TW201731879A - 抗5t4抗體和抗體-藥物共軛體 - Google Patents
抗5t4抗體和抗體-藥物共軛體 Download PDFInfo
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Abstract
本發明關於適合於臨床試驗中測試之針對人類5T4癌胚(oncofoetal)抗原之抗體及對應的抗體-藥物共軛體。該抗體對人類及食蟹獼猴顯現交叉反應性且對人類5T4抗原展現與彼等對食蟹獼猴5T4抗原之親和性呈相同的大小等級之親和性。本發明另關於該抗體及對應的ADC在治療實體腫瘤及血液惡性腫瘤之用途。
Description
本發明關於針對5T4(癌胚)抗原之抗體及對應的抗體-藥物共軛體(ADC)。
5T4癌胚抗原為針對經麥胚凝集素分離之來自人類胎盤融合細胞滋養層微絨毛膜的糖蛋白而提高之單株抗體所界定之72kDa糖蛋白。此單株抗體(mAb)在WO89/07947中稱為5T4。5T4抗原在正常組織中的表現有限,卻由各種類型的癌細胞(過度)表現。這使得5T4抗原成為特定的癌標靶及潛在且有希望的治療標靶。然而,儘管標靶已於80年代晚期被發現,但是仍為得不到批准的治療抗體。
WO2006/031653揭示原始的mAb 5T4,亦即H8及其人源化型式,二者對通常用於活體內臨床前(毒性)研究的各種非人類動物物種未顯現交叉反應性。該等臨床前研究旨在鑑定用於人類的後續劑量遞增方案之初始安全劑量;鑑定成為可逆或不可逆毒性效應之潛在標靶的健康組
織或器官;及鑑定臨床監控之安全性參數。用於生物醫藥(諸如單株抗體)的監管準則要求在至少一種相關物種中測試(例如ICH S6監管準則)。假如單株抗體對物種未顯現交叉反應性,則該物種為不相關的,且因此在該物種中效力不足。在此等例子中可使用替代的動物模式,例如基因改造物種。然而,這需要多方面的努力,不僅發展新的模式,且亦能夠提供監管當局可接受的科學證據。
WO2007/106744揭示抗5T4抗體A1、A2和A3,儘管該三種抗體對非人類動物物種(例如食蟹獼猴)展現某種交叉反應性,但是彼對人類5T4之親和性遠低於H8對人類5T4之親和性。
經由4-(4’-乙醯基苯氧基)-丁酸連結至卡奇黴素(calicheamicin)之抗5T4抗體H8、A1、A2和A3揭示於WO2007/106744的第73頁上。WO2012/131527揭示連結至順丁烯二醯亞胺基己酸(maleimidocapronic)-單甲基奧立他汀(auristatin)F之A1(A1-mc-MMAF)。
僅少數靶向5T4抗原之治療到達臨床試驗階段。編碼5T4抗原的經修飾之牛痘病毒安卡拉株(vaccinia virus Ankara)(MVA)載體之疫苗誘發針對5T4抗原之內源性抗體反應,但是其在轉移性腎癌的第III期研究無法滿足其增加存活率的主要終點。另一實例為他那莫單抗(naptumomab estafenatox),其為與經修飾之金黃色葡萄球菌腸毒素(Staphylococcal enterotoxin)E共軛之mAb 5T4的Fab片段。認為此共軛體活化在腫瘤附近的T
細胞反應。然而,他那莫單抗加上IFN-α相對IFN-α在晚期腎細胞癌中的第II/III期隨機研究不滿足其延長存活的主要終點。評估A1-mc-MMAF ADC之臨床發展亦於最近中斷。目前在US及EU臨床試驗登記中沒有列示積極的臨床試驗。
WO 2015/155345揭示新的抗5T4抗體及對應的ADC,其中抗5T4抗體係(經位點特異性)連結至吡咯並苯並二氮呯(PDB)二聚物或微管溶素(tubulysin)。然而,還沒有可用的臨床數據。
上文引導出經臨床測試之5T4靶向療法(亦即抗體、抗體-藥物共軛體及疫苗)不符合癌症治療之需求的結論。因此,對用於癌症療法之針對5T4抗原之新抗體及對應的抗體-藥物共軛體有要求。為了測定該等抗體及對應的ADC在臨床前設定中的適合性,此等抗體應對與候選藥物之臨床前發展相關的非人類動物物種之5T4抗原顯現交叉反應性。
本發明關於適合於臨床試驗中測試之針對人類5T4癌胚抗原之抗體及對應的ADC。適合於臨床前設定中的抗體及對應的ADC應對與候選藥物之臨床前發展相關的非人類動物物種之5T4抗原顯現交叉反應性。
抗體較佳地對人類及食蟹獼猴顯現交叉反應性且對人
類5T4抗原(hu 5T4)展現與彼等對食蟹獼猴5T4抗原(cyno 5T4)之親和性呈相同的大小等級之親和性。
本發明另關於抗體及對應的ADC在治療實體腫瘤及血液惡性腫瘤之用途。
圖1顯示嵌合mAb、具有HC-41C突變之人源化mAb及對應的抗5T4 ADC與表現hu 5T4之CHO細胞(CHOZN)的結合相對於H8及A1的結合(圖1A選殖株789、圖1B選殖株833、圖1C選殖株825)。
圖2顯示嵌合mAb、具有HC-41C突變之人源化mAb及對應抗5T4 ADC與表現cyno 5T4之CHO細胞(CHOZN)的結合相對於H8及A1的結合(圖2A選殖株789、圖2B選殖株833、圖2C選殖株825)。
圖3顯示抗5T4 ADC 833a-,833b-,833c-,833d-,825a-,825c-vc-seco-DUBA相對H8-vc-seco-DUBA及未結合之對照物利妥昔單抗(rituximab)-vc-seco-DUBA在免疫缺陷小鼠的5T4陽性BT474細胞株異種移植體中的活體內功效。
5T4癌胚抗原在正常組織中的表現有限,卻由各種類型的癌細胞(過度)表現,因此使得5T4抗原成為特定的
癌標靶及潛在且有希望的治療標靶。然而,儘管標靶已於80年代晚期被發現,但是目前沒有針對此標靶批准的治療方法。
本發明關於針對5T4抗原之抗體及對應的抗體-藥物共軛體(ADC),其對cyno 5T4顯現交叉反應性且亦對hu 5T4抗原展現極佳的親和性。根據本發明之抗5T4抗體及ADC對cyno 5T4抗原顯示與彼等對hu 5T4之親和性呈相同的大小等級之親和性。術語〝相同的大小等級〞意指對hu及cyno 5T4抗原之親和性彼此相差不到十分之一。本發明之抗5T4抗體與先前技術的抗5T4抗體A1和A3相比而對hu 5T4抗原具有改進之親和性及與先前技術的抗5T4抗體H8相比而對cyno 5T4抗原具有改進之親和性。親和性較佳地在基於細胞之檢定中使用表現hu或cyno 5T4抗原之細胞以微克/毫升計之EC50測量。本發明者測量經工程化以表現hu 5T4或cyno 5T4的各種細胞之EC50,諸如MDA-MB-468、PA-1和中國倉鼠卵巢(CHO)細胞。使用表現hu 5T4或cyno 5T4抗原之細胞所測量的本發明之抗體通常展現小於0.8微克/毫升之EC50,該測量係在細胞以抗體於4℃下培育30分鐘之後。
先前技術的抗5T4抗體A1係以來自US8044178,SEQ ID NO:2,位置20-138之小鼠A1胺基酸序列的重鏈(HC)可變區(VR)及來自US8044178,SEQ ID NO:4,位置21-127之小鼠A1胺基酸序列的輕鏈(LC)VR特徵化。先前技術的抗5T4抗體A3係以來自
US8044178,SEQ ID NO:10,位置20-141之小鼠A3胺基酸序列的HCVR及來自US8044178,SEQ ID NO:12,位置21-127之小鼠A3胺基酸序列的LCVR特徵化。先前技術的抗5T4抗體H8係以SEQ ID NO:52之HCVR及SEQ ID NO:53之LCVR特徵化。
如整個說明書所使用的術語〝抗體〞係指包含兩個重鏈及兩個輕鏈之單株抗體(mAb)或其抗原結合片段,例如Fab、Fab’或F(ab’)2片段、單鏈(sc)抗體、scFv、單功能域(sd)抗體、雙價抗體或微小抗體(minibody)。抗體可具有任何同型,諸如IgG、IgA或IgM抗體。抗體較佳為IgG抗體,更佳為IgG1或IgG2抗體。抗體可為嵌合、人源化或人類抗體。本發明的抗體較佳為人源化抗體。抗體甚至更佳為人源化或人類IgG抗體,最佳為人源化或人類IgG1 mAb。抗體可具有κ(kappa)或λ(lambda)輕鏈,較佳為κ(kappa)輕鏈,亦即人源化或人類IgG1-κ抗體。
在人源化抗體中,在HC及LC之可變區中的抗原結合互補性決定區(CDRs)係衍生自非人類物種之抗體,一般為小鼠、大鼠或兔子。該等非人類CDR安置在HC及LC之可變區的人類架構(FR1、FR2、FR3和FR4)內。可將人類FR中的經選擇之胺基酸與對應的原始非人類物種胺基酸交換,以改進結合親和性,同時保留低的免疫原性。另一選擇地,將原始非人類物種FR的經選擇之胺基酸與彼等對應的人類胺基酸交換,以降低免疫原性,
同時保留抗體的結合親和性。將因此的人源化可變區與人類恆定區組合。
本發明可特別關於抗5T4抗體,其包含選自由下列所組成之群組的HCVR及LCVR CDR:a. SEQ ID NO:1之CDR1、CDR2和CDR3胺基酸序列及SEQ ID NO:2之CDR1、CDR2和CDR3胺基酸序列;b. SEQ ID NO:3之CDR1、CDR2和CDR3胺基酸序列及SEQ ID NO:4之CDR1、CDR2和CDR3胺基酸序列;c. SEQ ID NO:5之CDR1、CDR2和CDR3胺基酸序列及SEQ ID NO:6之CDR1、CDR2和CDR3胺基酸序列;d. SEQ ID NO:7之CDR1、CDR2和CDR3胺基酸序列及SEQ ID NO:8之CDR1、CDR2和CDR3胺基酸序列;e. SEQ ID NO:9之CDR1、CDR2和CDR3胺基酸序列及SEQ ID NO:10之CDR1、CDR2和CDR3胺基酸序列;f. SEQ ID NO:11之CDR1、CDR2和CDR3胺基酸序列及SEQ ID NO:12之CDR1、CDR2和CDR3胺基酸序列;g. SEQ ID NO:13之CDR1、CDR2和CDR3胺基酸序列及SEQ ID NO:14之CDR1、CDR2和CDR3
胺基酸序列;h. SEQ ID NO:15之CDR1、CDR2和CDR3胺基酸序列及SEQ ID NO:16之CDR1、CDR2和CDR3胺基酸序列;i. SEQ ID NO:17之CDR1、CDR2和CDR3胺基酸序列及SEQ ID NO:18之CDR1、CDR2和CDR3胺基酸序列;j. SEQ ID NO:19之CDR1、CDR2和CDR3胺基酸序列及SEQ ID NO:20之CDR1、CDR2和CDR3胺基酸序列;k. SEQ ID NO:21之CDR1、CDR2和CDR3胺基酸序列及SEQ ID NO:22之CDR1、CDR2和CDR3胺基酸序列;l. SEQ ID NO:23之CDR1、CDR2和CDR3胺基酸序列及SEQ ID NO:24之CDR1、CDR2和CDR3胺基酸序列;m. SEQ ID NO:25之CDR1、CDR2和CDR3胺基酸序列及SEQ ID NO:26之CDR1、CDR2和CDR3胺基酸序列;n. SEQ ID NO:27之CDR1、CDR2和CDR3胺基酸序列及SEQ ID NO:28之CDR1、CDR2和CDR3胺基酸序列;o. SEQ ID NO:29之CDR1、CDR2和CDR3胺基酸序列及SEQ ID NO:30之CDR1、CDR2和CDR3
胺基酸序列;p. SEQ ID NO:31之CDR1、CDR2和CDR3胺基酸序列及SEQ ID NO:32之CDR1、CDR2和CDR3胺基酸序列;及q. SEQ ID NO:33之CDR1、CDR2和CDR3胺基酸序列及SEQ ID NO:34之CDR1、CDR2和CDR3胺基酸序列。
為了清楚起見,將上文以a至q所列示之抗體的HCVR之CDR1、CDR2和CDR3序列及LCVR之CDR1、CDR2和CDR3序列在本發明書的最後所給出之序列表中加註底線。
在一個實施態樣中,本發明之抗5T4抗體包含選自由下列所組成之群組的HCVR及LCVR CDR:a. SEQ ID NO:1之CDR1、CDR2和CDR3胺基酸序列及SEQ ID NO:2之CDR1、CDR2和CDR3胺基酸序列;b. SEQ ID NO:5之CDR1、CDR2和CDR3胺基酸序列及SEQ ID NO:6之CDR1、CDR2和CDR3胺基酸序列;c. SEQ ID NO:11之CDR1、CDR2和CDR3胺基酸序列及SEQ ID NO:12之CDR1、CDR2和CDR3胺基酸序列;d. SEQ ID NO:13之CDR1、CDR2和CDR3胺基酸序列及SEQ ID NO:14之CDR1、CDR2和CDR3
胺基酸序列;e. SEQ ID NO:17之CDR1、CDR2和CDR3胺基酸序列及SEQ ID NO:18之CDR1、CDR2和CDR3胺基酸序列;及f. SEQ ID NO:25之SEQ ID NO:1之CDR1、CDR2和CDR3胺基酸序列及SEQ ID NO:26之CDR1、CDR2和CDR3胺基酸序列。
在較佳的實施態樣中,本發明之抗5T4抗體包含選自由下列所組成之群組的HCVR及LCVR CDR:a. SEQ ID NO:1之CDR1、CDR2和CDR3胺基酸序列及SEQ ID NO:2之CDR1、CDR2和CDR3胺基酸序列;b. SEQ ID NO:5之CDR1、CDR2和CDR3胺基酸序列及SEQ ID NO:6之CDR1、CDR2和CDR3胺基酸序列;及c. SEQ ID NO:11之CDR1、CDR2和CDR3胺基酸序列及SEQ ID NO:12之CDR1、CDR2和CDR3胺基酸序列。
在更佳的實施態樣中,本發明之抗5T4抗體包含HCVR及LCVR CDRs選自由下列所組成之群組的:a. SEQ ID NO:5之CDR1、CDR2和CDR3胺基酸序列及SEQ ID NO:6之CDR1、CDR2和CDR3胺基酸序列;及b. SEQ ID NO:11之CDR1、CDR2和CDR3胺基酸
序列及SEQ ID NO:12之CDR1、CDR2和CDR3胺基酸序列。
在另一實施態樣中,本發明關於人源化抗5T4抗體,其包含選自由下列所組成之群組的HCVR和LCVR:a. SEQ ID NO:35之HCVR胺基酸序列及SEQ ID NO:45之LCVR胺基酸序列;b. SEQ ID NO:36之HCVR胺基酸序列及SEQ ID NO:45之LCVR胺基酸序列;c. SEQ ID NO:37之HCVR胺基酸序列及SEQ ID NO:44之LCVR胺基酸序列;d. SEQ ID NO:37之HCVR胺基酸序列及SEQ ID NO:46之LCVR胺基酸序列;e. SEQ ID NO:40之HCVR胺基酸序列及SEQ ID NO:51之LCVR胺基酸序列;f. SEQ ID NO:41之HCVR胺基酸序列及SEQ ID NO:51之LCVR胺基酸序列;g. SEQ ID NO:42之HCVR胺基酸序列及SEQ ID NO:49之LCVR胺基酸序列;h. SEQ ID NO:43之HCVR胺基酸序列及SEQ ID NO:50之LCVR胺基酸序列;i. SEQ ID NO:38之HCVR胺基酸序列及SEQ ID NO:47之LCVR胺基酸序列;j. SEQ ID NO:之39HCVR胺基酸序列及SEQ ID NO:47之LCVR胺基酸序列;及
k. SEQ ID NO:39之HCVR胺基酸序列及SEQ ID NO:48之LCVR胺基酸序列。
在本發明之第一個實施態樣中,人源化抗5T4抗體包含SEQ ID NO:35之HCVR胺基酸序列及SEQ ID NO:45之LCVR胺基酸序列。
在本發明之第二個實施態樣中,人源化抗5T4抗體包含ID NO:36之HCVR胺基酸序列及SEQ ID NO:45之LCVR胺基酸序列。
在本發明之第三個實施態樣中,人源化抗5T4抗體包含SEQ ID NO:37之HCVR胺基酸序列及SEQ ID NO:44之LCVR胺基酸序列。
在本發明之第四個實施態樣中,人源化抗5T4抗體包含SEQ ID NO:37之HCVR胺基酸序列及SEQ ID NO:46之LCVR胺基酸序列。
在本發明之第五個較佳的實施態樣中,人源化抗5T4抗體包含SEQ ID NO:40之HCVR胺基酸序列及SEQ ID NO:51之LCVR胺基酸序列。
在本發明之第六個較佳的實施態樣中,人源化抗5T4抗體包含SEQ ID NO:41之HCVR胺基酸序列及SEQ ID NO:51之LCVR胺基酸序列。
在本發明之第七個較佳的實施態樣中,人源化抗5T4抗體包含SEQ ID NO:42之HCVR胺基酸序列及SEQ ID NO:49之LCVR胺基酸序列。
在本發明之第八個較佳的實施態樣中,人源化抗5T4
抗體包含SEQ ID NO:43之HCVR胺基酸序列及SEQ ID NO:50之LCVR胺基酸序列。
在本發明之第九個較佳的實施態樣中,人源化抗5T4抗體包含SEQ ID NO:38之HCVR胺基酸序列及SEQ ID NO:47之LCVR胺基酸序列。
在本發明之第十個實施態樣中,人源化抗5T4抗體包含SEQ ID NO:39之HCVR胺基酸序列及SEQ ID NO:47之LCVR胺基酸序列。
在本發明之第十一個較佳的實施態樣中,人源化抗5T4抗體包含SEQ ID NO:39之HCVR胺基酸序列及SEQ ID NO:48之LCVR胺基酸序列。
本發明另關於ADC,其中連結子藥物係與根據本發明之抗5T4抗體共軛。
在一個實施態樣中,本發明關於ADC,其中連結子藥物係通過經由中間鏈二硫鍵還原所釋放的天然胱胺酸而與根據本發明之抗5T4抗體隨機共軛。
在另一實施態樣中,本發明關於ADC,其中連結子藥物係通過工程化半胱胺酸(位點特異性ADC)而與根據本發明之抗5T4抗體經位點特異性共軛。
包含至少一種工程化半胱胺酸於HC或LC中的抗5T4抗體具有許多優點。包含工程化半胱胺酸的抗體提供製備位點特異性ADC的機會,可提供與連結子藥物顯示良好的反應性之共軛位置,且同時具有減低在抗體之間形成額外的二硫鍵(導致聚集)或擾亂抗體結構之風險。在
HC或LC的特異性位置上具有半胱胺酸的額外優點為降低所得ADC之疏水性的效應。
適合於連結子藥物連接的多個共軛位置經鑑定在所有抗體結構中存在的孔穴內或在靠近孔穴附近,亦即工程化半胱胺酸在如WO2015/177360中所揭示且主張的該等所在位置上具有良好的可接近性。
當連結子藥物在如本文所主張的抗5T4抗體之特異性位置上共軛時,該連結子藥物適配在由抗體的恆定重鏈1(CH1)、可變重鏈(VH)、可變輕鏈(VL)及恆定輕鏈(CL)區所形成的Fab孔穴內。因此,使連結子藥物(大部分的毒素/連結子藥物為疏水性)避開圍繞於抗體及ADC之水環境,如此而具有與其中連結子藥物係通過抗體的天然中間鏈二硫鍵半胱胺酸共軛之ADC相比而較低的疏水性,及與其中連結子藥物在使連結子藥物被迫至抗體外部(亦即更暴露於親水性水環境)的不同位置上經位點特異性共軛之ADC相比而更低的疏水性。
在本發明較佳的實施態樣中,根據本發明之抗5T4抗體包含至少一種在HC可變區FR或LC可變區FR中之位置上的工程化半胱胺酸。如整個說明書所使用的術語〝工程化半胱胺酸〞意指以半胱胺酸取代在抗體的HC或LC中之非半胱胺酸胺基酸。如熟習本技術領域者所知,這可以胺基酸表現量(level)或DNA表現量完成,例如藉由使用定點突變作用(site-directed mutagenesis)。此等工程化半胱胺酸較佳地藉由取代在原始/母體抗體中存在的
胺基酸之特異點突變而引入。
至少一種工程化半胱胺酸較佳地存在於選自HC 40、41和89(根據Kabat編號);及LC 40和41(根據Kabat編號)的根據本發明之抗5T4抗體的一或多個位置上。語詞〝Kabat編號〞係指在Kabat,E.A.等人之Sequences of Proteins of Immunological Interest,5th Ed.Public Health Service,National Institutes of Health,Bethesda,MD.(1991)中常用於抗體編制之HC可變區或LC可變區的編號系統。使用此編號系統使實際的線性胺基酸序列可含有對應於縮短或插入可變區之FR或CDR而較少或添加的胺基酸。對給出之抗體的殘基之Kabat編號可藉由在抗體序列的同源區與〝標準的〞Kabat編號之序列配準來決定。
除了如上文所述之包含HCVR及LCVR CDR之抗5T4抗體與包含HCVR及LCVR之人源化抗體以外,本發明亦關於在HC及/或LC中包含至少一種在選自HC 40、41和89及LC 40和41之位置上的工程化半胱胺酸之該抗體。
在較佳的實施態樣中,本發明之抗5T4抗體包含至少一種在選自HC 40、41和89及LC 40和41之位置上的工程化半胱胺酸及包含選自由下列所組成之群組的HCVR及HCVR CDR:a. SEQ ID NO:1之CDR1、CDR2和CDR3胺基酸序列及SEQ ID NO:2之CDR1、CDR2和CDR3胺基
酸序列;b. SEQ ID NO:5之CDR1、CDR2和CDR3胺基酸序列及SEQ ID NO:6之CDR1、CDR2和CDR3胺基酸序列;及c. SEQ ID NO:11之CDR1、CDR2和CDR3胺基酸序列及SEQ ID NO:12之CDR1、CDR2和CDR3胺基酸序列。
在另一較佳的實施態樣中,本發明關於人源化抗5T4抗體,其包含至少一種在選自HC 40、41和89及LC 40和41之位置上的工程化半胱胺酸及包含選自由下列所組成之群組的HCVR及LCVR:a. SEQ ID NO:40之HC胺基酸序列及SEQ ID NO:51之LC胺基酸序列;b. SEQ ID NO:41之HC胺基酸序列及SEQ ID NO:51之LC胺基酸序列;c. SEQ ID NO:42之HC胺基酸序列及SEQ ID NO:49之LC胺基酸序列;d. SEQ ID NO:43之HC胺基酸序列及SEQ ID NO:50之LC胺基酸序列;e. SEQ ID NO:38之HC胺基酸序列及SEQ ID NO:47之LC胺基酸序列,及f. SEQ ID NO:39之HC胺基酸序列及SEQ ID NO:48之LC胺基酸序列。
位置HC 40、41和89及LC 40和41係位於抗體的可
變區FR內以及抗體的Fab部份內。
在較佳的實施態樣中,本發明關於ADC,其中連結子藥物係通過在選自HC 40、41和89(根據Kabat編號)及LC 40和41(根據Kabat編號)之該抗5T4抗體的一或多個位置上之工程化半胱胺酸而與根據本發明之抗5T4抗體經位點特異性共軛。
與其中連結子藥物係通過抗5T4抗體的天然中間鏈二硫鍵半胱胺酸共軛之習知的ADC相比,本發明者驚訝地發現本發明的經位點特異性共軛之ADC顯示改進之物化、藥理及/或藥物動力學特性。
通常避免抗體可變部位的修飾,因為可導致抗原結合親和性的部分或完全損失。然而,有別於一般的預期,頃發現在抗體的HC及LC之FR中的特異性殘基二者適合於共軛且在連結子藥物共軛後不導致(顯著)降低的抗原結合。在特別佳的實施態樣中,本發明關於ADC,其中該工程化半胱胺酸係在選自HC 40和41及LC 40和41之該抗5T4抗體的一或多個位置上(在該抗體之Fab部分內)。該工程化半胱胺酸較佳地在位置HC 41或LC 40或41上,更佳地在HC 41上。
如從文獻已知在腫瘤微環境中的腫瘤相關蛋白酶可部分切割在鉸鏈區的Fc恆定功能域,在Fab部分內共軛比在Fc部分內共軛更佳。Fc恆定功能域的切割會導致經Fc共軛之連結子藥物的損失,其依次可導致降低活體內的ADC活性(Fan等人之Breast Cancer Res.2012;14:
R116;及Brezsky等人之PNAS 2009;106:17864-17869)。而且,與Fab部分內的該等位置共軛亦能夠使用本文所揭示之抗5T4抗體的抗原結合片段。
依照本發明之(位點特異性)ADC具有類似於裸抗體的結合親和性且於試管內極佳的效力,且具有改進之活體內輪廓,超越自先前技術已知的5T4靶向之ADC。與先前技術的5T4靶向之ADC相比,預期依照本發明之位點特異性ADC展現於活體內低的非特異性毒性。在本發明之抗5T4 ADC中,將連結子藥物遮蔽(使得ADC不太容易被細胞外蛋白酶切割)且因此藥物不太可能過早釋出。
依照本發明,在ADC技術中已知的任何連結子藥物可用於與根據本發明之抗體(位點特異性)共軛,先決條件為其具有可與天然或工程化半胱胺酸之硫氫基反應的化學基團,通常為順丁烯二醯亞胺或鹵乙醯基團。適合的連結子藥物可包含倍癌黴素(duocarmycin)、卡奇黴素、吡咯並苯並二氮呯(PBD)二聚物、類美登素(maytansinoid)或奧立他汀衍生物作為細胞毒性藥物。依照本發明可使用可切割或不可切割的連結子。細胞毒性藥物較佳為倍癌黴素、類美登素或奧立他汀衍生物。類美登素藥物之適合的實例包括DM1和DM4。奧立他汀藥物之適合的實例包括MMAE和MMAF。
該等縮寫為熟習本技術領域者所熟知。熟習本技術領域者已知適合的連結子藥物的實例包括mc-vc-PAB-
MMAE(亦縮寫為mc-vc-MMAE和vc-MMAE)、mc-MMAF和mc-vc-MMAF。所使用的連結子較佳為包含纈胺酸-瓜胺酸(vc)或纈胺酸-丙胺酸(va)之可切割的連結子。
依照本發明之(位點特異性)vc-MMAE ADC和mc-MMAF ADC的通用化學結構描述於下。
與mAb連結之vc-MMAE的分子結構
與mAb連結之mc-MMAE的分子結構
在一個實施態樣中,本發明關於ADC,其中連結子藥物包含倍癌黴素衍生物。
最先自鏈球菌屬的培養液分離之倍癌黴素為包括倍癌黴素A、倍癌黴素SA和CC-1065之抗腫瘤抗生素家族的成員。倍癌黴素結合至DNA的小溝(minor groove)且接著引起DNA的不可逆烷基化反應。這破壞了核酸構造,其最終導致腫瘤細胞死亡。
WO2011/133039揭示包含CC-1065之倍癌黴素衍生
物的連結子藥物系列。欲依照本發明使用之適合的連結子-倍癌黴素衍生物揭示在第182至197頁。許多該等連結子藥物之化學合成說明於WO2011/133039的實施例1至12中。
在一個實施態樣中,本發明關於式(I)之ADC
其中〝抗5T4抗體〞為依照本發明之抗5T4抗體,不具有或具有如本文所揭示之至少一種在HC或LC中的工程化半胱胺酸,n為0-3,較佳為0-1,m代表1至6之平均DAR,較佳為1至4,R1係選自
y為1-16,及
R2係選自
在較佳的實施態樣中,式(I)之ADC包含依照本發明之抗5T4抗體,其包含至少一種在HC或LC中的工程化半胱胺酸,其中連結子藥物係通過工程化半胱胺酸與抗5T4抗體經位點特異性共軛。工程化半胱胺酸較佳地在位置HC 40、41或89或LC 40或41上,更佳地在HC 41或LC 40或41上,最佳地在HC 41上。
在本說明書中所示之結構式中,n代表0至3的整數,且m代表1至6之平均藥物對抗體比(DAR)。如本技術中所熟知,DAR及藥物負載分布(drug load distribution)可例如藉由使用疏水性交互作用層析術(HIC)或逆相高性能液相層析術(RP-HPLC)來測定。HIC特別適合於測定平均DAR。
依照本發明的式(I)之ADC可根據熟習本技術領域者熟知的方法及程序獲得。
適合於倍癌黴素連結子藥物的非特異性(隨機)共軛(亦即與天然半胱胺酸共軛)之方法揭示於WO2011/133039之實施例15中,而Doronina等人之Bioconjugate Chem.17(2006):114-124說明與mc-MMAF的非特異性共軛。
適合於經位點特異性共軛連結子藥物之方法可於例如
下列中發現:WO2005/084390之實施例7和8,其說明以連結子藥物vc-MMAE之抗體(部分)負載的完全還原策略,及WO2006/034488之實施例11和12,其說明包含類美登素(DM1)之連結子藥物的位點特異性共軛。
在特別的實施態樣中,本發明關於如上文揭示的式(I)之ADC,其中n為0-1,m代表1至6之平均DAR,較佳為1至4,更佳為1至2,甚佳為1.5至2,最佳為1.8至2,R1係選自
y為1-16,較佳為1-4,及R2係選自
在特定的實施態樣中,本發明關於如上文揭示的結構式(I)之ADC,其中n為0-1,m代表1.5至2之平均DAR,較佳為1.8至2,R1為
y為1-4,及R2係選自
在特別佳的實施態樣中,本發明關於式(II)之ADC
其中〝抗5T4抗體〞為根據本發明之抗5T4抗體,不具有或具有如本文所揭示之至少一種在HC或LC中的工程化半胱胺酸,及m代表1.5至2之平均DAR,較佳為1.8至2。
在較佳的實施態樣中,式(II)之ADC包含根據本發明之抗5T4抗體,其包含至少一種在HC或LC中的工程化半胱胺酸,其中連結子藥物係通過工程化半胱胺酸與抗體經位點特異性共軛。該工程化半胱胺酸較佳地在位置HC 40、41或89或LC 40或41上,更佳地在HC 41或LC 40或41上,最佳地在HC 41上。
在較佳的實施態樣中,本發明關於包含抗5T4抗體的式(II)之ADC,該抗體包含選自由下列所組成之群組的HCVR及LCVR CDR:a. SEQ ID NO:1之CDR1、CDR2和CDR3胺基酸序
列及SEQ ID NO:2之CDR1、CDR2和CDR3胺基酸序列;b. SEQ ID NO:5之CDR1、CDR2和CDR3胺基酸序列及SEQ ID NO:6之CDR1、CDR2和CDR3胺基酸序列;及c. SEQ ID NO:11之CDR1、CDR2和CDR3胺基酸序列及SEQ ID NO:12之CDR1、CDR2和CDR3胺基酸序列。
在更佳的實施態樣中,本發明關於包含人源化抗5T4抗體的式(II)之ADC,該抗體包含選自由下列所組成之群組的HCVR及LCVR:a. SEQ ID NO:40之HC胺基酸序列及SEQ ID NO:51之LC胺基酸序列;b. SEQ ID NO:41之HC胺基酸序列及SEQ ID NO:51之LC胺基酸序列;c. SEQ ID NO:42之HC胺基酸序列及SEQ ID NO:49之LC胺基酸序列;d. SEQ ID NO:43之HC胺基酸序列及SEQ ID NO:50之LC胺基酸序列;e. SEQ ID NO:38之HC胺基酸序列及SEQ ID NO:47之LC胺基酸序列;及f. SEQ ID NO:39之HC胺基酸序列及SEQ ID NO:48之LC胺基酸序列。
在甚至更佳的實施態樣中,本發明關於包含根據本發
明之抗5T4抗體的式(II)之ADC,該抗體包含至少一種在一或多個選自HC 40和41及LC 40和41之位置上的工程化半胱胺酸,其中連結子藥物係通過工程化半胱胺酸與抗5T4抗體經位點特異性共軛。該工程化半胱胺酸較佳地在位置HC 41或LC 40或41上,最佳地在HC 41上。
在最佳的實施態樣中,本發明關於包含人源化抗5T4抗體的式(II)之ADC,該抗體包含選自由下列所組成之群組的HCVR及LCVR:a. SEQ ID NO:61之HCVR胺基酸序列及SEQ ID NO:51之LCVR胺基酸序列;b. SEQ ID NO:62之HCVR胺基酸序列及SEQ ID NO:51之LCVR胺基酸序列;c. SEQ ID NO:63之HCVR胺基酸序列及SEQ ID NO:49之LCVR胺基酸序列;d. SEQ ID NO:64之HCVR胺基酸序列及SEQ ID NO:50之LCVR胺基酸序列;e. SEQ ID NO:59之HCVR胺基酸序列及SEQ ID NO:47之LCVR胺基酸序列;及f. SEQ ID NO:60之HCVR胺基酸序列及SEQ ID NO:48之LCVR胺基酸序列;其中連結子藥物係通過在位置HC 41上之工程化半胱胺酸與抗5T4抗體經位點特異性共軛。
本發明另關於包含如上文所述之抗5T4抗體或抗5T4 ADC及一或多種醫藥上可接受之賦形劑的醫藥組成物。
治療用蛋白質(諸如mAbs和(單株)ADC)之典型的醫藥調配物係呈凍乾塊(凍乾粉)形式,其必需在經靜脈內灌注前(水性)溶解(亦即重組),或呈冷凍(水性)溶液形式,其必需在使用前解凍。
醫藥組成物通常以凍乾塊的形式提供。適合於內含在依照本發明之醫藥組成物(冷凍乾燥前)的醫藥上可接受之賦形劑包括緩衝溶液(例如含有在水中的鹽之檸檬酸鹽、組胺酸或琥珀酸鹽)、凍乾保護劑(例如蔗糖、海藻糖)、張力調整劑(例如氯化鈉)、界面活性劑(例如聚山梨醇酯)及增積劑(例如甘露醇、甘胺酸)。用於冷凍乾燥之蛋白質調配物的賦形劑係以彼等防止蛋白質在冷凍乾燥過程期間以及在儲存期間變質之能力予以選擇。作為實例的KadcylaTM(Roche)之無菌的凍乾粉單次使用調配物在以用於注射的制菌或無菌水(BWFI或SWFI)重組時含有20毫克/毫升之阿多-曲妥珠單抗艾坦辛(ado-trastuzumab emtansine)、0.02% w/v之聚山梨醇酯20、10mM琥珀酸鈉及6% w/v之蔗糖,具有5.0之pH。
本發明另關於如上文所述之抗5T4抗體、ADC或醫藥組成物,其係用作為藥劑。
在一個實施態樣中,本發明關於如上文所述之抗5T4抗體、ADC或醫藥組成物,其係用於治療人體實體腫瘤及血液惡性腫瘤,較佳為人體實體腫瘤。
在較佳的實施態樣中,本發明關於如上文所述之抗5T4抗體、ADC或醫藥組成物,特別為包含倍癌黴素衍生
物連結子藥物之ADC,其係用於治療選自由下列所組成之群組的人體實體腫瘤:乳癌、胃癌、結腸直腸癌、卵巢癌、肺癌(尤其為非小細胞肺癌(NSCLC)和小細胞肺癌(SCLC))及(惡性肋膜)中皮瘤。
在另外的實施態樣中,本發明關於如上文所述之抗5T4抗體、ADC或醫藥組成物,特別為包含倍癌黴素衍生物連結子藥物之ADC,其係用於治療選自由下列所組成之群組的人類血液惡性腫瘤,特別為白血病:急性淋巴性白血病和骨髓性白血病(分別為ALL和AML)。
本發明另關於如上文所述之抗5T4抗體、抗5T4 ADC或醫藥組成物與針對非5T4抗原的癌症相關標靶之治療抗體、化學治療劑及/或ADC的依序或同時投予之組合的用途,其係用於治療如上文所述之人體實體腫瘤及血液惡性腫瘤。
在本發明之一個實施態樣中,特別在包含倍癌黴素衍生物連結子藥物之抗5T4 ADC的例子中,治療抗體為貝伐單抗(bevacizumab)、西妥昔單抗(cetuximab)、尼伏單抗(nivolumab)或雷莫蘆單抗(ramucirumab),及化學治療劑為烷化劑,特別為環磷醯胺、異環磷醯胺(ifosfamide)或三,特別為替莫唑胺(temozolomide),或鉑藥物,更特別為順鉑(cisplatin)或卡鉑(carboplatin),抗代謝物,特別為吉西他濱(gemcitabine)或培美曲塞(pemetrexed),拓樸異構酶II抑制劑,特別為依託泊苷(etoposide),有
絲分裂抑制劑,特別為紫杉烷(taxane),更特別為太平洋紫杉醇(paclitaxel)或多烯紫杉醇(docetaxel),或長春花生物鹼,更特別為長春鹼(vinblastine)或長春瑞賓(vinorelbine),或傳訊級聯抑製劑,特別為酪胺酸激酶抑制劑,更特別為伊馬替尼(imatinib)、埃羅替尼(erlotinib)、舍瑞替尼(ceritinib)、克卓替尼(crizotinib)或阿法替尼(afatinib)。
在本發明另外的實施態樣中,特別在包含倍癌黴素衍生物連結子藥物之抗5T4 ADC的例子中,治療抗體為貝伐單抗,及化學治療劑為烷化劑,特別為氮芥子氣,特別為異環磷醯胺或環磷醯胺,鉑藥物,特別為順鉑或卡鉑,或三,特別為替莫唑胺,抗腫瘤抗生素,特別為多柔比星(doxorubicin),抗代謝物,特別為吉西他濱,拓樸異構酶I或II抑制劑,特別為拓撲替康(topotecan)、伊立替康(irinotecan)或依託泊苷,或有絲分裂抑制劑,特別為紫杉烷,更特別為太平洋紫杉醇或多烯紫杉醇,或長春花生物鹼,更特別為長春新鹼(vincristine)或長春瑞賓。
在本發明又另外的實施態樣中,特別在包含倍癌黴素衍生物連結子藥物之抗5T4 ADC的例子中,治療抗體為阿瑪西單抗(amatuximab),及化學治療劑為烷化劑,特別為鉑藥物,更特別為順鉑或卡鉑,抗代謝物,特別為吉西他濱或培美曲塞,或有絲分裂抑制劑,特別為長春花生物鹼,更特別為長春瑞賓。
依照本發明之抗5T4抗體或ADC的治療有效量係位於約0.01至約15毫克/公斤體重之範圍內,特別在約0.1至約10毫克/公斤體重之範圍內,更特別在約0.3至約10毫克/公斤體重之範圍內。最後的範圍大約相當於在20至800毫克抗體或ADC之範圍的平調劑量(flat dose)。本發明化合物可以每週、每兩週、每三週、每月或每六週投予。適合的治療規程係取決於疾病的嚴重性、患者的年齡、投予的化合物及由治療醫師要考慮的其他因素而定。
將兔子重複以hu 5T4/cyno5T4蛋白質之混合物(2隻兔子)及MDA-MB-468細胞(2隻兔子)免疫。在不同的時間點收集約20毫升血液。將單一B細胞沉積在微量滴定盤的單一槽孔中。將該等B細胞在條件培養基及飼養細胞的存在下培養數天。該等B細胞在此期間產生且釋出單株抗體至培養基(B細胞上清液)中。分析該等單一B細胞的上清液之IgG生產量,隨後測定hu及cyno 5T4抗原之特異性結合及與表現5T4之MDA-MB-468細胞之結合。當該等抗體與人類及cyno 5T4抗原二者結合,以及與MDA-MB-468細胞結合時,選擇160個B細胞上清液且定序。獲得131個獨特的抗體重鏈及輕鏈可變區,合成基因且選殖在IgG1亞型的人類免疫球蛋白恆定部分上。將HEK 293細胞在Tecan Freedom Evo平臺上使用自動化
程序以含有質體的免疫球蛋白序列暫時轉染。在具有盤自動取樣器的Dionex Ultimate 3000 HPLC系統上使用親和性純化法(蛋白質A)純化來自細胞上清液的免疫球蛋白。排除具有非常低生產量的4個樣品,得到總數127個抗體重新測試。抗體係基於彼等與人類及cyno 5T4抗原之特異性結合及與表現人類5T4之MDA-MB-468細胞之結合予以選擇。
與hu及cyno 5T4抗原之結合係以下列程序來測定。在384格式微量滴定盤上塗佈Hu或cyno 5T4抗原。添加參考抗體、B細胞上清液或重組產生之抗體且經由抗兔子或人類POD抗體檢測結合。
關於與MDA-MB-468細胞之結合,將細胞接種在黑色的細胞培養微量滴定盤(Corning)上。容許源自B細胞上清液之特異性抗體或參考抗體與細胞交互作用。使用經Alexa Fluor 488標記之抗體檢測結合。使用CellInsight(Thermo Fischer)裝置讀取螢光。
選擇17個抗體且使用表現人類或cyno 5T4抗原之MDA-MB-468細胞、PA-1細胞及中國倉鼠卵巢(CHO)哺乳動物細胞測量對5T4抗原之親和性(表2)。在本申請案中,將所利用的CHO細胞稱為CHOZN,因為表現人類或cyno 5T4抗原之該等CHO細胞係使用Sigma-Aldrich之CHOZN®平臺獲得。將CHOZN細胞(SAFC)使用Amaxa nucleofector裝置(Lonza)根據製造商的指示暫時轉染。使用市場上可取得標準的哺乳動物表現載體
(SAFC,Life Technologies),其含有以人類CMV啟動子前置之全長的人類及cyno 5T4抗原編碼序列(分別根據存取編號NP_006661.1及Q4R8Y9)。將暫時轉染之CHOZN細胞根據製造商的指示培養,然後用於抗體結合研究中。17種選擇之抗體係根據下表(表1)的胺基酸序列特徵化。
將表現人類或cyno 5T4抗原之MDA-MB-468細胞、PA-1細胞或CHOZN細胞(在96槽孔盤中,100,000個細
胞/槽孔)以含有0.2% v/w BSA(Sigma-Aldrich,St.Louis,MO)及0.02% v/w NaN3(Sigma-Aldrich)之冰冷的FACS緩衝液(1x PBS(Lonza))清洗三次,接著添加在冰冷的FACS緩衝液中稀釋之各初級mAb(50微升/槽孔)的濃度範圍。在4℃下培育30分鐘之後,將細胞以冰冷的FACS緩衝液清洗三次且添加50微升/槽孔之二級mAb(AffiniPure F(ab’)2片段山羊抗人類IgG-APC,1:6,000稀釋,Jackson Immuno Research)。在4℃下30分鐘之後,將細胞清洗兩次且再懸浮於150微升FACS緩衝液中。以流動式細胞測量術(BD FACSVerse,Fanklin Lakes,NJ)測定螢光強度且以平均螢光強度(MFI)表示。曲線係使用GraphPad Prism(用於Windows的5.01/6.01版,GraphPad,San Diego,CA)的具有可變斜率之S曲線劑量反應方程式(四個參數)以非線性回歸擬合。EC50值係以微克/毫升之濃度計算,當使用4參數邏輯擬合時,給出在曲線的頂端與底端之間一半的反應之濃度。
在表現人類5T4抗原(hu 5T4)之MDA-MB-468細胞上所測量的嵌合抗體之親和性係在0.040微克/毫升至0.730微克/毫升之EC50值的範圍內,與H8之EC50值可相比,其為0.19微克/毫升。然而,當在MDA-MB-468細胞上測量時,A1抗體展現以較低的親和性(EC50值為4.72微克/毫升)與hu 5T4結合。嵌合抗體對hu 5T4之親和性亦在表現hu 5T4的PA-1細胞及CHOZN細胞上測
量。嵌合抗體之EC50值再與H8之EC50值在相同的範圍內,而A1顯示對hu 5T4至少3倍低的結合親和性(表2)。A3在表現hu 5T4的三種細胞類型上之EC50值比嵌合抗體在對應的細胞類型上之EC50值更低。
當使用表現hu 5T4之CHOZN或表現cyno 5T4之CHOZN細胞測量時,嵌合抗5T4抗體對hu 5T4及cyno 5T4具有類似的親和性,如表2中所示。比較H8與cyno 5T4之結合,對大部分的嵌合抗體之結合顯示32倍的改進,除了846(10倍)及828(7倍)以外。
人源化抗體係由CDR接枝來製備,如下文所述。
選殖株789、825和833之CDR係使用來自編號系統IMGT(LEFRANC,MP,The IMGT unique numbering for immunoglobulins,T cell receptors and Ig-like domains.
Immunologist,7(1999),pp.132-136)及Kabat之CDR定義來鑑定。
人類IgG序列之線上公用資料庫係利用BLAST搜尋演算法使用兔子VH功能域搜尋,且候選的人類可變功能域係選自前200個BLAST結果。5個候選物係基於下列標準選擇:諸如架構同源性、維持關鍵架構殘基、規範環形結構(canonical loop structure)及免疫原性。對抗體之VL功能域重複相同的程序。將所有的人源化VH變體與所有的人源化VL變體組合,得到用於各抗體的25個人源化變體。
包含HC-41C突變之人源化變體係根據下列程序合成且彼等對人類及cyno 5T4之親和性係使用表現人類或cyno 5T4之CHOZN細胞測量。選擇11種變體進一步評估。
將來自US8044178,SEQ ID NO:2,位置20-138之小鼠A1胺基酸序列的HCVR、來自US8044178,SEQ ID NO:10,位置20-141之小鼠胺基酸序列的HCVR及來自SEQ ID NO:52之H8人源化變體1胺基酸序列的HCVR分別在N端接合至HAVT20前導序列(SEQ ID NO:54)及在C端接合至根據SEQ ID NO:55之人類IgG1 HC的恆定功能域。將所得嵌合胺基酸序列返轉譯成cDNA序列
密碼子-在人類細胞(智人)中的表現最優化。
構築體之LC的嵌合cDNA序列同樣地藉由下列方式獲得:將適合的分泌信號序列(亦為HAVT20前導序列)、來自US8044178,SEQ ID NO:4,位置21-127之小鼠A1胺基酸序列的HCVR、來自US8044178,SEQ ID NO:12,位置21-127之小鼠A3胺基酸序列的HCVR或H8人源化變體1胺基酸序列SEQ ID NO:53的HCVR及人類IgG κ輕鏈恆定區(SEQ ID NO:56)接合且將所獲得的胺基酸序列返轉譯成cDNA序列密碼子-在人類細胞(智人)中的表現最優化。
具有HC-41C突變的人源化變體之LC及HC的cDNA序列係使用類似的程序獲得,然而在此例子中,將HC及LC序列在N端接合至兔子前導序列(分別為SEQ ID NO:57及58)及在C端接合至根據SEQ ID NO:55之人類IgG1 HC的恆定功能域。使用根據下表的序列,在根據Kabat編號的HCVR之位置41上具有半胱胺酸(表3)。
以市場上可取得的哺乳動物載體pcDNA3.3(Thermo Fisher)之衍生物用於抗體鏈的表現,該載體含有CMV:BGHpA表現卡匣(expression cassette)。此載體係藉由改變CMV啟動子的多重選殖位點下游而略微改造以含有AscI及NheI限制位點,產生表現載體0080pcDNA3.3-SYN。
構築體的HC及LC之cDNA係使用AscI及NheI限制位點直接接合至0080pcDNA3.3-SYN載體中。將含有HC或LC表現卡匣(分別為CMV:HC:BGHpA及CMV:LC-BGHpA)之最終載體轉染至大腸桿菌NEB 5-α細胞且於其中擴展。大規模產生用於轉染之最終表現載體係使用Maxi-或Megaprep套組(Qiagen)來進行。
將市場上取得的Expi293F細胞(Thermo Fisher)使用ExpiFectamine轉染劑根據製造商的如下指示以表現載體轉染:將75x107個細胞接種在300毫升FortiCHO培養基中,將300微克表現載體與800微升ExpiFectamine轉染劑組合且添加至細胞中。在轉染後一天,將1.5毫升Enhancer 1及15毫升Enhancer 2添加至培養物中。在轉染後六天,將細胞培養物上清液藉由在4,000g下離心15分鐘而收成且將收成物在PES瓶過濾器/MF 75過濾器(Nalgene)上過濾及濾淨。
當在表現hu 5T4或cyno 5T4的CHOZN細胞上測量時,人源化抗5T4抗體對hu 5T4及cyno 5T4具有類似的親和性,除了825a、825b和825c人源化抗5T4抗體以外,其顯示對cyno 5T4之結合比對hu 5T4之結合低2至3倍(表4)。人源化抗5T4抗體與cyno 5T4之結合比H8與cyno 5T4之結合改進4至17倍。與A1比較,有類似的結合改進。人源化抗5T4抗體對表現hu 5T4的CHOZN細胞之親和性與H8可相比。
將EDTA(在水中的25mM,4% v/v)添加至經半胱胺酸工程化之抗5T4抗體溶液(在4.2mM組胺酸、50mM海藻糖中的5-10毫克/毫升,pH 6)中。將pH使用TRIS(在水中的1M,pH 8)調整至~7.4,隨後添加TCEP(在水中的10mM,20當量)且將所得混合物在室溫下培育1至3小時。將過量TCEP以使用4.2mM組胺酸、50mM海藻糖,pH 6之PD-10脫鹽管柱或Vivaspin離心濃縮器(30kDa截止點,PES)移除。將所得抗體溶
液之pH使用TRIS(在水中的1M,pH 8)上升至~7.4,隨後添加去氫抗壞血酸(在水中的10mM,20當量)且將所得混合物在室溫下培育1至2小時。添加DMA及接著添加連結子藥物溶液(在DMA中的10mM)。DMA之最終濃度為5-10%。將所得混合物在無光的存在下於室溫下培育1至16小時。為了移除過量連結子藥物,添加活性木炭且將混合物在室溫下培育1小時。使用0.2μm PES過濾器移除木炭且將所得ADC使用Vivaspin離心濃縮器(30kDa截止點,PES)調配在4.2mM組胺酸、50mM海藻糖,pH 6中。最後將ADC溶液使用0.22μm PES過濾器無菌過濾。
將EDTA(在水中的25mM,4% v/v)添加至抗5T4抗體溶液(在4.2mM組胺酸、50mM海藻糖中的5-10毫克/毫升,pH 6)中。將pH使用TRIS(在水中的1M,pH 8)調整至~7.4,隨後添加TCEP(在水中的10mM,1-3當量,取決於抗體及所欲DAR)且將所得混合物在室溫下培育1至3小時。添加DMA及接著添加連結子藥物溶液(在DMA中的10mM)。DMA之最終濃度為5-10%。將所得混合物在無光的存在下於室溫下培育1至16小時。為了移除過量連結子藥物,添加活性木炭且將混合物在室溫下培育1小時。使用0.2μm PES過濾器移除木
炭且將所得ADC使用Vivaspin離心濃縮器(30kDa截止點,PES)調配在4.2mM組胺酸、50mM海藻糖,pH 6中。最後將ADC溶液使用0.22μm PES過濾器無菌過濾。
使用上述通用程序合成以vc-seco-DUBA(SYD980,亦即在WO2011/133039的第209頁之實施例10中的化合物18b,n=1)為底質的經半胱胺酸工程化之ADC及野生型ADC,且使用分析用疏水性交互作用層析術(HIC)、尺寸排阻層析術(SEC)、遮蔽式疏水相層析術(Shielded Hydrophobic Phase Chromatography)(SHPC)、RP-HPLC及LAL內毒素測試特徵化。
將用於分析性HIC之5-10微升樣品(1毫克/毫升)注射在TSKgel Butyl-NPR管柱(4.6毫米ID x 3.5公分L,Tosoh Bioscience,目錄編號14947)上。溶析方法係由從100%緩衝液A(25mM磷酸鈉、1.5M硫酸銨,pH 6.95)至100%緩衝液B(25mM磷酸鈉,pH 6.95,20%異丙醇)之線性梯度,以0.4毫升/分鐘經20分鐘所組成。使用配備有PDA檢測器及Empower軟體之Waters Acquity H-Class UPLC系統。在214奈米下測量吸收值且測量ADC之滯留時間。
如以分析性HIC所顯見,不同的經半胱胺酸工程化之ADC的DAR2種類有不同的滯留時間(RT)。大部分的經工程化之ADC的DAR2種類的RT亦比H8(具有)-共軛體的RT更低(表5),且在兩種連結子藥物共軛時以
經HC-41C工程化之人源化ADC增加的滯留時間(RTDAR2-RTDAR0)比H8(具有)-vc-seco-DUBA增加的更少。所有的經工程化之人源化ADC具有介於2.1-3.1之間的RTDAR2-RTDAR0值,其比H8-vc-seco-DUBA的3.5之RTDAR2-RTDAR0值更小,表明經工程化之人源化ADC展現降低的疏水性。
(位點特異性)抗5T4 ADC之抗原結合親和性不受連接之倍癌黴素衍生物連結子藥物的影響,如在表現hu 5T4或cyno 5T4之CHOZN細胞上所測量(圖1和2)。如預期般,未結合之對照物ADC(利妥昔單抗-vc-seco-
DUBA)僅在高濃度下對表現5T4之腫瘤細胞的生長有影響。所有的人源化抗5T4 ADC對SK-MEL-30,5T4-陰性人類腫瘤細胞株(每個細胞約400個5T4抗原結合位點)失活(IC50>10nM)。
經工程化之人源化抗5T4 ADC對表現hu 5T4之MDA-MB-468細胞及PA-1細胞之效力與照慣例共軛之H8(具有)-ADC對該等細胞之效力可相比(表6)。然而,833-ADC系列不能夠完全降低PA-1細胞生存力(功效65至72%)。此外,經工程化之人源化抗5T4 ADC比A3-vc-seco-DUBA高2.5倍的效力及比A1-vc-seco-DUBA高14倍的效力。
抗5T4 ADC之活體內功效係在B6;D2-Ces1ce Foxn1nu/J小鼠中的BT474(來自60歲白種女性患者之侵襲性管狀乳癌)細胞株異種移植體模式評估。免疫組織化學染色確認hu 5T4存在於BT474細胞株的細胞膜上。
將在200微升含有基質膠(50:50,v:v)之RPMI 1640培養基中的2x107個BT-474細胞注入110隻
雌性Ces1ce裸鼠的右側翼而於皮下誘發腫瘤,在24至72小時之後以γ-源(2 Gy,60Co,BioMep,Dijon,France)照射全身。當腫瘤到達200至300立方毫米平均體積時,對小鼠以3毫克/公斤之H8-、833a-、833b-、833c-、833d-、825a-或825c-vc-seco-DUBA ADC的單一注射給藥。使用媒劑及未結合之利妥昔單抗-vc-seco-DUBA ADC作為對照物。將血漿中具有Ces1c活性之小鼠自分析排除。
所有經位點特異性共軛之抗5T4 ADC比先前技術的H8-vc-seco-DUBA縮減更多的腫瘤體積(圖3),表明改進的活體內功效。
藥物動力學係在B6(Cg)-Ces1ctm1.1Loc/J小鼠品系中以抗5T4 ADC進行。該等小鼠缺乏Ces1c基因的exon 5,導致酵素功能消除。對小鼠以抗5T4 ADC(3毫克/公斤,在尾部靜脈中以i.v.)給藥且在給藥後0.25、1、6、24、48、96、168、336和504小時收集血漿。使用基於ELISA之檢定以定量全部的抗體及經共軛之抗體。經共軛之抗體檢定捕獲含有至少一種連結子藥物之ADC種類。在表7中呈示之結果顯示位點特異性ADC非常穩定,比先前技術的H8-vc-seco-DUBA ADC更慢清除且具有更長的半生期。
在HCVR及LCVR胺基酸序列中具有加註底線之CDR1、CDR2和CDR3胺基酸序列的序列表
SEQ ID NO:1(選殖株之HCVR/槽孔789-兔子)
SEQ ID NO:2(選殖株之LCVR/槽孔789-兔子)
SEQ ID NO:3(選殖株之HCVR/槽孔811-兔子)
SEQ ID NO:4(選殖株之LCVR/槽孔811-兔子)
SEQ ID NO:5(選殖株之HCVR/槽孔825-兔子)
SEQ ID NO:6(選殖株之LCVR/槽孔825-兔子)
SEQ ID NO:7(選殖株之HCVR/槽孔828-兔子)
SEQ ID NO:8(選殖株之LCVR/槽孔828-兔子)
SEQ ID NO:9(選殖株之HCVR/槽孔829-兔子)
SEQ ID NO:10(選殖株之LCVR/槽孔829-兔子)
SEQ ID NO:11(選殖株之HCVR/槽孔833-兔子)
SEQ ID NO:12(選殖株之LCVR/槽孔833-兔子)
SEQ ID NO:13(選殖株之HCVR/槽孔834-兔子)
SEQ ID NO:14(選殖株之LCVR/槽孔834-兔子)
SEQ ID NO:15(選殖株之HCVR/槽孔835-兔子)
SEQ ID NO:16(選殖株之LCVR/槽孔835-兔子)
SEQ ID NO:17(選殖株之HCVR/槽孔841-兔子)
SEQ ID NO:18(選殖株之LCVR/槽孔841-兔子)
SEQ ID NO:19(選殖株之HCVR/槽孔843-兔子)
SEQ ID NO:20(選殖株之LCVR/槽孔843-兔子)
SEQ ID NO:21(選殖株之HCVR/槽孔845-兔子)
SEQ ID NO:22(選殖株之LCVR/槽孔845-兔子)
SEQ ID NO:23(選殖株之HCVR/槽孔847-兔子)
SEQ ID NO:24(選殖株之LCVR/槽孔847-兔子)
SEQ ID NO:25(選殖株之HCVR/槽孔848-兔子)
SEQ ID NO:26(選殖株之LCVR/槽孔848-兔子)
SEQ ID NO:27(選殖株之HCVR/槽孔849-兔子)
SEQ ID NO:28(選殖株之LCVR/槽孔849-兔子)
SEQ ID NO:29(選殖株之HCVR/槽孔868-兔子)
SEQ ID NO:30(選殖株之LCVR/槽孔868-兔子)
SEQ ID NO:31(選殖株之HCVR/槽孔899-兔子)
SEQ ID NO:32(選殖株之LCVR/槽孔899-兔子)
SEQ ID NO:33(選殖株之HCVR/槽孔908-兔子)
SEQ ID NO:34(選殖株之LCVR/槽孔908-兔子)
具有加註底線的半胱胺酸突變40、41和89之較佳位置的人源化HCVR胺基酸序列
SEQ ID NO:35(HCVR 789人源化型式1)
SEQ ID NO:36(HCVR 789人源化型式2)
SEQ ID NO:37(HCVR 789人源化型式3)
SEQ ID NO:38(HCVR 825人源化型式1)
SEQ ID NO:39(HCVR 825人源化型式2)
SEQ ID NO:40(HCVR 833人源化型式1)
SEQ ID NO:41(HCVR 833人源化型式2)
SEQ ID NO:42(HCVR 833人源化型式3)
SEQ ID NO:43(HCVR區833人源化型式4)
具有加註底線的半胱胺酸突變40和41之較佳位置的人源化LCVR胺基酸序列
SEQ ID NO:44(LCVR 789人源化型式1)
SEQ ID NO:45(LCVR 789人源化型式2)
SEQ ID NO:46(LCVR 789人源化型式3)
SEQ ID NO:47(LCVR 825人源化型式1)
SEQ ID NO:48(LCVR 825人源化型式2)
SEQ ID NO:49(LCVR 833人源化型式1)
SEQ ID NO:50(LCVR 833人源化型式2)
SEQ ID NO:51(LCVR 833人源化型式3)
SEQ ID NO:52(H8 HC)
SEQ ID NO:53(H8 LC)
SEQ ID NO:54(HAVT20前導序列)
1 MACPGFLWAL VISTCLEFSM A
SEQ ID NO:55(人類IgG1抗體HC恆定區)
SEQ ID NO:56(人類IgG抗體LC κ恆定區)
SEQ ID NO:57(HC兔子前導序列)
1 MGWTLVFLFL LSVTAGVHS
SEQ ID NO:58(LC兔子前導序列)
1 MVSSAQFLGL LLLCFQGTRC
根據Kabat之編號系統在位置41上具有半胱胺酸突
變之人源化HCVR胺基酸序列
SEQ ID NO:59(HCVR 825人源化型式1 41C)
SEQ ID NO:60(HCVR 825人源化型式2 41C)
SEQ ID NO:61(HCVR 833人源化型式1 41C)
SEQ ID NO:62(HCVR 833人源化型式2 41C)
SEQ ID NO:63(HCVR 833人源化型式3 41C)
SEQ ID NO:64(HCVR 833人源化型式4 41C)
<110> 辛頌生物製藥公司
<120> 抗5T4抗體和抗體-藥物共軛體
<140> TW 105138698
<141> 2016-11-24
<150> EP 15195978.0
<151> 2015-11-24
<150> EP 16191272.0
<151> 2016-09-26
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<400> 33
<210> 34
<211> 110
<212> PRT
<213> 穴兔
<220>
<223> 選殖株之LC可變區/槽孔908-兔子
<400> 34
<210> 35
<211> 118
<212> PRT
<213> 人工序列
<220>
<223> HC可變區789人源化型式1
<400> 35
<210> 36
<211> 118
<212> PRT
<213> 人工序列
<220>
<223> HC可變區789人源化型式2
<400> 36
<210> 37
<211> 117
<212> PRT
<213> 人工序列
<220>
<223> HC可變區789人源化型式3
<400> 37
<210> 38
<211> 121
<212> PRT
<213> 人工序列
<220>
<223> HC可變區825人源化型式1
<400> 38
<210> 39
<211> 121
<212> PRT
<213> 人工序列
<220>
<223> HC可變區825人源化型式2
<400> 39
<210> 40
<211> 122
<212> PRT
<213> 人工序列
<220>
<223> HC可變區833人源化型式1
<400> 40
<210> 41
<211> 122
<212> PRT
<213> 人工序列
<220>
<223> HC可變區833人源化型式2
<400> 41
<210> 42
<211> 122
<212> PRT
<213> 人工序列
<220>
<223> HC可變區833人源化型式3
<400> 42
<210> 43
<211> 121
<212> PRT
<213> 人工序列
<220>
<223> HC可變區833人源化型式4
<400> 43
<210> 44
<211> 113
<212> PRT
<213> 人工序列
<220>
<223> LC可變區789人源化型式1
<400> 44
<210> 45
<211> 113
<212> PRT
<213> 人工序列
<220>
<223> LC可變區789人源化型式2
<400> 45
<210> 46
<211> 113
<212> PRT
<213> 人工序列
<220>
<223> LC可變區789人源化型式3
<400> 46
<210> 47
<211> 110
<212> PRT
<213> 人工序列
<220>
<223> LC可變區825人源化型式1
<400> 47
<210> 48
<211> 110
<212> PRT
<213> 人工序列
<220>
<223> LC可變區825人源化型式2
<400> 48
<210> 49
<211> 110
<212> PRT
<213> 人工序列
<220>
<223> LC可變區833人源化型式1
<400> 49
<210> 50
<211> 110
<212> PRT
<213> 人工序列
<220>
<223> LC可變區833人源化型式2
<400> 50
<210> 51
<211> 110
<212> PRT
<213> 人工序列
<220>
<223> LC可變區833人源化型式3
<400> 51
<210> 52
<211> 120
<212> PRT
<213> 人工序列
<220>
<223> H8 HC
<400> 52
<210> 53
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> H8 LC
<400> 53
<210> 54
<211> 21
<212> PRT
<213> 人工序列
<220>
<223> HAVT20前導序列
<400> 54
<210> 55
<211> 330
<212> PRT
<213> 人工序列
<220>
<223> 人類IgG1抗體HC恆定區
<400> 55
<210> 56
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> 人類IgG抗體LC kappa恆定區
<400> 56
<210> 57
<211> 19
<212> PRT
<213> 人工序列
<220>
<223> 重鏈之兔子前導序列
<400> 57
<210> 58
<211> 20
<212> PRT
<213> 人工序列
<220>
<223> 輕鏈之兔子前導序列
<400> 58
<210> 59
<211> 121
<212> PRT
<213> 人工序列
<220>
<223> HC可變區825人源化型式1 41C
<400> 59
<210> 60
<211> 121
<212> PRT
<213> 人工序列
<220>
<223> HC可變區825人源化型式2 41C
<400> 60
<210> 61
<211> 122
<212> PRT
<213> 人工序列
<220>
<223> HC可變區833人源化型式1 41C
<400> 61
<210> 62
<211> 122
<212> PRT
<213> 人工序列
<220>
<223> HC可變區833人源化型式2 41C
<400> 62
<210> 63
<211> 122
<212> PRT
<213> 人工序列
<220>
<223> HC可變區833人源化型式3 41C
<400> 63
<210> 64
<211> 121
<212> PRT
<213> 人工序列
<220>
<223> HC可變區833人源化型式4 41C
<400> 64
Claims (16)
- 一種抗5T4抗體,其包含選自由下列所組成之群組的重鏈(HC)及輕鏈(LC)可變區(VR)互補性決定區(CDR):a. SEQ ID NO:1之CDR1、CDR2和CDR3胺基酸序列及SEQ ID NO:2之CDR1、CDR2和CDR3胺基酸序列;b. SEQ ID NO:3之CDR1、CDR2和CDR3胺基酸序列及SEQ ID NO:4之CDR1、CDR2和CDR3胺基酸序列;c. SEQ ID NO:5之CDR1、CDR2和CDR3胺基酸序列及SEQ ID NO:6之CDR1、CDR2和CDR3胺基酸序列;d. SEQ ID NO:7之CDR1、CDR2和CDR3胺基酸序列及SEQ ID NO:8之CDR1、CDR2和CDR3胺基酸序列;e. SEQ ID NO:9之CDR1、CDR2和CDR3胺基酸序列及SEQ ID NO:10之CDR1、CDR2和CDR3胺基酸序列;f. SEQ ID NO:11之CDR1、CDR2和CDR3胺基酸序列及SEQ ID NO:12之CDR1、CDR2和CDR3胺基酸序列;g. SEQ ID NO:13之CDR1、CDR2和CDR3胺基酸序列及SEQ ID NO:14之CDR1、CDR2和CDR3 胺基酸序列;h. SEQ ID NO:15之CDR1、CDR2和CDR3胺基酸序列及SEQ ID NO:16之CDR1、CDR2和CDR3胺基酸序列;i. SEQ ID NO:17之CDR1、CDR2和CDR3胺基酸序列及SEQ ID NO:18之CDR1、CDR2和CDR3胺基酸序列;j. SEQ ID NO:19之CDR1、CDR2和CDR3胺基酸序列及SEQ ID NO:20之CDR1、CDR2和CDR3胺基酸序列;k. SEQ ID NO:21之CDR1、CDR2和CDR3胺基酸序列及SEQ ID NO:22之CDR1、CDR2和CDR3胺基酸序列;l. SEQ ID NO:23之CDR1、CDR2和CDR3胺基酸序列及SEQ ID NO:24之CDR1、CDR2和CDR3胺基酸序列;m. SEQ ID NO:25之CDR1、CDR2和CDR3胺基酸序列及SEQ ID NO:26之CDR1、CDR2和CDR3胺基酸序列;n. SEQ ID NO:27之CDR1、CDR2和CDR3胺基酸序列及SEQ ID NO:28之CDR1、CDR2和CDR3胺基酸序列;o. SEQ ID NO:29之CDR1、CDR2和CDR3胺基酸序列及SEQ ID NO:30之CDR1、CDR2和CDR3 胺基酸序列;p. SEQ ID NO:31之CDR1、CDR2和CDR3胺基酸序列及SEQ ID NO:32之CDR1、CDR2和CDR3胺基酸序列;及q. SEQ ID NO:33之CDR1、CDR2和CDR3胺基酸序列及SEQ ID NO:34之CDR1、CDR2和CDR3胺基酸序列。
- 根據申請專利範圍第1項之抗體,其包含選自由下列所組成之群組的HCVR及LCVR CDR:a. SEQ ID NO:1之CDR1、CDR2和CDR3胺基酸序列及SEQ ID NO:2之CDR1、CDR2和CDR3胺基酸序列;b. SEQ ID NO:5之CDR1、CDR2和CDR3胺基酸序列及SEQ ID NO:6之CDR1、CDR2和CDR3胺基酸序列;c. SEQ ID NO:11之CDR1、CDR2和CDR3胺基酸序列及SEQ ID NO:12之CDR1、CDR2和CDR3胺基酸序列;其中該抗體經人源化。
- 根據申請專利範圍第2項之人源化抗體,其包含a. SEQ ID NO:1之CDR1、CDR2和CDR3胺基酸序列及SEQ ID NO:2之CDR1、CDR2和CDR3胺基酸序列與SEQ ID NO:35之HCVR胺基酸序列及SEQ ID NO:45之LCVR胺基酸序列; b. SEQ ID NO:1之CDR1、CDR2和CDR3胺基酸序列及SEQ ID NO:2之CDR1、CDR2和CDR3胺基酸序列與SEQ ID NO:36之HCVR胺基酸序列及SEQ ID NO:45之LCVR胺基酸序列;c. SEQ ID NO:1之CDR1、CDR2和CDR3胺基酸序列及SEQ ID NO:2之CDR1、CDR2和CDR3胺基酸序列與SEQ ID NO:37之HCVR胺基酸序列及SEQ ID NO:44之LCVR胺基酸序列;d. SEQ ID NO:1之CDR1、CDR2和CDR3胺基酸序列及SEQ ID NO:2之CDR1、CDR2和CDR3胺基酸序列與SEQ ID NO:37之HCVR胺基酸序列及SEQ ID NO:46之LCVR胺基酸序列;e. SEQ ID NO:11之CDR1、CDR2和CDR3胺基酸序列及SEQ ID NO:12之CDR1、CDR2和CDR3胺基酸序列與SEQ ID NO:40之HCVR胺基酸序列及SEQ ID NO:51之LCVR胺基酸序列;f. SEQ ID NO:11之CDR1、CDR2和CDR3胺基酸序列及SEQ ID NO:12之CDR1、CDR2和CDR3胺基酸序列與SEQ ID NO:41之HCVR胺基酸序列及SEQ ID NO:51之LCVR胺基酸序列;g. SEQ ID NO:11之CDR1、CDR2和CDR3胺基酸序列及SEQ ID NO:12之CDR1、CDR2和CDR3胺基酸序列與SEQ ID NO:42之HCVR胺基酸序列及SEQ ID NO:49之LCVR胺基酸序列; h. SEQ ID NO:11之CDR1、CDR2和CDR3胺基酸序列及SEQ ID NO:12之CDR1、CDR2和CDR3胺基酸序列與SEQ ID NO:43之HCVR胺基酸序列及SEQ ID NO:50之LCVR胺基酸序列;i. SEQ ID NO:5之CDR1、CDR2和CDR3胺基酸序列及SEQ ID NO:6之CDR1、CDR2和CDR3胺基酸序列與SEQ ID NO:38之HCVR胺基酸序列及SEQ ID NO:47之LCVR胺基酸序列;j. SEQ ID NO:5之CDR1、CDR2和CDR3胺基酸序列及SEQ ID NO:6之CDR1、CDR2和CDR3胺基酸序列與SEQ ID NO:39之HCVR胺基酸序列及SEQ ID NO:47之LCVR胺基酸序列;及k. SEQ ID NO:5之CDR1、CDR2和CDR3胺基酸序列及SEQ ID NO:6之CDR1、CDR2和CDR3胺基酸序列與SEQ ID NO:39之HCVR胺基酸序列及SEQ ID NO:48之LCVR胺基酸序列。
- 根據申請專利範圍第1至3項中任一項之抗體,其中該抗體包含至少一種在重鏈架構區或輕鏈架構區中之位置上的工程化半胱胺酸。
- 根據申請專利範圍第4項之抗體,其中該至少一種工程化半胱胺酸係存在於選自下列之該抗體的一或多個位置上:重鏈40、41和89(根據Kabat編號);及輕鏈40和41(根據Kabat編號)。
- 一種抗體-藥物共軛體,其包含根據申請專利範圍第1至5項中任一項之抗體。
- 根據申請專利範圍第6項之抗體-藥物共軛體,其包含根據申請專利範圍第4或5項之抗體,其中連結子(連結子)藥物係通過該至少一種工程化半胱胺酸與該抗體經位點特異性共軛。
- 根據申請專利範圍第6或7項之抗體-藥物共軛體,其具有式(I):
- 根據申請專利範圍第8項之抗體-藥物共軛體,其中n為0-1,m代表1.5至2之平均DAR,R1為
- 根據申請專利範圍第6至9項中任一項之抗體-藥物共軛體,其具有式(II)
- 根據申請專利範圍第6至10項中任一項之抗體-藥物共軛體,其中該抗5T4抗體為人源化抗體,其包含選自由下列所組成之群組的HCVR及LCVR:a. SEQ ID NO:61之HCVR胺基酸序列及SEQ ID NO:51之LCVR胺基酸序列;b. SEQ ID NO:62之HCVR胺基酸序列及SEQ ID NO:51之LCVR胺基酸序列;c. SEQ ID NO:63之HCVR胺基酸序列及SEQ ID NO:49之LCVR胺基酸序列;d. SEQ ID NO:64之HCVR胺基酸序列及SEQ ID NO:50之LCVR胺基酸序列;e. SEQ ID NO:59之HCVR胺基酸序列及SEQ ID NO:47之LCVR胺基酸序列;及f. SEQ ID NO:60之HCVR胺基酸序列及SEQ ID NO:48之LCVR胺基酸序列;其中該連結子藥物係通過重鏈位置41上之該工程化半胱胺酸與該抗5T4抗體經位點特異性共軛。
- 一種醫藥組成物,其包含根據申請專利範圍第1 至5項中任一項之抗體或根據申請專利範圍第6至11項中任一項之抗體-藥物共軛體及一或多種醫藥上可接受之賦形劑,較佳地呈凍乾粉形式。
- 根據申請專利範圍第1至5項中任一項之抗體、根據申請專利範圍第6至11項中任一項之抗體-藥物共軛體或根據申請專利範圍第12項之醫藥組成物,其係作為藥劑。
- 根據申請專利範圍第13項之抗體、抗體-藥物共軛體或醫藥組成物,其係用於治療人體實體腫瘤及血液惡性腫瘤。
- 根據申請專利範圍第14項之抗體、抗體-藥物共軛體或醫藥組成物,其中該人體實體腫瘤係選自由下列所組成之群組:乳癌、胃癌、結腸直腸癌、卵巢癌、肺癌和中皮瘤。
- 一種根據申請專利範圍第1至5項中任一項之抗體、根據申請專利範圍第6至11項中任一項之抗體-藥物共軛體或根據申請專利範圍第12項之醫藥組成物與針對非該5T4抗原的癌症相關標靶之治療抗體、化學治療劑及/或ADC的組合,其係用於治療人體實體腫瘤及血液惡性腫瘤。
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US11161897B2 (en) | 2017-07-17 | 2021-11-02 | Janssen Biotech, Inc. | Antigen binding regions against fibronectin type III domains and methods of using the same |
CN108187065B (zh) * | 2017-12-29 | 2023-04-28 | 广东众生药业股份有限公司 | 抗5t4抗体与美登素衍生物dm4偶联复合物及制备方法和用途 |
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WO2005084390A2 (en) | 2004-03-02 | 2005-09-15 | Seattle Genetics, Inc. | Partially loaded antibodies and methods of their conjugation |
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- 2016-11-24 CN CN201680067751.2A patent/CN108348608B/zh active Active
- 2016-11-24 DK DK16801753.1T patent/DK3380122T3/da active
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2018
- 2018-04-18 ZA ZA2018/02584A patent/ZA201802584B/en unknown
- 2018-05-17 CL CL2018001334A patent/CL2018001334A1/es unknown
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2021
- 2021-04-13 US US17/229,483 patent/US11584801B2/en active Active
- 2021-08-09 HR HRP20211280TT patent/HRP20211280T1/hr unknown
- 2021-08-25 CY CY20211100758T patent/CY1124456T1/el unknown
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