至更佳地70nM或更小、甚至更佳地60nM或更小、甚至更佳地50nM或更小、甚至更佳
地40nM或更小、甚至更佳地30nM或更小、甚至更佳地20nM或更小及甚至更佳地10nM或更小。
在本申請案之上下文中,術語「靶分子」及「靶表位」分別係指由靶結合部分特異性結合之抗原及抗原表位。較佳地,靶分子係腫瘤相關性抗原,尤其係與非腫瘤細胞之表面相比以增加之濃度及/或以不同立體組態存在於一或多種類型腫瘤細胞或腫瘤相關性細胞之表面上的抗原或表位。較佳地,該抗原或表位存在於一或多種類型腫瘤或腫瘤間質細胞之表面上,而非存在於非腫瘤細胞之表面上。在特定實施例中,靶結合部分特異性結合至HER-2/neu或上皮細胞黏附分子(EpCAM)之表位上。在其他實施例中,該抗原或表位優先表現於涉及自體免疫疾病之細胞上。在特定該等實施例中,靶結合部分特異性結合至IL-6受體(IL-6R)之表位。在其他實施例中,該抗原或表位優先表現於涉及發炎性疾病之細胞上。
本文所用之術語「抗體或其抗原結合片段」係指免疫球蛋白分子及免疫球蛋白分子之免疫活性部分,亦即含有免疫特異性結合抗原之抗原結合位點之分子。亦包括經由包含(例如)噬菌體顯示之技術進行選擇以特異性結合至靶分子(例如結合至靶蛋白Her-2/neu或EpCAM)之免疫球蛋白樣蛋白。本發明之免疫球蛋白分子可為任一類型(例如IgG、IgE、IgM、IgD、IgA及IgY)、種類(例如IgG1、IgG2、IgG3、IgG4、IgA1及IgA2)或亞類之免疫球蛋白分子。適用於本發明之「抗體及其抗原結合片段」包含但不限於多株抗體、單株抗體、單價抗體、雙特異性抗體、雜偶聯抗體、多特異性抗體、人類抗體、人類化(尤其CDR接枝)抗體、去免疫化抗體或嵌合抗體、單鏈抗體(例如scFv)、Fab片段、F(ab')2片段、藉由Fab表現文庫產生之片段、雙價抗體或四價抗體(Holliger P.等人,1993)、奈米抗體、抗獨特型(抗Id)抗體(包含(例如)本發明抗體之抗Id抗體)及任一上述部分之表位結合片
段。
在一些實施例中,抗原結合片段係本發明之結合人類抗原之抗體片段且包含但不限於Fab、Fab'及F(ab')2、Fd、單鏈Fvs(scFv)、單鏈抗體、二硫化物連接之Fv(dsFv)及包括VL或VH結構域之片段。結合抗原之抗體片段(包含單鏈抗體)可包括單獨或與下列部分之全部或一部分組合之可變結構域:鉸鏈區、CL、CH1、CH2及CH3結構域。本發明亦包含亦包括可變結構域與鉸鏈區、CL、CH1、CH2及CH3結構域之任一組合之抗原結合片段。
可用於本發明之抗體可來自任一動物來源,包含鳥類及哺乳動物。較佳地,抗體係來自人類、齧齒類動物(例如小鼠、大鼠、天竺鼠或兔)、雞、豬、綿羊、山羊、駱駝、牛、馬、猴、貓或狗來源。尤佳地,抗體係人類或鼠類來源。如本文中所使用,「人類抗體」包含具有人類免疫球蛋白之胺基酸序列之抗體,且包含自人類免疫球蛋白文庫或自一或多種人類免疫球蛋白轉基因且並不表現內源性免疫球蛋白之動物分離之抗體,如(例如)Kucherlapati及Jakobovits之美國專利第5,939,598號中所闡述。
術語「抗體樣蛋白」係指經改造(例如藉由環突變誘發)特異性結合至靶分子之蛋白質。通常,此一抗體樣蛋白包括至少一個在兩端附接至蛋白質支架之可變肽環。此雙重結構限制將抗體樣蛋白之結合親和力大大增加至與抗體相當之程度。可變肽環之長度通常由10至20個胺基酸組成。支架蛋白可為任一具有良好溶解性之蛋白質。較佳地,支架蛋白為小球狀蛋白。抗體樣蛋白包含但不限於親和體、抗轉運蛋白及經設計錨蛋白重複蛋白(綜述可參見:Binz等人,2005)。抗體樣蛋白可源自大型突變體文庫(例如自大型噬菌體顯示文庫淘選)並可類似於規則抗體來分離。另外,可藉由球狀蛋白中之表面暴露殘基之組合突變誘發來獲得抗體樣結合蛋白。
術語「核酸適體」係指經由重複循環之活體外選擇或SELEX(配體指數級富集系統進化)加以改造以結合至靶分子之核酸分子(綜述可參見:Brody及Gold,2000)。核酸適體可為DNA或RNA分子。適體可含有改質,例如改質核苷酸,例如經2’-氟取代之嘧啶。
如本文中所使用,「適體偶聯物」係指靶結合部分毒素偶聯物,其中靶結合部分係上文選項(iii)之核酸適體。
在本發明之上下文中,「連接體」係指連結兩種組份之分子,每一組份皆附接至連接體之一端,該分子增加了兩種組份之間之距離且緩解了該等組份之間(例如在本發明情形下靶結合部分與毒傘肽之間)之立體干擾。在不存在連接體下,毒傘肽至靶結合部分之直接鏈接可降低毒傘肽與RNA聚合酶II相互作用之能力。在特定實施例中,連接體在其骨架中具有介於1與30個原子之間(例如1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29或30個原子)之連續鏈,亦即將連接體之長度界定為最短連結,如藉由毒傘肽部分與靶結合部分之間之原子或鍵之數量所量測,其中連接體骨架之一側與毒傘肽發生反應,且另一側與靶結合部分發生反應。在本發明之上下文中,連接體較佳係C1-20-伸烷基、C1-20-伸雜烷基、C2-20-伸烯基、C2-20-伸雜烯基、C2-20-伸炔基、C2-20-伸雜炔基、伸環烷基、伸雜環烷基、伸芳基、伸雜芳基、伸芳烷基或伸雜芳烷基,其視情況經取代。連接體可含有一或多種結構要素,例如羧醯胺、酯、醚、硫醚、二硫化物、脲、硫脲、烴部分及諸如此類。連接體亦可含有兩種或更多種該等結構要素之組合。該等結構要素中之每一者可存在於連接體中一次以上,例如兩次、三次、四次、五次或六次。在一些實施例中,連接體可包括二硫鍵。應理解,連接體必須在單一步驟中或在兩個或更多個後續步驟中附接至毒傘肽及靶結合部分。為此,連接體應較佳地在近端及遠端攜
載兩個基團,其可(i)形成至存在於擬連接組份中之一者上之基團、較佳地毒傘肽或靶結合肽上之活化基團的共價鍵,或(ii)其係或可經活化以與毒傘肽上之基團形成共價鍵。因此,較佳地,化學基團位於連接體之遠端及近端,其係此一偶合反應之結果,例如酯、醚、胺基甲酸酯、肽鍵等。
在本發明之上下文中,術語「毒傘肽」包含所有由8個胺基酸構成之環狀肽,如自毒傘(Amanita)屬所分離且闡述於Wieland,T.及Faulstich H.(Wieland T,Faulstich H.,CRC Crit Rev Biochem.1978 Dec;5(3):185-260)中,且另外包含其所有化學衍生物;另外包含其所有半合成類似物;另外其所有根據天然化合物(環狀,8個胺基酸)之主要結構自結構單元構建之合成類似物,另外包含所有含有非羥基化胺基酸代替羥基化胺基酸之合成或半合成類似物,另外包含所有硫醚亞碸部分由硫化物、碸或藉由不同於硫之原子(例如碳原子,如在瓢菌素之卡巴類似物(carba-analogue)中)代替之合成或半合成類似物,在每一情形下,其中任一該衍生物或類似物藉由抑制哺乳動物RNA聚合酶II而具有功能活性。
如本文中所使用,化合物之「化學衍生物」(或簡稱為:「衍生物」)係指化學結構類似於化合物但含有至少一種並不存在於化合物中之化學基團及/或缺少至少一種存在於化合物中之化學基團的物質。與衍生物進行比較之化合物稱為「母體」化合物。通常,「衍生物」可自母體化合物在一或多個化學反應步驟中產生。
如本文中所使用,化合物之「類似物」與化合物結構相關但並不相同並展現化合物之至少一種活性。與類似物進行比較之化合物稱為「母體」化合物。上述活性包含但不限於:至另一化合物之結合活性、抑制活性(例如酶抑制活性)、毒性效應、活化活性(例如酶活化活性)。無需類似物與母體化合物展現相同程度之此一活性。若化合物
與母體化合物活性展現至少1%(更佳地至少5%、更佳地至少10%、更佳地至少20%、更佳地至少30%、更佳地至少40%及更佳地至少50%)程度之相關活性,則其可視為本申請案背景內之類似物。因此,本文所用之「毒傘肽類似物」係指如下化合物:其與α-瓢菌素、β-瓢菌素、γ-瓢菌素、ε-瓢菌素、鵝膏素、鵝膏毒肽醯胺、一羥鵝膏毒肽醯胺及一羥鵝膏毒肽羧酸(如圖1中所展示)中之任一者結構相關,且與α-瓢菌素、β-瓢菌素、γ-瓢菌素、ε-瓢菌素、鵝膏素、鵝膏毒肽醯胺、一羥鵝膏毒肽醯胺及一羥鵝膏毒肽羧酸中之至少一者相比展現對哺乳動物RNA聚合酶II之抑制活性之至少1%(更佳地至少5%、更佳地至少10%、更佳地至少20%、更佳地至少30%、更佳地至少40%及更佳地至少50%)。適用於本發明之「毒傘肽類似物」甚至可對哺乳動物RNA聚合酶II展現大於α-瓢菌素、β-瓢菌素、γ-瓢菌素、ε-瓢菌素、鵝膏素、鵝膏毒肽醯胺、一羥鵝膏毒肽醯胺或一羥鵝膏毒肽羧酸中之任一者之抑制活性。可藉由測定發生50%抑制之濃度(IC50值)來量測抑制活性。可藉由量測對細胞增殖之抑制活性來間接測定對哺乳動物RNA聚合酶II之抑制活性。用於量測細胞增殖之抑制之適宜分析闡述於實例中。
「半合成類似物」係指藉由化學合成使用來自天然來源(例如植物材料、細菌培養物、真菌培養物或細胞培養物)之化合物作為起始材料獲得之類似物。通常,自分離自鵝膏菌科(Amanitaceae)家族蘑菇之化合物來合成本發明之「半合成類似物」。與之相比,「合成類似物」係指藉由所謂的全合成自小(通常係石油化學)結構單元合成之類似物。通常,在並不藉助生物過程下實施此全合成。
在功能上,毒傘肽定義為抑制哺乳動物RNA聚合酶II之肽或縮肽。較佳毒傘肽係彼等具有可與如上文所定義之連接體分子或靶結合部分進行反應之官能基(例如羧酸基團、胺基、羥基、硫醇或硫醇捕
獲基團)者。尤其適用於本發明偶聯物之毒傘肽係α-瓢菌素、β-瓢菌素、γ-瓢菌素、ε-瓢菌素、鵝膏素、鵝膏毒肽醯胺、一羥鵝膏毒肽醯胺及一羥鵝膏毒肽羧酸(如圖1中所展示)以及其鹽、化學衍生物、半合成類似物及合成類似物。用於本發明之尤佳毒傘肽係α-瓢菌素、β-瓢菌素及鵝膏毒肽醯胺。
在本發明之(iii)之毒傘肽之一特定實施例中,其中(iii)之毒傘肽之Y官能基係胺基。
在一特定該實施例中,X*係脲部分。
在本發明之一特定實施例中,為-Ln-X*-Y之該殘基R5係:(i)存在於R1中;(ii)存在於R3中;(iii)存在於R4中;或(iv)存在於R5中。
在本發明之一特定實施例中,該毒傘肽係選自α-瓢菌素、β-瓢菌素、鵝膏素、鵝膏毒肽醯胺或其鹽或類似物。
在特定實施例中,(ii)或(iii)之連接體L係具有1至20個獨立地選自C、O、N及S之原子、尤其2至16個原子、更尤其5至14個原子及甚至更尤其6至12個原子之直鏈。在特定實施例中,直鏈中至少60%之原子係C原子。在特定實施例中,直鏈中之原子由單鍵連接。
在特定實施例中,(ii)或(iii)之連接體之長度為最多12個原子、尤其2至10個、更尤其4至9及最尤其6至8個原子。
在特定實施例中,連接體L係包括1至4個選自N、O及S之雜原子之伸烷基、伸雜烷基、伸烯基、伸雜烯基、伸炔基、伸雜炔基、伸環烷基、伸雜環烷基、伸芳基、伸雜芳基、伸芳烷基或伸雜芳烷基,其中該連接體視情況經取代。
術語「伸烷基」係指具有1至20個碳原子之雙價直鏈飽和烴基
團,包含具有1至10個碳原子之基團。在某些實施例中,伸烷基可為低碳數伸烷基。術語「低碳數伸烷基」係指具有1至6個碳原子及在某些實施例中1至5或1至4個碳原子之伸烷基。伸烷基之實例包含但不限於亞甲基(-CH2-)、伸乙基(-CH2-CH2-)、伸正丙基、伸正丁基、伸正戊基及伸正己基。
術語「伸烯基」係指具有2至20個碳原子之雙價直鏈基團,其中碳-碳鍵中之至少一者係雙鍵,而其他鍵可為單鍵或其他雙鍵。本文中之術語「伸炔基」係指具有2至20個碳原子之基團,其中碳-碳鍵中之至少一者係三鍵,而其他鍵可為單鍵、雙鍵或其他三鍵。伸烯基之實例包含伸乙烯基(-CH=CH-)、1-伸丙烯基、2-伸丙烯基、1-伸丁烯基、2-伸丁烯基、3-伸丁烯基及諸如此類。伸炔基之實例包含伸乙炔基、1-伸丙炔基、2-伸丙炔基等。
如本文中所使用,「伸環烷基」意欲係指作為任一穩定單環或多環系統之一部分之雙價環,其中該環具有3至12個碳原子,但並無雜原子,且其中該環完全飽和,且術語「伸環烯基」意欲係指作為任一穩定單環或多環系統之一部分之雙價環,其中該環具有3至12個碳原子,但並無雜原子,且其中該環至少部分地不飽和(但不包含任一伸芳基環)。伸環烷基之實例包含但不限於伸環丙基、伸環丁基、伸環戊基、伸環己基及伸環庚基。伸環烯基之實例包含但不限於伸環戊烯基及伸環己烯基。
如本文中所使用,術語「伸雜環烷基」及「伸雜環烯基」意欲係指作為任一穩定單環或多環系統之一部分之雙價環,其中該環具有3至約12個原子,且其中該環由碳原子及至少一個雜原子、尤其至少一個獨立地選自由N、O及S組成之群之雜原子組成,其中伸雜環烷基係指完全飽和之環,且伸雜環烯基係指至少部分地不飽和之環(但不包含任一伸芳基或伸雜芳基環)。
術語「伸芳基」意欲意指作為任一穩定單環或多環系統之一部分之雙價環或環系統,其中該環或環系統具有3至20個碳原子,但並無雜原子,該環或環系統由如由「4n+2」π電子規則定義之芳族部分組成,包含伸苯基。
如本文中所使用,術語「伸雜芳基」係指作為任一穩定單環或多環系統之一部分之雙價環或環系統,其中該環或環系統具有3至20個原子,該環或環系統由如由「4n+2」π電子規則定義之芳族部分組成且含有碳原子及一或多個氮、硫及/或氧雜原子。
在本發明之上下文中,術語「經取代」意欲指示一或多個存在於連接體骨架中之氫經所選指示基團代替,前提係並不超出指示原子之正常化合價,或並不超出經取代基團之適當原子之正常化合價,且取代得到穩定化合物。術語「視情況經取代」意欲意指連接體未經取代或如本文所定義經一或多個如本文所定義之取代基取代。在取代基係酮基(或側氧基,亦即=O)、硫基或亞胺基或諸如此類時,則連接體骨架原子上之兩個氫被代替。實例性取代基包含(例如)烷基、烯基、炔基、環烷基、雜環烷基、芳基、雜芳基、芳烷基、雜芳烷基、醯基、芳醯基、雜芳醯基、羧基、烷氧基、芳氧基、醯氧基、芳醯氧基、雜芳醯氧基、烷氧基羰基、鹵素、(硫代)酯、氰基、磷醯基、胺基、亞胺基、(硫代)醯胺基、氫硫基、烷硫基、醯硫基、磺醯基、硫酸根基、磺酸根基、胺磺醯基、磺醯胺基、硝基、疊氮基、鹵代烷基(包含全氟烷基(例如三氟甲基))、鹵代烷氧基、烷基硫烷基、烷基亞磺醯基、烷基磺醯基、烷基磺醯基胺基、芳基磺基胺基、磷醯基、磷酸根基、膦酸根基、次膦酸根基、烷基羧基、烷基羧醯胺、側氧基、羥基、巰基、胺基(視情況經單取代或二取代,例如經烷基、芳基或雜芳基取代)、亞胺基、羧醯胺、胺基甲醯基(視情況經單取代或二取代,例如經烷基、芳基或雜芳基取代)、脒基、胺基磺醯基、醯基胺
基、芳醯基胺基、(硫代)脲基、芳基(硫代)脲基、烷基(硫代)脲基、環烷基(硫代)脲基、芳氧基、芳烷氧基或-O(CH2)n-OH、-O(CH2)n-NH2、-O(CH2)nCOOH、-(CH2)nCOOH、-C(O)O(CH2)nR、-(CH2)nN(H)C(O)OR或-N(R)S(O)2R,其中n為1-4且R獨立地選自氫、-烷基、-烯基、-炔基、-環烷基、-環烯基、-(C連接-雜環烷基)、-(C連接-雜環烯基)、-芳基及-雜芳基,且容許多重取代。彼等熟習此項技術者應理解,若適當,則取代基(例如雜環烷基、芳基、雜芳基、烷基等)或官能基(例如-OH、-NHR等)本身可經取代。彼等熟習此項技術者亦應理解,在適當時,經取代部分本身亦可經取代。
在特定實施例中,連接體L包括選自下列部分中之一者之部分:二硫化物(-S-S-)、醚(-O-)、硫醚(-S-)、胺(-NH-)、酯(-O-C(=O)-或-C(=O)-O-)、羧醯胺(-NH-C(=O)-或-C(=O)-NH-)、胺基甲酸酯(-NH-C(=O)-O-或-O-C(=O)-NH-)及脲部分(-NH-C(=O)-NH-)。
在本發明之特定實施例中,(ii)或(iii)之連接體L包括m個選自以下列表之基團:伸烷基、伸烯基、伸炔基、伸環烷基、伸雜烷基、伸雜烯基、伸雜炔基、伸雜環烷基、伸芳基、伸雜芳基、伸芳烷基及伸雜芳烷基,其中每一基團可視情況獨立地經取代,連接體進一步包括n個獨立地選自下列部分中之一者之部分:二硫化物(-S-S-)、醚(-O-)、硫醚(-S-)、胺(-NH-)、酯(-O-C(=O)-或-C(=O)-O-)、羧醯胺(-NH-C(=O)-或-C(=O)-NH-)、胺基甲酸酯(-NH-C(=O)-O-或-O-C(=O)-NH-)及脲部分(-NH-C(=O)-NH-),其中m=n+1。在特定實施例中,m為2且n為1,或m為3且n為2。在特定實施例中,連接體包括2或3個未經取代之伸烷基及分別1或2個連接未經取代之伸烷基之二硫化物、醚、硫醚、胺、酯、羧醯胺、胺基甲酸酯或脲部分。
在特定實施例中,直鏈中之C原子獨立地係視情況經取代之亞甲基(-CH2-)之一部分。在特定該等實施例中,可選取代基獨立地選自鹵
素及C1-6-烷基(尤其係甲基)。
在特定實施例中,連接體L、尤其如部分中所展示之連接體L係選自連接體之下列組:毒傘肽側:-(CH2)2-靶結合部分側;毒傘肽側:-(CH2)3-靶結合部分側;毒傘肽側:-(CH2)4-靶結合部分側;毒傘肽側:-(CH2)5-靶結合部分側;毒傘肽側:-(CH2)6-靶結合部分側;毒傘肽側:-(CH2)7-靶結合部分側;毒傘肽側:-(CH2)8-靶結合部分側;毒傘肽側:-(CH2)9-靶結合部分側;毒傘肽側:-(CH2)10-靶結合部分側;毒傘肽側:-(CH2)11-靶結合部分側;毒傘肽側:-(CH2)12-靶結合部分側;毒傘肽側:-(CH2)16-靶結合部分側;毒傘肽側:-(CH2)2-S-S-(CH2)2-靶結合部分側;毒傘肽側:-(CH2)3-S-S-(CH2)2-靶結合部分側;毒傘肽側:-(CH2)2-S-S-(CH2)3-靶結合部分側;毒傘肽側:-(CH2)3-S-S-(CH2)3-靶結合部分側;毒傘肽側:-(CH2)4-S-S-(CH2)4-靶結合部分側;毒傘肽側:-(CH2)2-CMe2-S-S-(CH2)2-靶結合部分側;毒傘肽側:-(CH2)2-S-S-CMe2-(CH2)2-靶結合部分側;毒傘肽側:-(CH2)2-O-(CH2)2-靶結合部分側;毒傘肽側:-(CH2)2-O-(CH2)2-O-(CH2)2-靶結合部分側;毒傘肽側:-(CH2)2-O-(CH2)2-O-(CH2)2-O-(CH2)2-靶結合部分側;毒傘肽側:-(CH2)2-O-(CH2)2-O-(CH2)2-O-(CH2)2-O-(CH2)2-靶結
合部分側;毒傘肽側:-CH2-C6H4-NH-Cit-Val-(CH2)6-靶結合部分側;毒傘肽側:-CH2-C6H4-NH-Lys-Phe-(CH2)6-靶結合部分側;毒傘肽側:-CH2-C6H4-NH-Val-Val-(CH2)6-靶結合部分側;毒傘肽側:-CH2-C6H4-NH-Ile-Val-(CH2)6-靶結合部分側;毒傘肽側:-CH2-C6H4-NH-His-Val-(CH2)6-靶結合部分側;毒傘肽側:-CH2-C6H4-NH-Met-Val-(CH2)6-靶結合部分側;及毒傘肽側:-CH2-C6H4-NH-Asn-Lys-(CH2)6-靶結合部分側。
在特定實施例中,靶結合部分特異性結合至存在於腫瘤細胞上之表位,特定而言,其中靶結合部分特異性結合至人類表皮生長因子受體2(HER2)之表位。
在特定實施例中,抗體係曲妥珠單抗或HEA125或包括曲妥珠單抗或HEA125之抗原結合片段之抗體片段。
在特定實施例中,一個以上之毒傘肽分子偶合至一個靶結合部分。增加每一偶聯物中之毒傘肽數量亦增加毒性。因此,在一特定實施例中,靶結合部分對毒傘肽之比率為1個靶結合部分對1至15個毒傘肽分子、尤其1、2、3、4、5、6、7、8、9、10、11、12、13、14或15個毒傘肽分子。出於計算諸如IgG等抗體二聚體情形下之比率之目的,二聚體可視為具有一個靶結合部分。
在特定實施例中,靶結合部分係選自由以下組成之群:(i)抗體或其抗原結合片段;(ii)抗體樣蛋白;及(iii)核酸適體。
在特定實施例中,抗體或其抗原結合片段係選自雙價抗體、四價抗體、奈米抗體、嵌合抗體、去免疫化抗體、人類化抗體或人類抗體。
在特定實施例中,抗原結合片段係選自由以下組成之群:Fab、F(ab’)2、Fd、Fv、單鏈Fv及二硫化物連接之Fv(dsFv)。
在另一態樣中,本發明係關於用作醫藥之本發明毒傘肽。
在另一態樣中,本發明係關於用於治療患者之癌症之本發明毒傘肽,特定而言,其中癌症係選自由以下組成之群:乳癌、胰臟癌、膽管上皮癌、結腸直腸癌、肺癌、前列腺癌、卵巢癌、前列腺癌、胃癌、腎癌、惡性黑素瘤、白血病及惡性淋巴瘤。
如本文中所使用,「患者」意指任一可受益於使用本文所闡述之靶結合部分毒素偶聯物之治療之哺乳動物或鳥。較佳地,「患者」係選自由以下組成之群:實驗室動物(例如小鼠或大鼠)、家養動物(包含(例如)天竺鼠、兔、雞、豬、綿羊、山羊、駱駝、牛、馬、猴、貓或狗)或靈長類動物(包含人類)。尤佳地,「患者」係人類。
如本文中所使用,「治療(treat、treating或treatment)」疾病或病症意指達成下列各項中之一或多者:(a)減小病症嚴重程度;(b)限制或預防所治療病症之症狀特性之發生;(c)抑制所治療病症之症狀特性之惡化;(d)限制或預防先前患有病症之患者之病症之復發;及(e)限制或預防先前具有病症症狀之患者之症狀之復發。
如本文中所使用,治療可包括向患者投與本發明之偶聯物或醫藥組合物,其中「投與」包含活體內投與以及直接離體投與組織(例如靜脈移植物)。
在特定實施例中,使用治療有效量之本發明偶聯物。
「治療有效量」係足以達成預期目的之治療劑之量。給定治療劑之有效量將隨諸如以下因素而有所變化:藥劑性質、投與途徑、接受治療劑之動物之大小及物種及投與目的。熟習此項技術者可根據業內之確立方法以經驗方式來確定每一個體情形下之有效量。
在另一態樣中,本發明係關於一種醫藥組合物,其包括本發明
毒傘肽且進一步包括一或多種醫藥上可接受之稀釋劑、載劑、賦形劑、填充劑、黏合劑、潤滑劑、助流劑、崩解劑、吸附劑及/或防腐劑。
「醫藥上可接受」意指由聯邦管理機構或州政府批准或列示於美國藥典(U.S.Pharmacopeia)或其他普遍公認之藥典中以用於動物及更尤其人類中。
在特定實施例中,以全身性投與之醫藥之形式來使用醫藥組合物。此包含非經腸物,其尤其包括可注射物及輸注物。以安瓶(ampoule)形式或以所謂的備用可注射物形式(例如備用注射器或一次性注射器)且此外以用於多次汲取之可刺穿燒瓶來調配可注射物。可以皮下(s.c.)、肌內(i.m.)、靜脈內(i.v.)或皮內(i.c.)應用之形式來投與可注射物。特定而言,可以晶體懸浮液、溶液、奈米顆粒或膠質分散系統(例如水溶膠)之形式產生分別適宜之注射調配物。
可注射調配物可另外以濃縮物形式產生,其可經水性等滲稀釋劑溶解或分散。輸注物亦可製成等滲溶液、脂肪乳液、脂質體調配物及微乳液之形式。類似於可注射物,輸注調配物亦可製成稀釋用濃縮物形式亦可中住院療法及能走動療法中以永久性輸注物形式(例如)藉助微型幫浦施加可注射調配物。
可向非經腸藥物調配物中添加(例如)白蛋白、血漿、膨脹劑、表面活性物質、有機稀釋劑、pH影響物質、複合物質或聚合物質(特定而言係影響本發明之靶結合部分毒素偶聯物至蛋白質或聚合物之吸附之物質),或其亦可經添加以有助於減小本發明之靶結合部分毒素偶聯物至諸如注射儀器或封裝材料等材料(例如塑膠或玻璃)之吸附。
包括靶結合部分之本發明毒傘肽可以非經腸物結合至微載劑或奈米顆粒,例如結合至基於聚(甲基)丙烯酸酯、聚乳酸酯、聚乙醇酸酯、聚胺基酸或聚醚胺基甲酸酯之微細分散顆粒。亦可將非經腸調配
物改質為(例如)基於「多單元原理」之儲積製劑(若分別以微細分散、分散及懸浮形式引入本發明之靶結合部分毒素偶聯物),或改質為存於醫藥中或基於「單一單元原理」之晶體懸浮液(若將本發明之靶結合部分毒素偶聯物包封於調配物,例如包封於隨後植入之錠劑或棒形物中)。呈單一單元及多單元調配物形式之該等植入物或儲積醫藥通常由所謂的生物可降解聚合物(例如乳酸及乙醇酸之聚酯、聚醚胺基甲酸酯、聚胺基酸、聚(甲基)丙烯酸酯或多糖)組成。
在產生本發明醫藥組合物(調配為非經腸物)期間添加之佐劑及載劑較佳係無菌水(aqua sterilisata(sterilized water))、pH值影響物質(例如有機或無機酸或鹼以及其鹽)、用於調節pH值之緩衝物質、用於等滲之物質(例如氯化鈉、碳酸氫鈉、葡萄糖及果糖)、表面活性劑(tensides及surfactant)及乳化劑(例如聚氧乙烯山梨醇酐之脂肪酸之偏酯(例如Tween®)或例如聚氧乙烯之脂肪酸酯(例如Cremophor®)、脂肪油(例如花生油、大豆油或蓖麻油)、脂肪酸之合成酯(例如油酸乙酯、肉豆蔻酸異丙基酯)及中性油(例如Miglyol®))以及聚合佐劑(例如明膠、右旋糖酐、聚乙烯基吡咯啶酮)、增加有機溶劑(例如丙二醇、乙醇、N,N-二甲基乙醯胺、丙二醇)之溶解度之添加劑或複合物形成物質(例如檸檬酸鹽及脲)、防腐劑(例如苯甲酸酸羥丙基酯及苯甲酸酸甲酯、苯甲醇)、抗氧化劑(例如亞硫酸鈉)及穩定劑(例如EDTA)。
在一較佳實施例中,在將本發明醫藥組合物調配為懸浮液時,添加增稠劑以防止本發明之靶結合部分毒素偶聯物發生沉降或添加表面活性劑及聚電解質以確保沉降物之再懸浮性及/或添加複合物形成劑(例如EDTA)。亦可達成活性成份與各種聚合物之複合物。該等聚合物之實例係聚乙二醇、聚苯乙烯、羧甲基纖維素、Pluronics®或聚乙二醇山梨醇脂肪酸酯。亦可將本發明之靶結合部分毒素偶聯物納入呈包含化合物(例如使用環糊精)形式之液體調配物中。在特定實施例
中,可添加分散劑作為其他佐劑。為產生凍乾物,可使用支架劑,例如甘露醇、右旋糖酐、蔗糖、人類白蛋白、乳糖、PVP或各種明膠。
在本發明之特定實施例中,X係胺基甲酸衍生物-NH-C(O)-Z,其中Z係離去基團,其可由靶結合部分之親核基團、尤其由靶結合部分之一級胺代替。
在特定實施例中,Z係選自:-第三丁氧基、-琥珀醯亞胺氧基、-1-O-琥珀醯亞胺氧基-3-磺酸根基(-磺基-NHS)、-O-(4-硝基苯氧基)、-O-(3-硝基苯氧基)、-O-(2,4-二硝基苯氧基)、-O-(2,4-二氯-6-硝基苯氧基)、-五氟苯氧基、-五氯苯氧基、-O-(2,4,5-三氯苯氧基)、-O-(3,4-二氫-3-羥基-4-側氧基-1,2,3-苯并三嗪-3-基)、-O-(內-1-羥基-5-降冰片烯-2,3-二甲醯亞胺-1-基)、-1-鄰苯二甲醯亞胺基氧基、-1-苯并三唑基氧基、-1-(7-氮雜-苯并三唑基)氧基及-N-咪唑基。
在另一態樣中,本發明係關於合成本發明毒傘肽之方法,其包括使以下物質進行反應之步驟:式II毒傘肽
其中:R2係選自S=O、SO2及S;R3係選自NHR5及OR5;R4係選自H、OR5及OC1-6-烷基;R6係選自C1-6-伸烷基-R5、伸環烷基-R5、伸雜環烷基-R5、伸芳基-R5及伸雜芳基-R5;R7及R8獨立地選自H、C1-6-伸烷基-R5、伸環烷基-R5、伸雜環烷基-R5、伸芳基-R5及伸雜芳基-R5;其中R5中之一者係-Ln-X,其中L係連接體,n係選自0及1,且X係可與靶向部分偶合之化學部分,且其中剩餘R5係H;(i)N,N’-二琥珀醯亞胺基碳酸酯(DSC);(ii)硫代羰基化試劑,尤其係硫光氣、1,1'-硫代羰基二咪唑或1,1'-硫代羰基二-2(1H)-吡啶酮;(iii)亞胺基羰基化試劑,尤其係二氯異腈或異硫氰酸苯基酯;或(iv)醛、酮或非環狀縮醛。
在氬及室溫下,將180mg(196μmol)真空乾燥之α-瓢菌素溶於5000μl無水二甲基亞碸(DMSO)中。添加N-Boc-胺基己基溴(439mg,
8當量)及1M氫氧化鈉(215.5μl,1.1當量)。在室溫下保持2h之後,使用100μl存於DMSO中之1M乙酸溶液將反應混合物酸化至pH=5。在真空中蒸發揮發物且將殘餘物溶於500μl甲醇中並添加至40ml冰冷卻甲基第三丁基醚(MTBE)中。將沈澱物離心並藉由再懸浮於40ml MTBE中進行洗滌。將沈澱物吸收於4000μl甲醇中,過濾並以500μl部分藉由製備型HPLC在C18管柱上(250×21.2mm,Luna RP-18,10μm,100Å)純化。溶劑A:水,溶劑B:甲醇;梯度:0min 5% B;5min 5% B;20min 100% B;25min 100% B;27min 5% B;35min 5% B;流速:30ml/min。收集滯留時間為18.4-19.1min之部分且蒸發溶劑以提供126mg(57%)無色固體形式之HDP 30.0132。
MS(ESI+)1118.5[M+H]+,1140.5[M+Na]+
藉由蒸發滯留時間為12.8-13.4min之部分,可回收35mg(19%)α-瓢菌素。
將6'-NH-boc-6-胺基己基-α-瓢菌素(HDP 30.0132,81.82mg,73.17μmol)溶於300μl三氟乙酸(TFA)中。在氬及環境溫度下攪拌反應混合物。在2min之後,在20℃下於真空中去除酸且藉由使用2×3ml無水甲苯共蒸發來去除痕量TFA。將殘餘物溶於3000μl含有0.05% TFA之水/甲醇(95:5)中並以500μl部分藉由製備型HPLC在C18管柱(250×
21.2mm,Luna RP-18,10μm,100Å)上純化。溶劑A:水(含有0.05% TFA),溶劑B:甲醇(含有0.05% TFA。)梯度:0min 5% B;5min 5% B;20min 100% B;25min 100% B;27min 5% B;35min 5% B;流速:30ml/min。收集滯留時間為13.4-13.9min之部分且蒸發溶劑以提供75.52mg(89%)無色固體形式之HDP 30.0134。
C45H68N11O14S之HR-MS(ESI+)[M+H]+ 1018.46749,計算值:1018.46679
將HDP 30.0134(160.52mg,141.78μmol)溶於1000μl無水二甲基甲醯胺(DMF)中且一次性添加363.19mg(10當量)存於4000μl無水DMF中之碳酸N,N'-二琥珀醯亞胺基酯(DSC),隨後添加39.3μl(2當量)三乙胺且在室溫下攪拌混合物。在30min之後,將反應混合物以等量部分逐滴添加至兩個填充有40ml冰冷卻MTBE之離心管中。將所得沈澱物離心並藉由各自再懸浮於40ml MTBE中進行洗滌。在真空中乾燥沈澱物,溶解且合併於2400μl含有0.05% TFA之95%甲醇中並以400μl部分藉由製備型HPLC在C18管柱(250×21.2mm,Luna RP-18,10μm,100Å)上純化。溶劑A:水(含有0.05% TFA)。溶劑B:甲醇(含有0.05% TFA)。梯度:0min 5% B;5min 5% B;20min 100% B;25min 100% B;27min 5% B;35min 5% B;流速:30ml/min。收集滯
留時間為15.4-16.5min之部分並蒸發溶劑且自8ml第三丁醇凍乾殘餘物以提供151.46mg(92%)白色粉末形式之HDP 30.0643。
MS(ESI+)1159.1[M+H]+,1181.0[M+Na]+
將10.23mg(9.04μmol)HDP 30.0134溶於500μl無水二甲基甲醯胺(DMF)中且一次性添加452μl(10當量)存於無水DMF中之碳酸N,N'-二琥珀醯亞胺基酯(DSC)之0.2M溶液。添加三乙胺(2.51μl,2當量)且將混合物在室溫下攪拌90min。隨後,在真空中於40℃浴溫度下去除揮發物。將殘餘物溶於500μl含有0.05% TFA之95%甲醇中並藉由製備型HPLC在C18管柱上(250×21.2mm,Luna RP-18,10μm,100Å)純化。溶劑A:水(0.05% TFA)。溶劑B:甲醇(0.05% TFA)。梯度:0min 5% B;5min 5% B;20min 100% B;25min 100% B;27min 5% B;35min 5% B;流速:30ml/min。收集滯留時間為15.4-16.5min之部分並蒸發溶劑且自2ml第三丁醇凍乾殘餘物以提供9.06mg(85%)白色粉末形式之HDP 30.1065。
MS(ESI+)1185.10[M+H]+,1207.07[M+Na]+
向存於2ml乙醇中之HDP 30.0132(18.64mg,16.67μmol)之溶液中添加六羰基鉬(51mg,11.6當量)且將混合物在密封管中加熱至75℃保持25h。隨後在真空中去除揮發物且將殘餘物吸收於2ml甲醇中。藉由離心去除不溶性材料且將上清液濃縮至500μl並藉由製備型HPLC在C18管柱上(250×21.2mm,Luna RP-18,10μm,100Å)純化。溶劑A:水,溶劑B:甲醇;梯度:0min 5% B;5min 5% B;20min 100% B;25min 100% B;27min 5% B;35min 5% B;流速:30ml/min。收集滯留時間為17.9-18.6min之部分且蒸發溶劑以提供10.95mg(60%)無色固體形式之HDP 30.0741。
MS(ESI+)1102.3[M+H]+,1124.5[M+Na]+
將HDP 30.0741(10.95mg,9.93μmol)溶於500μl TFA中並在室溫下培育2min。然後在真空中蒸發揮發物且藉由使用2×1ml無水甲苯共蒸發來去除痕量TFA。12.38mg粗產物未經進一步純化即用於下一步驟中。
MS(ESI+)1002.4[M+H]+,1024.3[M+Na]+
將HDP 30.0743(12.38mg,10.51μmol)溶於500μl無水二甲基甲醯胺(DMF)中且一次性添加525(10當量)存於無水DMF中之N,N'-二琥珀醯亞胺基碳酸酯(DSC)之0.2N溶液,隨後添加2.91μl(2當量)三乙胺且在室溫下攪拌混合物。在30min之後,將反應混合物逐滴添加至填充有10ml冰冷MTBE之離心管中。將所得沈澱物離心並每次藉由再懸浮於10ml MTBE中進行洗滌。在真空中乾燥沈澱物,溶於500μl含有0.05% TFA之95%甲醇中並藉由製備型HPLC在C18管柱上(250×21.2mm,Luna RP-18,10μm,100Å)來純化。溶劑A:水(含有0.05% TFA)。溶劑B:甲醇(含有0.05% TFA)。梯度:0min 5% B;5min 5% B;20min 100% B;25min 100% B;27min 5% B;35min 5% B;流速:30ml/min.。收集滯留時間為16.0-17.2min之部分並蒸發溶劑,且自3ml第三丁醇凍乾殘餘物以提供10.93mg(91%)白色粉末形式之HDP 30.1033。
MS(ESI+)1143.3[M+H]+
將粗製HDP 30.0743(12.38mg,9.93μmol)溶於500μl無水二甲基甲醯胺(DMF)中且一次性添加497μl(10當量)存於無水DMF中之碳酸N,N'-二琥珀醯亞胺基酯之0.2M溶液。添加三乙胺(2.75μl,2當量)且將混合物在室溫下攪拌90min。隨後,在40℃浴溫度下於真空中去除揮發物。將殘餘物溶於500μl含有0.05% TFA之95%甲醇中並藉由製備型HPLC在C18管柱上(250×21.2mm,Luna RP-18,10μm,100Å)純化。溶劑A:水(0.05% TFA)。溶劑B:甲醇(0.05% TFA)。梯度:0min 5% B;5min 5% B;20min 100% B;25min 100% B;27min 5% B;35min 5% B;流速:30ml/min。收集滯留時間為15.9-17.2min之部分並蒸發溶劑且自3ml第三丁醇凍乾殘餘物以提供10.06mg(87%)白色粉末形式之HDP 30.1036
MS(ESI+)1191.08[M+Na]+
將1.15mg預活化毒傘肽-連接體衍生物HDP 30.0643溶於230μl無水二甲基亞碸(DMSO)中並添加至存於磷酸鹽緩衝鹽水(PBS,pH=7.4)中之3.33ml 6mg/ml抗體溶液中。將所得溶液在4℃下搖動過夜並藉由Sephadex G-25凝膠過濾(PD-10管柱;GE Healthcare Life Sciences)分離。使用6×5ml PBS溶液(pH=7.4)預洗滌PD-10管柱。藉由布拉
德福溶液(Bradford solution)檢測偶聯物部分併合併為一種溶液。然後在4℃下於Slide-A-Lyzer卡匣(Thermo Scientific;0.5-3ml;20.000 MWCO)中針對1L PBS(pH 7.4)透析溶液過夜。藉由RotiQuant-Assay(Carl Roth;Germany)測定蛋白質濃度。在Amicon Ultra Centrifugal Filters 50'000 MWCO(Millipore;以4000rpm離心)中增加ADC濃度並最終調節至3mg/ml。藉由測定A=280nm及A=310nm下之UV吸光度來測定曲妥珠單抗之瓢菌素有效負載。
將2.00mg預活化毒傘肽-連接體衍生物HDP 30.1033溶於400μl無水二甲基亞碸(DMSO)中並添加至存於磷酸鹽緩衝鹽水(PBS,pH=7.4)中之2.62ml 10mg/ml抗體溶液中。將所得溶液在4℃下搖動過夜並藉由Sephadex G-25凝膠過濾(PD-10管柱;GE Healthcare Life Sciences)分離。使用6×5ml PBS溶液(pH=7.4)預洗滌PD-10管柱。藉由布拉德福溶液檢測偶聯物部分併合併為一種溶液。然後在4℃下於Slide-A-Lyzer卡匣(Thermo Scientific;0.5-3ml;20.000 MWCO)中針對1L PBS(pH 7.4)透析溶液過夜。藉由RotiQuant-Assay(Carl Roth;Germany)測定蛋白質濃度。在Amicon Ultra Centrifugal Filters 50'000 MWCO(Millipore;以4000rpm離心)中增加ADC濃度並最終調節至3mg/ml。藉由測定A=280nm及A=310nm下之UV吸光度來測定曲妥珠單抗之瓢菌素有效負載。
將2.00mg預活化毒傘肽-連接體衍生物HDP 30.1036溶於400μl無水二甲基亞碸(DMSO)中並添加至存於磷酸鹽緩衝鹽水(PBS,pH=7.4)中之2.57ml 10mg/ml抗體溶液中。將所得溶液在4℃下搖動過夜並藉由Sephadex G-25凝膠過濾(PD-10管柱;GE Healthcare Life Sciences)分離。使用6×5ml PBS溶液(pH=7.4)預洗滌PD-10管柱。藉由布拉
德福溶液檢測偶聯物部分併合併為一種溶液。然後在4℃下於Slide-A-Lyzer卡匣(Thermo Scientific;0.5-3ml;20.000 MWCO)中針對1L PBS(pH 7.4)透析溶液過夜。藉由RotiQuant-Assay(Carl Roth;Germany)測定蛋白質濃度。在Amicon Ultra Centrifugal Filters 50'000 MWCO(Millipore;以4000rpm離心)中增加ADC濃度並最終調節至3mg/ml。藉由測定A=280nm及A=310nm下之UV吸光度來測定曲妥珠單抗之瓢菌素有效負載。
將0.90mg預活化毒傘肽-連接體衍生物HDP 30.1165溶於180μl無水二甲基亞碸(DMSO)中並添加至存於磷酸鹽緩衝鹽水(PBS,pH=7.4)中之2.00ml 5mg/ml抗體溶液中。將所得溶液在4℃下搖動過夜並藉由Sephadex G-25凝膠過濾(PD-10管柱;GE Healthcare Life Sciences)分離。使用6×5ml PBS溶液(pH=7.4)預洗滌PD-10管柱。藉由布拉德福溶液檢測偶聯物部分併合併為一種溶液。然後在4℃下於Slide-A-Lyzer卡匣(Thermo Scientific;0.5-3ml;20.000 MWCO)中針對1L PBS(pH 7.4)透析溶液過夜。藉由RotiQuant-Assay(Carl Roth;Germany)測定蛋白質濃度。在Amicon Ultra Centrifugal Filters 50'000 MWCO(Millipore;以4000rpm離心)中增加ADC濃度並最終調節至3mg/ml。藉由測定A=280nm及A=310nm下之UV吸光度來測定曲妥珠單抗之瓢菌素有效負載。
在活體外使用HER2-陽性腫瘤細胞系SK-OV-3(卵巢)、SKBR-3(乳房)及JIMT-1(乳房)及化學發光BrdU納入分析(Roche Diagnostics)評估曲妥珠單抗-毒傘肽偶聯物之細胞毒性活性。在與不同濃度之偶聯物在37℃及5% CO2下培育72h之後藉由使用抗BrdU-HRP抗體在BMG Labtech Optima微量板讀數儀上量測固定及滲透細胞來測定細胞存活率。藉由Graphpad Prism 4.0軟體計算劑量-反應曲線之EC50值。
曲妥珠單抗-毒傘肽偶聯物在不同Her2陽性細胞系中之EC50值(亦參見圖2至5):
購買6週齡完整雌性NMRI nu/nu無胸腺小鼠(Janvier)並隨機分成三組(每組8只小鼠)。將5×106 JIMT-1細胞經皮下注射至每一小鼠之側腹中。在腫瘤接種之後第14天以30μg/kg及150μg/kg之劑量(關於瓢菌素)經靜脈內注射曲妥珠單抗-毒傘肽偶聯物Her-30.0643[4.4]及Her-30.1036[4.0]一次,而向陰性對照注射媒劑(PBS緩衝液)。記錄腫瘤體積(參見圖6)。兩種偶聯物在30μg及150μg/kg下展示高抗腫瘤活性,從而完全減小腫瘤。
購買7週齡完整雌性NMRI nu/nu無胸腺小鼠(Janvier)並隨機分成
三組(每組3只小鼠)。以300μg/kg之劑量經靜脈內注射Herceptin-毒傘肽偶聯物Her-30.0643[4.4]及Her-30.1036[4.0]一次,而向陰性對照注射媒劑(PBS緩衝液)。記錄小鼠之重量(參見圖7)。所有使用Her-30.0643[4.4]治療之動物皆在施加之後9天內死亡,而所有使用Her-30.1036[4.0]治療之動物在第14天之後皆展示與陰性對照組相當之體重。
Claims (18)
- 一種式I毒傘肽(amatoxin),
- 如請求項1(iii)之毒傘肽,其中Y之該官能基係胺基。
- 如請求項2之毒傘肽,其中X*係脲部分。
- 如請求項1(iii)、2及3中任一項之毒傘肽,其中為-Ln-X*-Y之該殘基R5係:(v)存在於R1中;(vi)存在於R3中;(vii)存在於R4中;或(viii)存在於R5中。
- 如請求項1至4中任一項之毒傘肽,其中該毒傘肽係選自α-瓢菌素、β-瓢菌素、鵝膏素、鵝膏毒肽醯胺或其鹽或類似物。
- 如請求項1(ii)、1(iii)及2至5中任一項之毒傘肽,其中n為1,且其中該連接體具有最多12個原子、尤其2至10個、更尤其4至9個及最尤其6至8個原子之長度。
- 如請求項1(ii)、1(iii)及2至6中任一項之毒傘肽,其中該連接體L係伸烷基、伸雜烷基、伸烯基、伸雜烯基、伸炔基、伸雜炔基、伸環烷基、伸雜環烷基、伸芳基、伸雜芳基、伸芳烷基或伸雜芳烷基,其包括1至4個選自N、O及S之雜原子,其中該連接體視情況經取代。
- 如請求項1(ii)、1(iii)及2至7中任一項之毒傘肽,其中該連接體L包括選自下列部分中之一者之部分:二硫化物、醚、硫醚、胺、酯、羧醯胺、胺基甲酸酯及脲部分。
- 如請求項1(iii)至8中任一項之毒傘肽,其中該靶結合部分特異性 結合至存在於腫瘤細胞上之表位,特定而言,其中該靶結合部分特異性結合至人類表皮生長因子受體2(HER2)之表位。
- 如請求項1(iii)至9中任一項之毒傘肽,其中該靶結合部分係選自由以下組成之群:(i)抗體或其抗原結合片段;(ii)抗體樣蛋白;及(iii)核酸適體。
- 如請求項10之毒傘肽,其中該抗體或其抗原結合片段係選自雙價抗體、四價抗體、奈米抗體、嵌合抗體、去免疫化抗體、人類化抗體或人類抗體。
- 如請求項10或11之毒傘肽,其中該抗原結合片段係選自由以下組成之群:Fab、F(ab’)2、Fd、Fv、單鏈Fv及二硫化物連接之Fv(dsFv)。
- 如請求項1(iii)至12中任一項之毒傘肽,其用作醫藥。
- 如請求項1(iii)至12中任一項之毒傘肽,其用於治療患者之癌症,特定而言,其中該癌症係選自由以下組成之群:乳癌、胰臟癌、膽管上皮癌、結腸直腸癌、肺癌、前列腺癌、卵巢癌、胃癌、腎癌、惡性黑素瘤、白血病及惡性淋巴瘤。
- 一種醫藥組合物,其包括如請求項1(iii)至12中任一項之毒傘肽且進一步包括一或多種醫藥上可接受之稀釋劑、載劑、賦形劑、填充劑、黏合劑、潤滑劑、助流劑、崩解劑、吸附劑及/或防腐劑。
- 如請求項1(ii)之毒傘肽,其中X係胺基甲酸衍生物-NH-C(O)-Z,其中Z係離去基團,其可由靶結合部分之親核基團、尤其由靶結合部分之一級胺代替。
- 如請求項16之毒傘肽,其中Z係選自:-第三丁氧基、-琥珀醯亞 胺氧基、-1-O-琥珀醯亞胺氧基-3-磺酸根基(-磺基-NHS)、-O-(4-硝基苯氧基)、-O-(3-硝基苯氧基)、-O-(2,4-二硝基苯氧基)、-O-(2,4-二氯-6-硝基苯氧基)、-五氟苯氧基、-五氯苯氧基、-O-(2,4,5-三氯苯氧基)、-O-(3,4-二氫-3-羥基-4-側氧基-1,2,3-苯并三嗪-3-基)、-O-(內-1-羥基-5-降冰片烯-2,3-二甲醯亞胺-1-基)、-1-鄰苯二甲醯亞胺基氧基、-1-苯并三唑基氧基、-1-(7-氮雜-苯并三唑基)氧基及-N-咪唑基。
- 一種合成如請求項16或17之毒傘肽之方法,其包括使以下物質進行反應之步驟:式II毒傘肽
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JP2022530026A (ja) | 2019-04-24 | 2022-06-27 | ハイデルベルク ファルマ リサーチ ゲゼルシャフト ミット ベシュレンクテル ハフツング | アマトキシン抗体薬物複合体及びその使用 |
AU2020278178A1 (en) * | 2019-05-23 | 2021-11-25 | Heidelberg Pharma Research Gmbh | Antibody drug conjugates with cleavable linkers |
KR102092817B1 (ko) * | 2019-08-22 | 2020-03-24 | 한국화학연구원 | 아마톡신 유도체 및 이의 제조방법 |
CN111308100B (zh) * | 2020-04-13 | 2023-04-21 | 北京维德维康生物技术有限公司 | 一种检测β-鹅膏毒肽的酶联免疫试剂盒及其制备和应用 |
EP4213886A1 (en) | 2020-09-18 | 2023-07-26 | Araris Biotech AG | Transglutaminase conjugation method with amino acid-based linkers |
WO2022084560A1 (en) | 2020-10-25 | 2022-04-28 | Araris Biotech Ag | Means and methods for producing antibody-linker conjugates |
CA3208117A1 (en) * | 2021-03-19 | 2022-09-22 | Torsten HECHLER | B-lymphocyte specific amatoxin antibody conjugates |
WO2023072934A1 (en) | 2021-10-25 | 2023-05-04 | Araris Biotech Ag | Methods for producing antibody-linker conjugates |
WO2023161291A1 (en) | 2022-02-22 | 2023-08-31 | Araris Biotech Ag | Peptide linkers comprising two or more payloads |
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SG48759A1 (en) | 1990-01-12 | 2002-07-23 | Abgenix Inc | Generation of xenogenic antibodies |
EP2015782A4 (en) * | 2006-04-12 | 2010-04-07 | Crosslink Genetics Corp | COMPOSITIONS AND METHODS FOR MODULATING GENE EXPRESSION |
EP1859811B1 (en) | 2006-05-27 | 2011-08-24 | Faulstich, Heinz, Dr. | Use of conjugates of amatoxins or phallotoxins with macromolecules for tumor and inflammation therapy |
EP2416805B1 (en) | 2009-04-08 | 2013-07-24 | Heinz Dr. Faulstich | Amatoxin antibody conjugates for the treatment of cancer |
US9233173B2 (en) | 2009-04-08 | 2016-01-12 | Deutsches Krebsforschungszentrum | Amatoxin-armed therapeutic cell surface binding components designed for tumour therapy |
ES2402254T3 (es) * | 2010-09-30 | 2013-04-30 | Heidelberg Pharma Ag | Conjugados de amatoxinas con ligadores mejorados |
EP2497499A1 (en) * | 2011-03-10 | 2012-09-12 | Heidelberg Pharma GmbH | Amatoxin-conjugates with improved linkages |
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IL240863B (en) | 2019-02-28 |
EP2964264B1 (en) | 2017-09-13 |
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WO2014135282A1 (en) | 2014-09-12 |
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NO2964264T3 (zh) | 2018-02-10 |
SG11201507089PA (en) | 2015-10-29 |
BR112015021838B1 (pt) | 2021-12-28 |
AU2014224928B2 (en) | 2017-10-19 |
ZA201505790B (en) | 2017-11-29 |
MX2015011583A (es) | 2016-07-29 |
KR20160006162A (ko) | 2016-01-18 |
ES2652182T3 (es) | 2018-01-31 |
CA2903614A1 (en) | 2014-09-12 |
RU2695370C2 (ru) | 2019-07-23 |
HK1200312A1 (zh) | 2015-08-07 |
EP2774624A1 (en) | 2014-09-10 |
EP2964264A1 (en) | 2016-01-13 |
MX366503B (es) | 2019-07-11 |
CA2903614C (en) | 2021-07-06 |
WO2014135282A8 (en) | 2015-09-17 |
NZ710729A (en) | 2019-05-31 |
AU2014224928A1 (en) | 2015-09-10 |
UA117364C2 (uk) | 2018-07-25 |
US9982018B2 (en) | 2018-05-29 |
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