TW202306588A - 抗體-藥物結合物與免疫檢查點抑制劑組合用於治療泌尿上皮癌之用途 - Google Patents
抗體-藥物結合物與免疫檢查點抑制劑組合用於治療泌尿上皮癌之用途 Download PDFInfo
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Abstract
本發明提供靶向Her2之抗體-藥物結合物與免疫檢查點抑制劑(諸如PD-1抗體或PD-L1抗體)組合於製備用於治療患有泌尿上皮癌(尤其局部晚期或轉移性泌尿上皮癌)之患者之藥劑中的用途。與單獨利用兩種藥物中之任一者之治療相比,利用二者組合之治療具有顯著協同效應及顯著治療效應。此外,該組合治療針對具有低HER2 IHC表現(1+)之患者具有良好功效。
Description
本發明係關於精確治療癌症之領域,關於靶向HER2 (人類表皮生長因子受體2)之抗體藥物結合物(ADC)與免疫檢查點抑制劑組合於治療泌尿上皮癌中之用途。
泌尿上皮癌(UC;或移行性細胞癌,TCC)為通常於泌尿系統:腎、膀胱及附屬器官中出現之一種癌症。其最常見類型為膀胱癌以及輸尿管、尿道及臍尿管癌。其第二常見類型為腎癌,佔所有原發性腎惡性腫瘤之5至10%。(en.wikipedia.org:https://en.wikipedia.org/wiki/Transitional_cell_carcinoma)。
尿道上皮(亦稱作移行性上皮)為膀胱、輸尿管及尿道之內側,及腎盂(腎臟之一部分,於其中收集尿液)之內襯。其由泌尿上皮細胞及移行性細胞組成。此等細胞可變成癌細胞,即,稱作泌尿上皮癌(或移行性細胞癌)。
取決於癌細胞之侵襲力,泌尿上皮癌可係非侵襲性(僅於膀胱之內襯中)或侵襲性(生長至膀胱壁之其他層)。在此等中,非侵襲性泌尿上皮癌僅於膀胱之內膜中生長且不於膀胱壁中更深生長。在診斷時,50至60%患有泌尿上皮癌之患者之腫瘤係非侵襲性。非侵襲性泌尿上皮癌之類型包括:非侵襲性鱗狀泌尿上皮癌(亦稱作原位癌)、高惡性度非侵襲性乳頭狀泌尿上皮癌、及具有低惡性度惡性腫瘤之非侵襲性乳頭狀泌尿上皮癌,其中具有低惡性潛力之非侵襲性乳頭狀泌尿上皮腫瘤較少可能發展成侵襲性癌症。
相比之下,侵襲性泌尿上皮癌自膀胱內膜生長至膀胱壁之更深層,諸如結締組織(稱作固有層)及肌肉層(稱作肌層)。在診斷時,40至50%患有泌尿上皮癌之患者之腫瘤係侵襲性。
理論上,泌尿上皮癌可於尿道之任何位置(包括但不限於腎盂、輸尿管、膀胱或尿道)開始。
當相關腫瘤細胞尚未轉移時,手術切除為較佳治療選項。針對具有轉移性腫瘤之患者,一般需求抗癌藥物治療。目前一線療法為吉西他濱(gemcitabine)及順鉑(cisplatin)之組合療法。然而,放射療法於泌尿上皮癌中效果不佳及一般用作輔助療法。當治療腎盂/輸尿管上皮癌時,可使用BCG注射療法(牛分支桿菌(
Mycobacterium bovis)之導管注射)。
泌尿上皮癌轉移及頻繁復發。根治性膀胱切除術為具有涉及肌層之腫瘤之患者之第一選擇,及於手術後需要嚴格及定期審查。因此,其治療係困難且復發率高。(Li Xuesong、Wang Gang及Zhang Qian編輯,Essence of Urology Cases, Peking University Medical Press, 2017)。於手術後早期(於24小時內)以單劑量或於手術後若干週以六劑量方案向膀胱投與絲裂黴素(Mitomycin) (化療藥物)亦為一些患者之治療選項。
於歐洲已批准長春氟寧(Vinflunine)用於治療泌尿上皮晚期或轉移性TCC (Bellmunt, J.等人,J Clin Oncol. 27(27): 4454-4461 (2009))。當以單劑療法測試時,若干藥劑已顯示中等活性,具有5至10個月之中值生存期(Yafi, F.A.等人,Current Oncol. 18(1): e25-e34 (2011))。於轉移性環境下,向患有移行性細胞癌之患者投與多西他賽(docetaxel)作為緩和選項(NCCN 2014)。此外,基於來自2期研究(WO2016/064649A1)之證據,美國及加拿大醫學界讚同多西他賽作為晚期疾病之治療方案。
於最近幾年中,用於治療泌尿上皮癌之新穎藥物主要包括:
1. Roche之阿特珠單抗(Atezolizumab) (2016),歐盟批准之首個抗PD-L1癌症免疫療法藥物,其可用於治療轉移性泌尿上皮癌。被分配至實驗組之患者之客觀緩解率(ORR)為63%,而化療組之患者之ORR為21%。來自IMvigor210研究之隊組之結果顯示阿特珠單抗小組中之15.9個月之中值總生存期(OS)。阿特珠單抗之常見不良反應包括疲勞、食慾下降、噁心、呼吸困難、腹瀉(18.6%)、發熱、皮疹、嘔吐、關節痛、虛弱及發癢。
2. Bristol-Myers Squibb之納武單抗(Nivolumab) (2017),由US FDA批准用於患有局部晚期或轉移性泌尿上皮癌之患者。納武單抗為抗PD-1單株抗體。臨床數據顯示,客觀緩解率(ORR)為19.6%,中值治療持續時間為3.3個月(時間範圍:0至13.4個月),及54%之患者經歷嚴重不良事件。具有至少2%之發生率之最常見嚴重不良事件包括尿道感染、膿毒症、腹瀉、小腸梗阻及一般健康惡化。最常見不良反應包括疲勞、肌肉及骨痛、噁心及食慾下降。由於於17%之患者中之不良反應,中止納武單抗治療,及由於不良反應,於46%之患者中延遲給藥。由於肺炎或心血管衰竭,治療相關之死亡於4名患者中發生。
3. Johnson & Johnson’s Janssen之厄達替尼(erdafitinib),纖維母細胞生長因子受體(FGFR)酪胺酸激酶抑制劑,由US FDA (2018)批准用於治療泌尿上皮癌。研究結果顯示,厄達替尼於患有復發/難治性轉移性泌尿上皮癌之59名患者中具有42%之客觀緩解率(ORR),該等患者之腫瘤具有FGFR突變(Janssen宣佈厄達替尼於治療轉移性泌尿上皮癌中之U.S. FDA突破療法認定)。
4. Padcev (維汀-恩弗妥單抗(enfortumab vedotin)),由US FDA於2019年12月批准用於患有局部晚期或轉移性泌尿上皮癌之患者,該等患者先前已接受PD-1/L1抑制劑之治療且已於新輔助/輔助療法中或於治療局部晚期或轉移性疾病中接受以鉑為主之化療方案。數據顯示,Padcev治療於大多數患者中快速收縮腫瘤,具有44% (55/125,95% CI:35.1至53.2)之客觀緩解率,12% (15/125)之完全緩解率及7.6個月(範圍:0.95至11.3+)之中值緩解持續時間。Padcev為靶向於膀胱癌中高度表現之細胞表面蛋白之第一類ADC。該藥物藉由結合靶向黏連蛋白(Nectin)-4之人類IgG1單株抗體恩弗妥單抗與細胞毒性劑MMAE (單甲基澳瑞他汀(auristatin) E,微管干擾劑)來製備。
5.抗體-藥物結合物(即,維迪西妥單抗(Disitamab vedotin)),其可特異性結合至HER2標靶且具有由公開案號CN105008398A之中國專利揭示之為MMAE之藥物部分。目前,正在探索該藥物作為各種HER2表現(IHC 1+或以上)癌症適應症(包括乳癌,諸如胃癌及泌尿上皮癌)及HER2低表現(IHC 2+/FISH-或IHC 1+)癌症適應症(諸如HER2低表現乳癌)之治療。於2020年9月,U.S. FDA亦對維迪西妥單抗用於HER2表現(IHC 2+或IHC 3+)局部晚期或轉移性泌尿上皮癌適應症之第二線治療授予突破療法認定。
目前,針對轉移性泌尿上皮癌(mUC)之第一線化療之ORR為約50%,及鉑不耐受患者之第一線治療之維汀-恩弗妥單抗組合免疫的ORR (EV-103研究)於海外國家經報導為73.3%。
本文中引用之所有參考文獻(包括專利申請案、專利公開案及UniProtKB/Swiss-Prot寄存編號)之全文係以引用的方式併入本文中,如同明確且個別指定各個別參考文獻以引用的方式併入般。
本發明提供利用抗HER2抗體-藥物結合物(ADC)及免疫檢查點抑制劑治療泌尿上皮癌患者之方法及用途。此等方法及用途至少部分基於本文中所呈現之動物模型及臨床數據之深入分析,其證實申請者之出人意料發現,Her2抗體-藥物結合物(ADC)及免疫檢查點抑制劑組合於治療泌尿上皮癌中,尤其於患有局部晚期或轉移性泌尿上皮癌之患者中具有協同效應,及與現有標準療法相比之臨床效益。ORR隨著HER2或PD-L1之更高表現而增加。此外,針對具有低HER2 IHC表現(1+)之患者,組合治療仍具有良好功效。
例如,維迪西妥單抗及PD-L1抗體之組合具有對經皮下移植HT-29之腫瘤之增殖抑制的協同效應。此外,於維迪西妥單抗與PD-1抗體(特瑞普利單抗(Toripalimab))組合之臨床試驗中,結果指示組合療法與單獨單一治療相比產生改善之患者結果,特定言之關於PFS。
本文中提供抗體-藥物結合物(ADC)與免疫檢查點抑制劑組合於製備用於治療泌尿上皮癌患者之藥劑中的用途,其中該抗體-藥物結合物具有通式Ab-(L-U)
n之結構,其中Ab表示抗Her2 (人類表皮生長因子受體2)抗體;L表示連接子;U表示結合之細胞毒性分子;且n為1至8之整數,及表示鍵結至各抗體之細胞毒性分子之數目,且其中:該抗體包含重鏈可變區及輕鏈可變區,其中該重鏈可變區之CDR及/或該輕鏈可變區之CDR具有與維迪西妥單抗相同之CDR序列;該連接子L包括馬來醯亞胺基-己醯基-纈胺酸-瓜胺酸-對胺基苄氧基(mc-vc-pAB),其中該連接子藉助巰基結合共價連接至該抗體,及該連接位點為該抗體之鏈間二硫鍵位點;該細胞毒性分子U包括MMAE (單甲基澳瑞他汀E);及該免疫檢查點抑制劑為PD-1抗體或PD-L1抗體。
本文中亦提供治療泌尿上皮癌患者之方法,其包括向該患者投與有效量之抗體-藥物結合物(ADC)及免疫檢查點抑制劑,其中該抗體-藥物結合物具有通式Ab-(L-U)
n之結構,其中Ab表示抗Her2 (人類表皮生長因子受體2)抗體;L表示連接子;U表示結合之細胞毒性分子;且n為1至8之整數,及表示鍵結至各抗體之細胞毒性分子之數目,且其中:該抗體包含重鏈可變區及輕鏈可變區,其中該重鏈可變區之CDR及/或該輕鏈可變區之CDR具有與維迪西妥單抗相同之CDR序列;該連接子L包括馬來醯亞胺基-己醯基-纈胺酸-瓜胺酸-對胺基苄氧基(mc-vc-pAB),其中該連接子藉助巰基結合共價連接至該抗體,及該連接位點為該抗體之鏈間二硫鍵位點;該細胞毒性分子U包括MMAE (單甲基澳瑞他汀E);及該免疫檢查點抑制劑為PD-1抗體或PD-L1抗體。
於以上所有之一些實施例中,該患者針對HER2表現陽性。於以上所有之一些實施例中,自該患者之泌尿上皮癌獲得之樣品係HER2陽性。於以上所有之一些實施例中,基於免疫組織化學(IHC)分析自該患者之泌尿上皮癌獲得之該樣品係HER2陽性。於以上所有之一些實施例中,自該患者之泌尿上皮癌獲得之該樣品之HER2表現為IHC 3+或IHC 2+。於以上所有之一些實施例中,該患者針對PD-L1或PD-1表現係陽性。
於以上所有之一些實施例中,該抗體包含重鏈可變(VH)區及輕鏈可變(VL)區;其中該VH區包含包含GYTFTDYY (
SEQ ID NO:3)之胺基酸序列之HCDR1,包含VNPDHGDS (
SEQ ID NO:4)之胺基酸序列之HCDR2,及包含ARNYLFDH (
SEQ ID NO:5)之胺基酸序列之HCDR3;且其中該VL區包含包含QDVGTA (
SEQ ID NO:6)之胺基酸序列之LCDR1,包含WAS (
SEQ ID NO:7)之胺基酸序列之LCDR2,及包含HQFATYT (
SEQ ID NO:8)之胺基酸序列之LCDR3。於以上所有之一些實施例中,該抗體包含重鏈可變(VH)區及輕鏈可變(VL)區;其中該VH區包含包含DYYIH (
SEQ ID NO:31)之胺基酸序列之HCDR1,包含RVNPDHGDSYYNQKFKD (
SEQ ID NO:32)之胺基酸序列之HCDR2及包含ARNYLFDHW (
SEQ ID NO:33)之胺基酸序列之HCDR3;且其中該VL區包含包含KASQDVGTAVA (
SEQ ID NO:34)之胺基酸序列之LCDR1,包含WASIRHT (
SEQ ID NO:35)之胺基酸序列之LCDR2及包含HQFATYT (
SEQ ID NO:8)之胺基酸序列之LCDR3。於以上所有之一些實施例中,該抗體包含重鏈可變(VH)區及輕鏈可變(VL)區,該抗體為鼠科、嵌合或人源化抗體。於以上所有之一些實施例中,該抗體包含重鏈可變(VH)區及輕鏈可變(VL)區;其中該VH區包含EVQLVQSGAEVKKPGATVKISCKVSGYTFTDYYIHWVQQAPGKGLEWMGRVNPDHGDSYYNQKFKDKATITADKSTDTAYMELSSLRSEDTAVYFCARNYLFDHWGQGTLVTVSS (
SEQ ID NO:9)之胺基酸序列;且其中該VL區包含DIQMTQSPSSVSASVGDRVTITCKASQDVGTAVAWYQQKPGKAPKLLIYWASIRHTGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCHQFATYTFGGGTKVEIK (
SEQ ID NO:10)之胺基酸序列。於以上所有之一些實施例中,該抗體為人類IgG抗體。於以上所有之一些實施例中,該抗體為人類IgG1、IgG2及IgG4抗體。於以上所有之一些實施例中,該抗體之重鏈之胺基酸序列為SEQ ID NO:1,及該抗體之輕鏈之胺基酸序列為SEQ ID NO:2。
於以上所有之一些實施例中,該抗體-藥物結合物為維迪西妥單抗或其生物類似物。於以上所有之一些實施例中,該抗體-藥物結合物之平均DAR (即,藥物抗體比率)值為2至7之任何數字。於以上所有之一些實施例中,該平均DAR值為4 ± 0.5。
於以上所有之一些實施例中,該免疫檢查點抑制劑為PD-1抗體。於以上所有之一些實施例中,該PD-1抗體為特瑞普利單抗、多塔利單抗(Dostarlimab)、普高利單抗(Prolgolimab)、替雷利珠單抗(Tislelizumab)、卡瑞利珠單抗(Camrelizumab)、信迪利單抗(Sintilimab)、西米單抗(Cemiplimab)、派立珠單抗(Pembrolizumab)、納武單抗、派安普利單抗(Penpulimab)、格諾利單抗(Genolimzumab)、津貝利單抗(Zimberelimab)或巴替利單抗(Balstilimab)。於以上所有之一些實施例中,該免疫檢查點抑制劑為PD-L1抗體。於以上所有之一些實施例中,該免疫檢查點抑制劑為PD-L1抗體,其為德瓦魯單抗(Durvalumab)、阿維單抗(Avelumab)、阿特珠單抗、恩沃利單抗(Envafolimab)或RC98。
於以上所有之一些實施例中,該患者先前已接收諸如化療藥物、靶向療法、免疫療法或內分泌療法之一或多種先前治療。於以上所有之一些實施例中,該泌尿上皮癌患者為患有不可手術切除之局部晚期泌尿上皮癌之患者、患有局部晚期或轉移性泌尿上皮癌之患者、患有HER2陽性泌尿上皮癌之患者、患有HER2陽性局部晚期或轉移性泌尿上皮癌之患者、或不可耐受以鉑為主之化療之泌尿上皮癌患者。於以上所有之一些實施例中,該泌尿上皮癌患者為患有不可切除局部晚期或轉移性泌尿上皮癌之患者。於以上所有之一些實施例中,該泌尿上皮癌患者為針對不適合以順鉑為主之化療或已拒絕以順鉑為主化療之患者。於以上所有之一些實施例中,該泌尿上皮癌患者為於化療後進展之患者。於以上所有之一些實施例中,該泌尿上皮癌患者為於完成新輔助或輔助以順鉑為主化療之12個月內經歷疾病進展之患者。
於以上所有之一些實施例中,該藥劑經鼻內、經皮下、經皮內、經肌肉內或經靜脈內投與。於以上所有之一些實施例中,該ADC係以1.5 mg/kg或2.0 mg/kg之劑量投與。於以上所有之一些實施例中,每2週或14天投與該ADC。
於以上所有之一些實施例中,該抗體-藥物結合物及免疫檢查點抑制劑至該泌尿上皮癌患者之投與導致大於7.5個月之無進展生存期(PFS)。
應瞭解,可組合本文中所述之各種實施例之性質中之一者、一些或所有以形成本發明之其他實施例。本發明之此等及其他態樣將對熟習此項技術者變得顯然。藉由跟隨實施方式進一步描述本發明之此等及其他實施例。
相關申請案之交互參照
本申請案主張2021年5月21日申請之中國申請案第202110559728.8號之優先權,其全文係以引用的方式併入本文中。
I. 定義
除非另有指定,否則本文中所用之所有技術及科學術語具有與一般技術者所理解相同之含義。針對該領域中之定義及術語,專業人士可參考Current Protocols in Molecular Biology (Ausubel)。
用於本發明之胺基酸之三字母及一字母代碼係如T J. biol. chem, 243,第3558頁 (1968)中所述。
於本發明中,抗體之可變域之互補決定區(CDR)之測定或編號方法包括IMGT及Kabat系統,其於此項技術中熟知。
用於本發明之「
抗體」包含各種抗體結構,包括(但不限於)單株抗體、多株抗體、多特異性抗體(例如,雙特異性抗體)及抗原結合片段。用於本發明之「
抗原結合片段」係指包含抗體之重鏈可變區或輕鏈可變區且足以保留與其源抗體相同之結合特異性及足夠親和力之抗體片段。特定言之,抗原結合片段包括Fab、F(ab’)及F(ab’)2,其含有足以使特定抗原結合至多肽之至少一個免疫球蛋白片段。以上片段可藉由合成,或藉由酶方法,或藉由完整免疫球蛋白之化學切割,或藉由使用重組DNA技術遺傳工程改造來製備。以上片段之生產方法係此項技術中熟知。
如本發明中所用,術語「
鼠科抗體」為根據此項技術中之知識及能力製備之單株抗體。在製備期間,將相應抗原注射至測試個體,及然後將表現具有所需序列或功能特徵之抗體之雜交瘤分離。於一些實施例中,該鼠科抗體或其抗原結合片段可進一步包含鼠科κ或λ鏈或其變異體之輕鏈恆定區,或進一步包含鼠科IgG1、IgG2、IgG3或其變異體之重鏈恆定區。
如本發明中所用,術語「
嵌合抗體」為鼠科抗體之可變區與人類抗體之恆定區之融合,及可降低藉由鼠科抗體誘導之免疫反應之抗體。當建立嵌合抗體時,首先建立分泌鼠科特異性單株抗體之雜交瘤。然後,自鼠科雜交瘤細胞選殖可變區基因,及視需要,自人類抗體選殖恆定區基因。將小鼠可變區基因及人類恆定區基因連接以形成嵌合基因及插入人類載體。最後,於真核工業體系或原核工業體系中表現嵌合抗體分子。於一些實施例中,嵌合抗體之抗體輕鏈進一步包含人類κ或λ鏈或其變異體之輕鏈恆定區。嵌合抗體之抗體重鏈可進一步包含人類IgG1、IgG2、IgG3、IgG4或其變異體之重鏈恆定區。人類抗體之恆定區可選自人類IgG1、IgG2、IgG3或IgG4或其變異體之重鏈恆定區,及包含人類IgG2或IgG4之重鏈恆定區。或者,使用於胺基酸突變發生後不具有ADCC毒性(抗體依賴性細胞介導之細胞毒性)之IgG4。
如本發明中所用,術語「
人源化抗體」,亦稱作CDR接枝之抗體係指藉由將小鼠CDR序列接枝至人類抗體可變區框架(即,不同類型之人類生殖系抗體框架序列)產生之抗體。其包含源自非人類抗體之CDR區及抗體分子之其餘部分係源自一種人類抗體(或若干人類抗體)。此外,為保留結合親和力,可修改框架區(稱作FR)片段之一些殘基(Jones等人,Nature, 321:522-525, 1986;Verhoeyen等人,Science, 239:1534-1536, 1988;及Riechmann等人,Nature, 332:323-327, 1988)。根據本發明之人源化抗體或其片段可藉由熟習此項技術者已知之技術製備(例如,如Singer等人,J. Immun.150: 2844-2857, 1992;Mountain等人,Biotechnol. Genet. Eng. Rev., 10: 1-142, 1992;或Bebbington等人,Bio/Technology, 10: 169-175, 1992中所述)。
如本發明中所用,術語「
平均 DAR」值,即藥物抗體比率係指於抗體-藥物結合物製劑中連接至抗體之藥物數目之平均值。
如本發明中所用,術語「
巰基結合」係指連接子共價連接至抗體上之游離巰基之結合方式。半胱胺酸於抗體中以二硫鍵之形式存在,及於IgG抗體中存在4對鏈間二硫鍵,其容易被還原。因此,在抗體-藥物結合物之製備期間,IgG抗體中之4對鏈間二硫鍵被頻繁還原,其產生以上提及之「抗體上之游離巰基」。此外,因為於IgG抗體中存在4對鏈間二硫鍵,當其被還原時,將產生最多8個游離巰基。因此,IgG抗體最多具有8個巰基結合位點。因此,當於通式Ab-(L-U)
n之抗體-藥物結合物中n為1時,「L-U」可共價連接至8個巰基結合位點之任何1個位點;相似地,當n為2時,「L-U」可共價連接至8個巰基結合位點之任何2個位點;當n為3時,「L-U」可連接至8個巰基結合位點之任何3個位點;當n為4時,「L-U」可共價連接至8個巰基結合位點之任何4個位點;當n為5時,「L-U」可共價連接至8個巰基結合位點之任何5個位點;當n為6時,「L-U」可共價連接至8個巰基結合位點之任何6個位點;當n為7時,「L-U」可共價連接至8個巰基結合位點之任何7個位點;當n為8時,「L-U」可共價連接至8個巰基結合位點。
II. 用途及方法
本發明之某些態樣係關於結合HER2之抗體-藥物結合物(以及其方法及用途)。於一些實施例中,所涉及之抗體-藥物結合物具有通式Ab-(L-U)n之結構,其中Ab表示抗HER2 (人類表皮生長因子受體2)抗體;L表示連接子;U表示結合之細胞毒性分子;且n為1至8之整數(例如,1、2、3、4、5、6、7、8),及表示鍵結至各抗體之細胞毒性分子之數目。
於一些實施例中,該細胞毒性分子為澳瑞他汀或其類似物或衍生物。澳瑞他汀為天然產物朵拉司他汀(dolastatin)之衍生物。示例性澳瑞他汀包括朵拉司他汀-10、澳瑞他汀E、澳瑞他汀T、MMAE (N-甲基纈胺酸-纈胺酸-朵拉異白胺酸-朵拉脯胺酸-去甲麻黃鹼或單甲基澳瑞他汀E)及MMAF (N-甲基纈胺酸-纈胺酸-朵拉異白胺酸-朵拉脯胺酸-苯丙胺酸或多纈胺酸(dovaline)-纈胺酸-朵拉異白胺酸-朵拉脯胺酸-苯丙胺酸)、AEB (藉由澳瑞他汀E與對乙醯基苯甲酸反應產生之酯)、AEVB (藉由澳瑞他汀E與苯甲醯基戊酸反應產生之酯)及AFP (二甲基纈胺酸-纈胺酸-朵拉異白胺酸-朵拉脯胺酸-苯丙胺酸-對苯二胺或澳瑞他汀苯丙胺酸苯二胺)。WO 2015/057699描述經PEG化之澳瑞他汀,包含MMAE。考慮使用之另外朵拉司他汀衍生物揭示於美國專利第9,345,785號中,出於任何目的,其以引用的方式併入本文中。
於一些實施例中,該細胞毒性分子為MMAE。於其他實施例中,該細胞毒性劑為MMAF。
於一些實施例中,藉由本發明提供之抗體-藥物結合物中之抗HER2 (人類表皮生長因子受體2)抗體或其功能片段包含重鏈可變區及輕鏈可變區,其中該重鏈可變區之CDR及/或該輕鏈可變區之CDR具有與維迪西妥單抗相同之CDR序列;該連接子L包括馬來醯亞胺基-己醯基-纈胺酸-瓜胺酸-對胺基苄氧基(mc-vc-pAB);及該細胞毒性分子U包括MMAE (單甲基澳瑞他汀E)。
於一些實施例中,該連接子L藉助巰基結合共價連接至抗體,及連接位點為抗體之鏈間二硫鍵位點。
於一些較佳實例中,本發明之抗體-藥物結合物為連接2至7個細胞毒性分子之抗體-藥物結合物之混合物,其中抗體-藥物結合物之平均DAR (即,藥物對抗體比率)值為2至7之任何數字;更佳地,本發明之抗體-藥物結合物之平均DAR值約等於2、3、4、5、6或7。於本發明之一些特定實例中,本發明之抗體-藥物結合物之平均DAR值為4 ± 0.5。
更具體而言,本發明之抗體-藥物結合物為維迪西妥單抗,其為靶向HER2標靶之抗體-藥物結合物,其中該連接子部分L為馬來醯亞胺基-己醯基-纈胺酸-瓜胺酸-對胺基苄氧基(mc-vc-pAB);該細胞毒性分子U包括MMAE (單甲基澳瑞他汀E);該連接子L藉助巰基結合共價連接至抗體;且平均DAR值為4 ± 0.5。
於一些實施例中,本發明中涉及之抗HER2抗體之重鏈可變區及輕鏈可變區之對應CDR 1至3係如下(IMGT編號):
表 1 IMGT
表2 Kabat
HCDR1: | GYTFTDYY | SEQ ID NO: 3 |
HCDR2: | VNPDHGDS | SEQ ID NO: 4 |
HCDR3: | ARNYLFDH | SEQ ID NO: 5 |
LCDR1: | QDVGTA | SEQ ID NO: 6 |
LCDR2: | WAS | SEQ ID NO: 7 |
LCDR3: | HQFATYT | SEQ ID NO: 8 |
HCDR1: | DYYIH | SEQ ID NO: 31 |
HCDR2: | RVNPDHGDSYYNQKFKD | SEQ ID NO: 32 |
HCDR3: | ARNYLFDHW | SEQ ID NO: 33 |
LCDR1: | KASQDVGTAVA | SEQ ID NO: 34 |
LCDR2: | WASIRHT | SEQ ID NO: 35 |
LCDR3: | HQFATYT | SEQ ID NO: 8 |
於一些實施例中,該抗HER2抗體包含由
SEQ ID NO:3 至 8表示之重鏈可變區及輕鏈可變區之對應CDR 1至3,但是相對於
SEQ ID NO:3 至 8具有1、2或3個取代(例如,保守取代)、插入或缺失,但是包含該序列之抗HER2抗體保留結合至HER2之能力。於一些實施例中,該抗HER2抗體包含由
SEQ ID NO:31 至 35 及 8表示之重鏈可變區及輕鏈可變區之對應CDR 1至3,但是相對於
SEQ ID NO:31 至 35 及 8具有1、2或3個取代(例如,保守取代)、插入或缺失,但是包含該序列之抗HER2抗體保留結合至HER2之能力。
於一些實施例中,藉由本發明提供之抗體-藥物結合物中之抗HER2 (人類表皮生長因子受體2)抗體為鼠科、嵌合、人源化或全人類抗體,較佳地人源化單株抗體。於一些實施例中,該抗體為單株抗體。
於一些實施例中,藉由本發明提供之抗體-藥物結合物中之抗HER2 (人類表皮生長因子受體2)抗體為IgG,包含IgG1、IgG2、IgG3及IgG4,及更佳地IgG1、IgG2及IgG4。
於一些實施例中,該抗HER2抗體包含重鏈可變(VH)區及輕鏈可變(VL)區;其中該VH區包含與序列EVQLVQSGAEVKKPGATVKISCKVSGYTFTDYYIHWVQQAPGKGLEWMGRVNPDHGDSYYNQKFKDKATITADKSTDTAYMELSSLRSEDTAVYFCARNYLFDHWGQGTLVTVSS (
SEQ ID NO:9)具有至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%或100%同一性之胺基酸序列;及/或其中該VL區包含與序列DIQMTQSPSSVSASVGDRVTITCKASQDVGTAVAWYQQKPGKAPKLLIYWASIRHTGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCHQFATYTFGGGTKVEIK (
SEQ ID NO:10)具有至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%或100%同一性之胺基酸序列。於某些實施例中,該VH序列(例如,具有與
SEQ ID NO:9至少90%、91%、92%、93%、94%、95%、96%、97%、98%或99%同一性)相對於
SEQ ID NO:9含有取代(例如,保守取代)、插入或缺失,但是包含該序列之抗HER2抗體保留結合至HER2之能力。於某些實施例中,
SEQ ID NO: 9中之總計1至10個胺基酸已經取代、插入及/或缺失。於某些實施例中,取代、插入或缺失於CDR外部區域中(即,於FR中)發生。於某些實施例中,該VL序列(例如,具有與
SEQ ID NO:10至少90%、91%、92%、93%、94%、95%、96%、97%、98%或99%同一性)相對於
SEQ ID NO:10含有取代(例如,保守取代)、插入或缺失,但是包含該序列之抗HER2抗體保留結合至HER2之能力。於某些實施例中,
SEQ ID NO: 10中之總計1至10個胺基酸已經取代、插入及/或缺失。於某些實施例中,取代、插入或缺失於CDR外部區域中(即,於FR中)發生。
於一些實施例中,該抗體包含重鏈可變(VH)區及輕鏈可變(VL)區;其中該VH區包含EVQLVQSGAEVKKPGATVKISCKVSGYTFTDYYIHWVQQAPGKGLEWMGRVNPDHGDSYYNQKFKDKATITADKSTDTAYMELSSLRSEDTAVYFCARNYLFDHWGQGTLVTVSS (
SEQ ID NO:9)之胺基酸序列;且其中該VL區包含DIQMTQSPSSVSASVGDRVTITCKASQDVGTAVAWYQQKPGKAPKLLIYWASIRHTGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCHQFATYTFGGGTKVEIK (
SEQ ID NO:10)之胺基酸序列。
於一些實施例中,本發明中涉及之抗體-藥物結合物中之抗體Ab之重鏈胺基酸序列示於
SEQ ID NO: 1中,及其輕鏈胺基酸序列示於
SEQ ID NO: 2中。於一些實施例中,該重鏈包含
SEQ ID NO:1之胺基酸序列,不具有C端離胺酸。
重鏈胺基酸序列 - SEQ ID NO: 1 輕鏈胺基酸序列 - SEQ ID NO: 2
用途及方法之某些態樣係關於免疫檢查點抑制劑。示例性PD-1抗體包括特瑞普利單抗、多塔利單抗、普高利單抗、替雷利珠單抗、卡瑞利珠單抗、信迪利單抗、西米單抗、派立珠單抗、納武單抗、派安普利單抗、格諾利單抗、津貝利單抗及巴替利單抗。示例性PD-L1抗體包括德瓦魯單抗、阿維單抗、阿特珠單抗及恩沃利單抗。
抗體-藥物結合物及免疫檢查點抑制劑可以任何順序投與。例如,抗體-藥物結合物及免疫檢查點抑制劑可依序(在不同時間)或合併(在相同時間)投與。於一些實施例中,抗體-藥物結合物及免疫檢查點抑制劑係於分開組合物中。於一些實施例中,抗體-藥物結合物及免疫檢查點抑制劑係於相同組合物中。
於一些實施例中,本發明之患者先前已接受一或多種先前治療,諸如化療藥物、靶向療法、免疫療法及內分泌療法。
於一些實施例中,該患者為患有不可手術切除之局部晚期泌尿上皮癌者、患有局部晚期或轉移性泌尿上皮癌者、患有HER2陽性泌尿上皮癌者、患有HER2陽性局部晚期或轉移性泌尿上皮癌者、或不可耐受以鉑為主之化療者。
於一些實施例中,本發明之患者為化療失敗之患者。
實例
以下實例為但是不意欲限制本發明之範圍。根據習知方法及條件或根據產品說明書選擇針對下列實例中之特定條件未指定之實驗方法。
實例 1 維迪西妥單抗 (RC48) 與 PD‑L1 抗體組合之協同治療效應
所用之PD-L1抗體(RC98)揭示於WO2021/037007A1中。重鏈胺基酸序列述於
SEQ ID NO: 21中,及輕鏈胺基酸序列述於
SEQ ID NO: 22中。該抗體之重鏈之CDR1至3序列述於
SEQ ID NO: 23 至 25中,該抗體之輕鏈之CDR1至3序列述於
SEQ ID NO: 26 至 28中,重鏈胺基酸序列之可變區述於
SEQ ID NO: 29中,及輕鏈胺基酸序列之可變區述於
SEQ ID NO: 30中。
評價對來自植入人類PBMC之NSG小鼠(來源:Biocytogen jiangsu Co., Ltd.)之人類結腸癌細胞HT-29 (來源:ATCC)之經皮下移植的腫瘤的生長是否存在協同抑制效應。
方法:將2×10
6個人類結腸癌細胞HT-29接種至靠近NSG小鼠背部之右腋窩。當腫瘤體積生長至約100至300 mm
3時,於各NSG小鼠中靜脈內植入5×10
6個人類PBMC。第二天,根據腫瘤體積將小鼠隨機分成4組,命名為對照(鹽水)組、RC98 (10 mg/kg)組、RC48-ADC (2 mg/kg)組及RC98 (10 mg/kg)及RC48-ADC (2 mg/kg)組合投與組,各組中具有5隻實驗動物。每週一次向來自對照(鹽水)組之小鼠靜脈內投與氯化鈉注射液總計2次;每週兩次對來自RC98組之小鼠經腹膜內給藥總計8次;每週一次對來自RC48-ADC組之小鼠經靜脈內給藥總計2個劑量;及針對RC98及RC48-ADC組合投與組,每週兩次向小鼠經腹膜內投與RC98總計8次,及每週一次經靜脈內投與RC48-ADC總計2次。基於用於計算兩種藥物是否具有協同效應之公式:Q=P0/[P(A)+P(B)-P(A)P(B)],評價RC48-ADC及RC98之組合是否對經皮下移植HT-29之腫瘤之生長具有協同抑制效應。
表 3 荷瘤小鼠之腫瘤體積之變化 ( 平均值 ±
SEM)
註釋:與對照組相比,**P<0.01;與RC98組相比,
△△<0.01;及與RC48-ADC相比,
#P<0.05。
組 | 劑量 (mg/kg) | TV (mm 3) | T/C (%) | TGI RTV(%) | 腫瘤重量 (g) | TGI TW(%) | 使用 TGI RTV(%) 作為效應指數以計算 Q 值 | 使用 TGI TW 作為效應指數以計算 Q 值 | |
D0 | D29 | ||||||||
對照 ( 鹽水 ) | -- | 254.4 ± 21.9 | 1846.7 ± 109.8 | -- | 2.08 ± 0.12 | -- | 1.5 | 2.0 | |
RC98 | 10 | 253.2 ± 20.9 | 1697.5 ± 146.2 | 91 | 9 | 2.03 ± 0.19 | 3 | ||
RC48-ADC | 2 | 257.3 ± 21.1 | 1577.7 ± 121.9 | 85 | 15 | 1.70 ± 0.15 | 18 | ||
RC98 及 RC48-ADC | 10及2 | 259.0 ± 23.6 | 1214.4 ± 127.3** | 65 | 35 | 1.22 ± 0.13 ** △△ # | 41 |
結果:(1)在試驗期間,於動物之各組中未發現藥物相關之重量損失。(2)腫瘤體積量測之結果顯示,在RC98組或RC48-ADC組與對照組之間不存在統計差異(P>0.05),及在組合投與組與對照組之間之統計差異極其顯著(P<0.01)。(3)腫瘤質量檢測之結果顯示,在RC98組或RC48-ADC組與對照組之間不存在統計差異(P>0.05),及腫瘤抑制率(TGITW%)各自為3%及18%。在組合投與組與對照組之間之統計差異極其顯著(P<0.01),及腫瘤抑制率(TGITW%)為41%。(4)基於用於計算兩種藥物之間是否存在協同效應Q值之公式:Q=P0/[P(A)+P(B)-P(A)P(B)],藉由使用相對腫瘤抑制率(TGIRTV)作為效應指數計算Q=1.5,或藉由使用腫瘤抑制率(TGITW)作為效應指數計算Q=2.0。
結論:RC98及RC48-ADC之組合對來自植入人類PBMC之NSG小鼠之人類結腸癌細胞HT-29之經皮下移植的腫瘤具有顯著抑制效應。藉由使用兩種不同效應指數計算之Q值均大於1.2。可斷定RC98及RC48-ADC之組合具有對經皮下移植HT-29之腫瘤之增殖抑制之協同效應。
實例 2 利用 維迪西妥單抗 (RC48) 與 PD-1 抗體 ( 特瑞普利單抗, JS001) 組合治療之臨床試驗:中期分析
RC48與抗PD-1單株抗體(特瑞普利單抗,JS001)組合係用於治療mUC,包括於一線治療中不可耐受以鉑為主之化療之患者。
特瑞普利單抗之重鏈胺基酸序列述於
SEQ ID NO: 11中,及其輕鏈胺基酸序列述於
SEQ ID NO: 12中。該抗體之重鏈之CDR1至3序列述於
SEQ ID NO: 13 至 15中,該抗體之輕鏈之CDR1至3序列述於
SEQ ID NO: 16 至 18中,重鏈胺基酸序列之可變區述於
SEQ ID NO: 19中,及輕鏈胺基酸序列之可變區述於
SEQ ID NO: 20中。
關鍵納入標準:● 組織學證實係不可切除、局部晚期或轉移性之泌尿上皮癌;
● 於利用至少1種先前全身化療方案治療後,於完成新輔助或以順鉑為主之輔助化療後之12月內緩慢進展且不能耐受以順鉑為主之化療;及
● ECOG性能狀態為0至1。
給藥方案:● RC48 2.0 mg/kg + JS001 3 mg/kg Q2W (n=3)
● RC48 2.0 mg/kg + JS001 3 mg/kg Q2W (n=13)
● RC48 1.5 mg/kg + JS001 3 mg/kg Q2W (n=3)
表 4 :患者之數據 (%)
特徵 | 總計 (N=19) |
年齡(歲,中值,範圍) | 66 (52,76) |
男性(n,%) | 12 (63.2%) |
ECOG PS狀態(n,%) | |
0 | 4 (21.0%) |
1 | 15 (79.0%) |
HER2表現 | |
IHC 3+ (n,%) | 3 (15.8%) |
IHC 2+ (n,%) | 9 (47.4%) |
IHC 1+ (n,%) | 5 (26.3%) |
IHC 0 (n,%) | 2 (10.5%) |
原發性病變 | |
膀胱(n,%) | 6 (31.6%) |
腎盂(n,%) | 5 (26.3%) |
輸尿管(n,%) | 5 (26.3%) |
多病竈(n%) | 3 (15.8%) |
內臟轉移(n,%) | 14 (73.7%) |
肺(n,%) | 6 (31.6%) |
肝(n,%) | 8 (42.1%) |
先前全身治療 | |
0線(n,%) | 10 (52.6%) |
≥1線(n,%) | 9 (47.4%) |
藉由組合之正分數之PD-L1狀態(CPS,n,%) | |
< 10 | 12 (63.2%) |
≥ 10 | 7 (36.8%) |
治療結果:總計19名患者完成至少一個治療劑量,及17名患者完成至少一個功效評價。結果顯示,客觀緩解率(ORR)為94.1% (16/17),其中3名患者達成完全緩解及13名達成部分緩解。在接受研究治療之19名患者中,所報告之最常見TRAE為厭食症(15,79.0%)、疲勞(13,68.4%)、升高之ALT/AST (11,57.9%)及外周感覺神經病變(11,57.9%)。於表現Her2之患者(Her2 1+、2+或3+)中,ORR達到100%
實例 3 利用維迪西妥單抗 (RC48) 與 PD-1 抗體 ( 特瑞普利單抗, JS001) 組合治療之臨床試驗
此實例包含關於實例2中所述之臨床試驗之進一步細節,以及於招募另外參與者後之數據分析。
轉移性泌尿上皮癌之預後係不良的,及局部晚期或轉移性泌尿上皮癌(la/mUC)之5年生存率為約15%。針對對一線順鉑化療治療不耐受或鉑療法失敗之患者仍存在未滿足的臨床需求。雖然對新穎治療或有效組合療法之需求仍未滿足,但是突破性治療,諸如抗體藥物結合物(ADC)及免疫檢查點抑制劑(ICI)作為單藥療法已達成有前景的功效結果。
臨床前研究顯示,連接至MMAE (單甲基澳瑞他汀E)之ADC引起免疫原性細胞死亡(ICD)且對樹突狀細胞(DC)成熟及活化具有直接效應,其可具有增強之抗腫瘤免疫。最近II期研究評估治療HER2陽性局部晚期或轉移性泌尿上皮癌之兩種重組人源化抗HER2單株抗體-MMAE化合物(下文中統稱作「RC48-ADC」),其顯示積極功效及安全性結果。於NCT03507166研究中,其中RC48-ADC為過度表現HER2 (IHC 2+/3+)之la/mUC之二線治療,cORR為51.2%,mPFS為6.9個月,且mOS為13.9個月。於評估第二RC48-ADC化合物之NCT03809013研究中,其中RC48-ADC為過度表現HER2 (IHC 2+/3+)之la/mUC之二線治療,cORR為50.0%,mPFS為5.1個月,且mOS為14.2個月。於此等研究後,RC48-ADC化合物被FDA及CDE視為突破性療法。
評估稱作特瑞普利單抗(JS001)之抗PD-1單株抗體作為la/mUC之二線治療之功效及安全性之單獨臨床試驗POLARIS-03研究(NCT03113266)證實,cORR為26%,mPFS為2.3個月,及mOS為14.4個月。
設計此實例中所述之研究以建立所述RC48-ADC及JS001組合療法模型之臨床相關性,特定言之以評價RC48-ADC及JS001組合療法於患有晚期或轉移性泌尿上皮癌之患者中之安全性及藥物動力學。
方法
於3+3劑量遞增II期臨床試驗中,RC48-ADC以3.0 mg/kg JS001及1.5 mg/kg或2.0 mg/kg與JS001組合以每兩週(Q2W)注射方式向n = 3個患者投與RC48-ADC化合物以評估任何初始安全性問題。2 mg/kg之RC48-ADC之建議II期劑量(recommended phase II dose;RP2D)係藉由RC48-ADC與標準批准之JS001劑量3 mg/kg組合之初始6名患者安全性導入判定的。然後針對總計n = 41名招募之患者,於擴展階段,總計n = 35名患者接受Q2W 2.0 mg/kg之RC48及3 mg/kg之JS001組合。患者特徵於下
表 5中報告。監測患者以確保無劑量限制毒性(dose limiting toxicity;DLT)出現。針對大多數終點跟蹤患者至多12個月及60週以評估客觀反應率(objective response rate;ORR)以分析共同治療安全性及功效概況,如下所述。
圖 3描述此臨床試驗中所用之研究方法之概述。
納入標準包含:
(a)年齡(≥18歲);
(b)性別(所有);
(c) 患有局部晚期或轉移性惡性泌尿上皮癌的患者,為未經鉑治療及不適合順鉑治療或於至少一個線標準全身化療後進展(包括於新輔助/輔助療法之12個月內進展)
(d)東部合作腫瘤學組(Eastern Cooperative Oncology Group/ECOG)性能狀態(PS) 0或1;
(e)藉由下列標準所界定之適當器官功能之證明:
(i)絕對嗜中性白血球計數(ANC) ≥ 1.0倍正常值上限(ULN)或CrCl < 60 mL/min;
(ii)血小板≥ 100倍10
9/L;
(iii)總血清肌酸酐≤ 1.5倍ULN;
(iv)血清天冬胺酸轉胺酶(AST)及血清丙胺酸轉胺酶(ALT) ≤ 2.5倍ULN,或若肝功能異常係由於潛在惡性病,則AST及ALT ≤ 5倍ULN;正常血清肌酸酐;
(v)左心室射血分數(LVEF) ≥ 50%;及
(vi)血紅蛋白≥ 9 g/dL
排除標準包含:
(a)對RC48-ADC或JS001或其組分過敏;
(b)於開始研究治療之3週內接受抗癌療法,包括化療、放射療法、免疫療法或其他臨床試驗治療;
(c)來自先前抗癌療法之未解決之毒性,除了脫髮;
(d)先前利用HER2-ADC及/或抗PD-1或抗PD-L1或抗PD-L2療法治療;
(e)於研究藥物之第一劑量之4週內經歷大手術且未完全恢復;
(f)於研究藥物之第一劑量之4週內接受疫苗;
(g)在研究開始日期時或於前6個月內臨床顯著心血管疾病活動;
(h)於接受研究藥物之前之3年內其他贅生性疾病之歷史,除解決/可治癒癌症,諸如基底皮膚癌或鱗狀細胞皮膚癌外;
(i)轉移至中樞神經系統(CNS)及/或癌性腦膜炎,除了接受轉移或CNS及/或癌性腦膜炎之治療且具有穩定疾病至少3個月及於研究治療之第一劑量之4週內無進展之證據的患者外;
(j)新轉移或擴大轉移之證據;
(k)於研究治療之第一劑量之4週內利用放射療法、手術或類固醇療法治療;
(l)同種異體造血幹細胞移植或器官移植之歷史;
(m)於研究治療之第一劑量之前之前2年內接受全身類固醇療法;
(n)測試HIV陽性;
(o)活性B型或C型肝炎病毒(HBV或HCV)或結核病感染;
(p)針對根據研究者之判斷認為臨床顯著之其他病症陽性;及
(q)不願或不能參與所有要求之研究評價及程序。
主要結果量度包含RC48-ADC及JS001組合療法之安全性及耐受性之分析以識別患者之建議之劑量。此結果量度包含劑量限制毒性(DLT)及不良事件(AE)之評估。
次要結果量度包含下列:
(a)客觀反應率(ORR);
(b)無進展生存期(PFS);
(c)總生存期(OS);及
(d)藥物動力學(PK)之表徵。
表 5.臨床試驗招募之患者之人口統計學及基線特徵。
安全性
特徵 | N = 41 名患者 |
年齡 ( 歲,中值,範圍 ) | 66.0 (42, 76) |
男性 (n, %) | 22 (53.66%) |
ECOG PS 狀態 (n, %)0 1 | 12 (29.27%) 29 (70.73%) |
原發性病變 (n, %)膀胱 腎盂 輸尿管 尿道 多發性原發性 | 10 (24.39%) 12 (29.27%) 10 (24.39%) 3 (7.32%) 6 (14.63%) |
轉移性病變 (n, %)內臟 肺 肝 骨 | 22 (53.66%) 17 (41.46%) 10 (24.39%) 9 (21.95%) |
先前全身治療 (n, %)0線 ≥ 1線 | 25 (60.98%) 16 (39.02%) |
HER2 表現 (n, %)IHC 3+ IHC 2+ FISH – FISH + IHC 1+ IHC 0 | 5 (12.20%) 19 (46.34%) 16 (39.02%) 3 (7.32%) 14 (34.15%) 3 (7.32%) |
PD-L1 狀態 (n, %)– + | 28 (68.29%) 13 (31.71%) |
HER2 及 PD-L1 表現 (n, %)HER2 IHC (2+/3+),PD-L1(+) HER2 IHC (2+/3+),PD-L1(–) HER2 IHC (1+),PD-L1(+) HER2 IHC (1+),PD-L1(–) HER2 IHC (0),PD-L1(+) HER2 IHC (0),PD-L1(–) | 8 (19.51%) 16 (39.02%) 4 (9.76%) 10 (24.39%) 1 (2.44%) 2 (4.88%) |
顯示RC48-ADC及JS001組合療法於患有la/mUC之患者中良好耐受,具有有前景功效。的確,大多數治療相關之不良事件(TRAE)為1至2級,最常出現為厭食症及高甘油三酯血症。
表 6 至 7提供來自此研究之安全性結果。在接受研究治療之41名患者中,最常報告之TRAE為AST (65.9%)及ALT之增加(63.4%)、外周感覺神經病變(63.4%)、衰弱(58.5%),食慾下降(56.1%)、高甘油三酯血症(56.1%),及γ-麩胺醯基轉移酶之增加(51.2%)。所報告之等級≥3之TRAE包括γ-麩胺醯基轉移酶(12.2%)及ALT之增加(7.3%)、虛弱(7.3%)及高甘油三酯血症(7.3%)。於16名患者中報告免疫相關之不良事件(irAE),包括免疫相關之肺炎、間質性肺病、肝炎、肌炎、高血糖及皮疹。
表 6.接受RC48-ADC及JS001組合療法之患者之治療相關之不良事件(TRAE)結果,其中發生率≥ 20%及等級≥ 3 TRAE。
表 7.接受RC48-ADC及JS001組合療法之患者之免疫相關之不良事件(irAE)結果。
功效
TRAE | 所有等級 – n (%) | 等級 ≥ 3 – n (%) |
總體 | 41 (100%) | 15 (%) |
天冬胺酸轉胺酶增加 | 27 (65.85%) | 2 (%) |
丙胺酸轉胺酶增加 | 26 (63.41%) | 3 (%) |
外周感覺神經病變 | 26 (63.41%) | 0 |
衰弱 | 24 (58.54%) | 3 (%) |
食慾下降 | 23 (56.1%) | 0 |
高甘油三酯血症 | 23 (56.1%) | 3 (%) |
γ-麩胺醯基轉移酶增加 | 21 (51.22%) | 5 (%) |
脫髮 | 17 (41.46%) | 0 |
噁心 | 16 (39.02%) | 0 |
高膽固醇血症 | 15 (36.59%) | 0 |
白血球計數減少 | 14 (34.15%) | 1 (%) |
血液肌酸磷酸激酶增加 | 14 (34.15%) | 1 (%) |
貧血 | 14 (34.15%) | 0 |
irAE | 所有等級 – n (%) |
總體 | 16 (39.02%) |
間質性肺病 | 3 (7.32%) |
免疫相關之肺炎 | 5 (12.2%) |
皮疹 | 8 (19.51%) |
高血糖 | 1 (2.44%) |
免疫相關之肝炎 | 1 (2.44%) |
免疫相關之肌炎 | 1 (2.44%) |
在此研究之41名患者中,39名患者接受至少兩次腫瘤評估,其顯示在所有患者中71.8%之證實之ORR (95% CI: 55.1,85),包含於3名患者中完全反應(7.7%)及於25名患者中部分反應(64.1%),如下
表 8中所述;DCR為92.3% (95%CI: 79.1,98.4)。未治療la/mUC患者之cORR為73.9%。la/mUC患者中之HER2表現(IHC 1 +、IHC2 +、IHC3 +)之cORR為77.8%。具有HER2 (3+)、HER2 (2+)、HER2 (1+)及HER2 (0)之患者之ORR各自為100%、77.8%、66.7%及50%,如下
表 9中所示。ORR隨著HER2或PD-L1之高表現而增加。具有PD-L1 CPS ≥ 1之患者之對應ORR為91.7%及於CPS < 1中為50%。同樣,mPFS為9.2個月,及未達到mOS。
圖 4A 至 B顯示於接受RC48-ADC及JS001組合療法之患者中之標靶病變自量測之基線的變化%。於
圖 4A中,HER2狀態指示IHC等級。於
圖 4B中,歷時至多500天之時間分析患者標靶病變之直徑的加總的變化%。
圖 4C顯示藉由cORR以進一步分解成各子組及個體之反應評估之反應時間及反應持續時間之RC48-ADC及JS001組合療法的功效。
圖 4D顯示於此研究中招募之患者隨時間之無進展生存期的百分比。一併考慮,此等結果指示RC48-ADC及JS001組合療法與單獨單一治療相比產生改善之患者結果,特定言之關於PFS。
表 8.對RC48-ADC及JS001組合療法之患者反應。
表 9.患者HER2及PD-L1子組cORR分析。
總群體 | RC48-ADC (N = 39) |
證實之客觀反應率(cORR) | 28 (71.8%) |
完全緩解或反應(CR) | 3 (7.7%) |
部分緩解或反應(PR) | 25 (64.1%) |
穩定疾病(SD) | 8 (20.5%) |
進行性疾病(PD) | 3 (7.7%) |
疾病控制率(DCR) | 36 (92.3%) |
反應持續時間(DOR) | 8.18個月 |
子組 | cORR (%, 95% CI) |
先前全身治療 | |
0線(n = 23) | 80 (44.4, 97.5) |
1+線(n = 16) | 75 (34.9, 96.8) |
HER2 及 PD-L1 表現 | |
HER2 IHC (2+/3+),PD-L1(+) (n = 8) | 100 (29.2, 100) |
HER2 IHC (2+/3+),PD-L1(-) (n = 16) | 77.8 (40, 97.2) |
HER2 IHC (1+),PD-L1(+) (n = 4) | 66.7 (22.3, 95.7) |
HER2 IHC (1+),PD-L1(-) (n = 10) | 50 (1.3, 98.7) |
HER2 IHC (0),PD-L1(+) (n = 1) | |
HER2 IHC (0),PD-L1(-) (n = 2) | 50 (15.7, 84.3) |
圖 2為本發明之結構通式Ab-(L-U)
n在一組可能結合條件下(L通過巰基結合連接至抗體之一或多個鏈間二硫鍵位點)之抗體-藥物結合物之示例性結構的示意圖,其中n各自為1、2、3、4、5、6、7及8;L為馬來醯亞胺基-己醯基-纈胺酸-瓜胺酸-對胺基苄氧基(mc-vc-pAB);U為MMAE (單甲基澳瑞他汀E);及「-L-U」之結構係如下:
圖 3為II期臨床試驗中所用方法之示意性概述。
圖 4A 至 D為患者對利用RC48-ADC及JS001共同治療之反應之圖示。
圖 4A 至 C顯示患者之總體反應率,及
圖 4D顯示患者之無進展生存期。
<![CDATA[<110> 中國大陸商榮昌生物製藥(煙臺)股份有限公司(Remegen Co., Ltd.)]]> <![CDATA[<120> 抗體-藥物結合物與免疫檢查點抑制劑組合用於治療泌尿上皮癌之用途]]> <![CDATA[<130> 76168-20086.42]]> <![CDATA[<140> TW 111118595]]> <![CDATA[<141> 2022-05-18]]> <![CDATA[<150> CN 202110559728.8]]> <![CDATA[<151> 2021-05-21 ]]> <![CDATA[<160> 35]]> <![CDATA[<170> FastSEQ for Windows Version 4.0]]> <![CDATA[<210> 1]]> <![CDATA[<211> 445]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人造序列]]> <![CDATA[<220> ]]> <![CDATA[<223> 合成構築體]]> <![CDATA[<400> 1]]> Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Thr Val Lys Ile Ser Cys Lys Val Ser Gly Tyr Thr Phe Thr Asp Tyr 20 25 30 Tyr Ile His Trp Val Gln Gln Ala Pro Gly Lys Gly Leu Glu Trp Met 35 40 45 Gly Arg Val Asn Pro Asp His Gly Asp Ser Tyr Tyr Asn Gln Lys Phe 50 55 60 Lys Asp Lys Ala Thr Ile Thr Ala Asp Lys Ser Thr Asp Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Phe Cys 85 90 95 Ala Arg Asn Tyr Leu Phe Asp His Trp Gly Gln Gly Thr Leu Val Thr 100 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Arg His Thr Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys His Gln Phe Ala Thr Tyr Thr Phe 85 90 95 Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala Pro Ser 100 105 110 Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala 115 120 125 Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val 130 135 140 Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser 145 150 155 160 Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr 165 170 175 Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys 180 185 190 Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn 195 200 205 Arg Gly Glu Cys 210 <![CDATA[<210> 3]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人造序列]]> <![CDATA[<220> ]]> <![CDATA[<223> 合成構築體]]> <![CDATA[<400> 3]]> Gly Tyr Thr Phe Thr Asp Tyr Tyr 1 5 <![CDATA[<210> 4]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人造序列]]> <![CDATA[<220> ]]> <![CDATA[<223> 合成構築體]]> <![CDATA[<400> 4]]> Val Asn Pro Asp His Gly Asp Ser 1 5 <![CDATA[<210> 5]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人造序列]]> <![CDATA[<220> ]]> <![CDATA[<223> 合成構築體]]> <![CDATA[<400> 5]]> Ala Arg Asn Tyr Leu Phe Asp His 1 5 <![CDATA[<210> 6]]> <![CDATA[<211> 6]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人造序列]]> <![CDATA[<220> ]]> <![CDATA[<223> 合成構築體]]> <![CDATA[<400> 6]]> Gln Asp Val Gly Thr Ala 1 5 <![CDATA[<210> 7]]> <![CDATA[<211> 3]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人造序列]]> <![CDATA[<220> ]]> <![CDATA[<223> 合成構築體]]> <![CDATA[<400>]]> 7 Trp Ala Ser 1 <![CDATA[<210> 8]]> <![CDATA[<211> 7]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人造序列]]> <![CDATA[<220> ]]> <![CDATA[<223> 合成構築體]]> <![CDATA[<400> 8]]> His Gln Phe Ala Thr Tyr Thr 1 5 <![CDATA[<210> 9]]> <![CDATA[<211> 115]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人造序列]]> <![CDATA[<220> ]]> <![CDATA[<223> 合成構築體]]> <![CDATA[<400> 9]]> Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Thr Val Lys Ile Ser Cys Lys Val Ser Gly Tyr Thr Phe Thr Asp Tyr 20 25 30 Tyr Ile His Trp Val Gln Gln Ala Pro Gly Lys Gly Leu Glu Trp Met 35 40 45 Gly Arg Val Asn Pro Asp His Gly Asp Ser Tyr Tyr Asn Gln Lys Phe 50 55 60 Lys Asp Lys Ala Thr Ile Thr Ala Asp Lys Ser Thr Asp Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Phe Cys 85 90 95 Ala Arg Asn Tyr Leu Phe Asp His Trp Gly Gln Gly Thr Leu Val Thr 100 105 110 Val Ser Ser 115 <![CDATA[<210> 10]]> <![CDATA[<211> 105]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人造序列]]> <![CDATA[<220> ]]> <![CDATA[<223> 合成構築體]]> <![CDATA[<400> 10]]> Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Val Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asp Val Gly Thr Ala 20 25 30 Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Trp Ala Ser Ile Arg His Thr Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys His Gln Phe Ala Thr Tyr Thr Phe 85 90 95 Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105 <![CDATA[<210> 11]]> <![CDATA[<211> 452]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人造序列]]> <![CDATA[<220> ]]> <![CDATA[<223> 合成構築體]]> <![CDATA[<400> 11]]> Gln Gly 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 Thr Phe Thr Asp Tyr 20 25 30 Glu Met His Trp Val Arg Gln Ala Pro Ile His Gly Leu Glu Trp Ile 35 40 45 Gly Val Ile Glu Ser Glu Thr Gly Gly Thr Ala Tyr Asn Gln Lys Phe 50 55 60 Lys Gly Arg Val Thr Ile Thr Ala Asp Lys 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 Ile Thr Thr Val Ala Thr Thr Tyr Tyr Trp Tyr Phe 100 105 110 Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr 115 120 125 Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser 130 135 140 Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu 145 150 155 160 Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His 165 170 175 Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser 180 185 190 Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys 195 200 205 Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu 210 215 220 Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu 225 230 235 240 Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu 245 250 255 Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser 260 265 270 Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu 275 280 285 Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr 290 295 300 Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn 305 310 315 320 Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser 325 330 335 Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln 340 345 350 Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val 355 360 365 Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val 370 375 380 Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro 385 390 395 400 Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr 405 410 415 Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val 420 425 430 Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu 435 440 445 Ser Leu Gly Lys 450 <![CDATA[<210> 12]]> <![CDATA[<211> 219]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人造序列]]> <![CDATA[<220> ]]> <![CDATA[<223> 合成構築體]]> <![CDATA[<400> 12]]> Asp Val Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Leu Gly 1 5 10 15 Gln Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Ile Val His Ser 20 25 30 Asn Gly Asn Thr Tyr Leu Glu Trp Tyr Leu Gln Lys Pro Gly Gln Ser 35 40 45 Pro Gln Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro 50 55 60 Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile 65 70 75 80 Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Phe Gln Gly 85 90 95 Ser His Val Pro Leu 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> 13]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人造序列]]> <![CDATA[<220> ]]> <![CDATA[<223> 合成構築體]]> <![CDATA[<400> 13]]> Gly Tyr Thr Phe Thr Asp Tyr Glu 1 5 <![CDATA[<210> 14]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人造序列]]> <![CDATA[<220> ]]> <![CDATA[<223> 合成構築體]]> <![CDATA[<400> 14]]> Ile Glu Ser Glu Thr Gly Gly Thr 1 5 <![CDATA[<210> 15]]> <![CDATA[<211> 18]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人造序列]]> <![CDATA[<220> ]]> <![CDATA[<223> 合成構築體]]> <![CDATA[<400> 15]]> Ala Arg Glu Gly Ile Thr Thr Val Ala Thr Thr Tyr Tyr Trp Tyr Phe 1 5 10 15 Asp Val <![CDATA[<210> 16]]> <![CDATA[<211> 11]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人造序列]]> <![CDATA[<220> ]]> <![CDATA[<223> 合成構築體]]> <![CDATA[<400> 16]]> Gln Ser Ile Val His Ser Asn Gly Asn Thr Tyr 1 5 10 <![CDATA[<210> 17]]> <![CDATA[<211> 3]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人造序列]]> <![CDATA[<220> ]]> <![CDATA[<223> 合成構築體]]> <![CDATA[<400> 17]]> Lys Val Ser 1 <![CDATA[<210> 18]]> <![CDATA[<211> 9]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人造序列]]> <![CDATA[<220> ]]> <![CDATA[<223> 合成構築體]]> <![CDATA[<400> 18]]> Phe Gln Gly Ser His Val Pro Leu Thr 1 5 <![CDATA[<210> 19]]> <![CDATA[<211> 125]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人造序列]]> <![CDATA[<220> ]]> <![CDATA[<223> 合成構築體]]> <![CDATA[<400> 19]]> Gln Gly 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 Thr Phe Thr Asp Tyr 20 25 30 Glu Met His Trp Val Arg Gln Ala Pro Ile His Gly Leu Glu Trp Ile 35 40 45 Gly Val Ile Glu Ser Glu Thr Gly Gly Thr Ala Tyr Asn Gln Lys Phe 50 55 60 Lys Gly Arg Val Thr Ile Thr Ala Asp Lys 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 Ile Thr Thr Val Ala Thr Thr Tyr Tyr Trp Tyr Phe 100 105 110 Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser 115 120 125 <![CDATA[<210> 20]]> <![CDATA[<211> 115]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人造序列]]> <![CDATA[<220> ]]> <![CDATA[<223> 合成構築體]]> <![CDATA[<400> 20]]> Asp Val Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Leu Gly 1 5 10 15 Gln Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Ile Val His Ser 20 25 30 Asn Gly Asn Thr Tyr Leu Glu Trp Tyr Leu Gln Lys Pro Gly Gln Ser 35 40 45 Pro Gln Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro 50 55 60 Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile 65 70 75 80 Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Phe Gln Gly 85 90 95 Ser His Val Pro Leu Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys 100 105 110 Arg Thr Val 115 <![CDATA[<210> 21]]> <![CDATA[<211> 450]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人造序列]]> <![CDATA[<220> ]]> <![CDATA[<223> 合成構築體]]> <![CDATA[<400> 2]]>1 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 Phe Ser Leu Ser Arg Tyr 20 25 30 Ser Val His Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Leu 35 40 45 Gly Met Ile Trp Gly Val Gly Thr Thr Asp Tyr Asn Ser Ala Leu Lys 50 55 60 Ser Arg Leu Thr Ile Ser Lys Asp Thr Ser Lys Asn Gln Phe Ser Leu 65 70 75 80 Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95 Arg Asn Trp Gly Thr Ala Asp Tyr Phe Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Thr Val Thr Val Ser Ser Ala 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 Glu Glu Met 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> 22]]> <![CDATA[<211> 220]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人造序列]]> <![CDATA[<220> ]]> <![CDATA[<223> 合成構築體]]> <![CDATA[<400> 22]]> Asp Ile Val Leu Thr Gln Ser Pro Ala Ser Leu Ala Val Ser Pro Gly 1 5 10 15 Gln Arg Ala Thr Ile Thr Cys Arg Ala Ser Lys Ser Val His Thr Ser 20 25 30 Gly Tyr Ser Tyr Met His Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro 35 40 45 Lys Leu Leu Ile Tyr Leu Ala Ser Asn Leu Glu Ser Gly Val Pro Ala 50 55 60 Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Asn 65 70 75 80 Pro Val Glu Ala Asn Asp Thr Ala Asn Tyr Tyr Cys Gln His Ser Gly 85 90 95 Glu Leu Pro Tyr Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg 100 105 110 Thr Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp 115 120 125 Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn 130 135 140 Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu 145 150 155 160 Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp 165 170 175 Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr 180 185 190 Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser 195 200 205 Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 210 215 220 <![CDATA[<210> 23]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人造序列]]> <![CDATA[<220> ]]> <![CDATA[<223> 合成構築體]]> <![CDATA[<400> 23]]> Gly Phe Ser Leu Ser Arg Tyr Ser 1 5 <![CDATA[<210> 24]]> <![CDATA[<211> 7]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人造序列]]> <![CDATA[<220> ]]> <![CDATA[<223> 合成構築體]]> <![CDATA[<400> 24]]> Ile Trp Gly Val Gly Thr Thr 1 5 <![CDATA[<210> 25]]> <![CDATA[<211> 12]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人造序列]]> <![CDATA[<220> ]]> <![CDATA[<223> 合成構築體]]> <![CDATA[<400> 25]]> Ala Arg Asn Trp Gly Thr Ala Asp Tyr Phe Asp Tyr 1 5 10 <![CDATA[<210> 26]]> <![CDATA[<211> 10]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人造序列]]> <![CDATA[<220> ]]> <![CDATA[<223> 合成構築體]]> <![CDATA[<400> 26]]> Lys Ser Val His Thr Ser Gly Tyr Ser Tyr 1 5 10 <![CDATA[<210> 27]]> <![CDATA[<211> 3]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人造序列]]> <![CDATA[<220> ]]> <![CDATA[<223> 合成構築體]]> <![CDATA[<400> 27]]> Leu Ala Ser 1 <![CDATA[<210> 28]]> <![CDATA[<211> 9]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人造序列]]> <![CDATA[<220> ]]> <![CDATA[<223> 合成構築體]]> <![CDATA[<400> 28]]> Gln His Ser Gly Glu Leu Pro Tyr Thr 1 5 <![CDATA[<210> 29]]> <![CDATA[<211> 120]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人造序列]]> <![CDATA[<220> ]]> <![CDATA[<223> 合成構築體]]> <![CDATA[<400]]>> 29]]> <br/><![CDATA[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 Phe Ser Leu Ser Arg Tyr 20 25 30 Ser Val His Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Leu 35 40 45 Gly Met Ile Trp Gly Val Gly Thr Thr Asp Tyr Asn Ser Ala Leu Lys 50 55 60 Ser Arg Leu Thr Ile Ser Lys Asp Thr Ser Lys Asn Gln Phe Ser Leu 65 70 75 80 Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95 Arg Asn Trp Gly Thr Ala Asp Tyr Phe Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Thr Val Thr Val Ser Ser Ala Ser 115 120 <![CDATA[<210> 30]]> <![CDATA[<211> 113]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人造序列]]> <![CDATA[<220> ]]> <![CDATA[<223> 合成構築體]]> <![CDATA[<400> 30]]> Asp Ile Val Leu Thr Gln Ser Pro Ala Ser Leu Ala Val Ser Pro Gly 1 5 10 15 Gln Arg Ala Thr Ile Thr Cys Arg Ala Ser Lys Ser Val His Thr Ser 20 25 30 Gly Tyr Ser Tyr Met His Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro 35 40 45 Lys Leu Leu Ile Tyr Leu Ala Ser Asn Leu Glu Ser Gly Val Pro Ala 50 55 60 Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Asn 65 70 75 80 Pro Val Glu Ala Asn Asp Thr Ala Asn Tyr Tyr Cys Gln His Ser Gly 85 90 95 Glu Leu Pro Tyr Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg 100 105 110 Thr <![CDATA[<210> 31]]> <![CDATA[<211> 5]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人造序列]]> <![CDATA[<220> ]]> <![CDATA[<223> 合成構築體]]> <![CDATA[<400> 31]]> Asp Tyr Tyr Ile His 1 5 <![CDATA[<210> 32]]> <![CDATA[<211> 17]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人造序列]]> <![CDATA[<220> ]]> <![CDATA[<223> 合成構築體]]> <![CDATA[<400> 32]]> Arg Val Asn Pro Asp His Gly Asp Ser Tyr Tyr Asn Gln Lys Phe Lys 1 5 10 15 Asp <![CDATA[<210> 33]]> <![CDATA[<211> 9]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人造序列]]> <![CDATA[<220> ]]> <![CDATA[<223> 合成構築體]]> <![CDATA[<400> 33]]> Ala Arg Asn Tyr Leu Phe Asp His Trp 1 5 <![CDATA[<210> 34]]> <![CDATA[<211> 11]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人造序列]]> <![CDATA[<220> ]]> <![CDATA[<223> 合成構築體]]> <![CDATA[<400> 34]]> Lys Ala Ser Gln Asp Val Gly Thr Ala Val Ala 1 5 10 <![CDATA[<210> 35]]> <![CDATA[<211> 7]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人造序列]]> <![CDATA[<220> ]]> <![CDATA[<223> 合成構築體]]> <![CDATA[<400> 35]]> Trp Ala Ser Ile Arg His Thr 1 5
Claims (36)
- 一種抗體-藥物結合物(antibody-drug conjugate;ADC)與免疫檢查點抑制劑組合於製備用於治療泌尿上皮癌患者之藥劑中的用途,其中該抗體-藥物結合物具有通式Ab-(L-U) n之結構,其中Ab表示抗-Her2 (人類表皮生長因子受體2)抗體;L表示連接子;U表示結合之細胞毒性分子;且n為1至8之整數,及表示鍵結至各抗體之細胞毒性分子之數目,且其中: 該抗體包含重鏈可變區及輕鏈可變區,其中該重鏈可變區之CDR及/或該輕鏈可變區之CDR具有與維迪西妥單抗(Disitamab vedotin)相同之CDR序列; 該連接子L包括馬來醯亞胺基-己醯基-纈胺酸-瓜胺酸-對胺基苄氧基(Maleimido-Caproyl-Valine-Citrulline-p-Aminobenzyloxy;mc-vc-pAB),其中該連接子藉助巰基結合共價連接至該抗體,及該連接位點為該抗體之鏈間二硫鍵位點; 該細胞毒性分子U包括MMAE (單甲基澳瑞他汀(auristatin) E);及 該免疫檢查點抑制劑為PD-1抗體或PD-L1抗體。
- 一種治療泌尿上皮癌患者之方法,其包括向該患者投與有效量之抗體-藥物結合物(ADC)及免疫檢查點抑制劑, 其中該抗體-藥物結合物具有通式Ab-(L-U) n之結構,其中Ab表示抗-Her2 (人類表皮生長因子受體2)抗體;L表示連接子;U表示結合之細胞毒性分子;且n為1至8之整數,及表示鍵結至各抗體之細胞毒性分子之數目,且其中: 該抗體包含重鏈可變區及輕鏈可變區,其中該重鏈可變區之CDR及/或該輕鏈可變區之CDR具有與維迪西妥單抗相同之CDR序列; 該連接子L包括馬來醯亞胺基-己醯基-纈胺酸-瓜胺酸-對胺基苄氧基(mc-vc-pAB),其中該連接子藉助巰基結合共價連接至該抗體,及該連接位點為該抗體之鏈間二硫鍵位點; 該細胞毒性分子U包括MMAE (單甲基澳瑞他汀E);及 該免疫檢查點抑制劑為PD-1抗體或PD-L1抗體。
- 如以上請求項中任一項之用途或方法,其中該患者針對HER2表現為陽性。
- 如以上請求項中任一項之用途或方法,其中獲自該患者之泌尿上皮癌之樣品係HER2陽性。
- 如以上請求項中任一項之用途或方法,其中基於免疫組織化學(immunohistochemistry;IHC)分析,獲自該患者之泌尿上皮癌之該樣品係HER2陽性。
- 如以上請求項中任一項之用途或方法,其中獲自該患者之泌尿上皮癌之該樣品之HER2表現為IHC 3+或IHC 2+。
- 如以上請求項中任一項之用途或方法,其中該患者針對PD-L1或PD-1表現為陽性。
- 如以上請求項中任一項之用途或方法,其中該抗體包含重鏈可變(heavy chain variable;VH)區及輕鏈可變(light chain variable;VL)區; 其中該VH區包含:包含GYTFTDYY ( SEQ ID NO:3)之胺基酸序列之HCDR1,包含VNPDHGDS ( SEQ ID NO:4)之胺基酸序列之HCDR2,及包含ARNYLFDH ( SEQ ID NO:5)之胺基酸序列之HCDR3;且 其中該VL區包含:包含QDVGTA ( SEQ ID NO:6)之胺基酸序列之LCDR1,包含WAS ( SEQ ID NO:7)之胺基酸序列之LCDR2,及包含HQFATYT ( SEQ ID NO:8)之胺基酸序列之LCDR3。
- 如以上請求項中任一項之用途或方法,其中該抗體包含重鏈可變(VH)區及輕鏈可變(VL)區; 其中該VH區包含:包含DYYIH ( SEQ ID NO:31)之胺基酸序列之HCDR1,包含RVNPDHGDSYYNQKFKD ( SEQ ID NO:32)之胺基酸序列之HCDR2及包含ARNYLFDHW ( SEQ ID NO:33)之胺基酸序列之HCDR3;且 其中該VL區包含:包含KASQDVGTAVA ( SEQ ID NO:34)之胺基酸序列之LCDR1,包含WASIRHT ( SEQ ID NO:35)之胺基酸序列之LCDR2及包含HQFATYT ( SEQ ID NO:8)之胺基酸序列之LCDR3。
- 如以上請求項中任一項之用途或方法,其中該抗體為鼠科、嵌合或人源化抗體。
- 如以上請求項中任一項之用途或方法,其中該抗體包含重鏈可變(VH)區及輕鏈可變(VL)區;其中該VH區包含EVQLVQSGAEVKKPGATVKISCKVSGYTFTDYYIHWVQQAPGKGLEWMGRVNPDHGDSYYNQKFKDKATITADKSTDTAYMELSSLRSEDTAVYFCARNYLFDHWGQGTLVTVSS ( SEQ ID NO:9)之胺基酸序列;且其中該VL區包含DIQMTQSPSSVSASVGDRVTITCKASQDVGTAVAWYQQKPGKAPKLLIYWASIRHTGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCHQFATYTFGGGTKVEIK ( SEQ ID NO:10)之胺基酸序列。
- 如以上請求項中任一項之用途或方法,其中該抗體為人類IgG抗體。
- 如以上請求項中任一項之用途或方法,其中該抗體為人類IgG1、IgG2及IgG4抗體。
- 如以上請求項中任一項之用途或方法,其中該抗體重鏈之胺基酸序列為SEQ ID NO:1,及該抗體輕鏈之胺基酸序列為SEQ ID NO:2。
- 如以上請求項中任一項之用途或方法,其中該抗體-藥物結合物為維迪西妥單抗或其生物類似物。
- 如以上請求項中任一項之用途或方法,其中該抗體-藥物結合物之平均DAR (Drug-to-Antibody Ratio,即,藥物對抗體比率)值為2至7之任何數值。
- 如請求項16之用途或方法,其中該平均DAR值為4 ± 0.5。
- 如以上請求項中任一項之用途或方法,其中該免疫檢查點抑制劑為PD-1抗體。
- 如請求項18之用途或方法,其中該PD-1抗體選自由以下組成之群:特瑞普利單抗(Toripalimab)、多塔利單抗(Dostarlimab)、普高利單抗(Prolgolimab)、替雷利珠單抗(Tislelizumab)、卡瑞利珠單抗(Camrelizumab)、信迪利單抗(Sintilimab)、西米單抗(Cemiplimab)、派立珠單抗(Pembrolizumab)、納武單抗(Nivolumab)、派安普利單抗(Penpulimab)、格諾利單抗(Genolimzumab)、津貝利單抗(Zimberelimab)及巴替利單抗(Balstilimab)。
- 如以上請求項中任一項之用途或方法,其中該免疫檢查點抑制劑為PD-L1抗體。
- 如請求項20之用途或方法,其中該免疫檢查點抑制劑為PD-L1抗體,其選自由德瓦魯單抗(Durvalumab)、阿維單抗(Avelumab)、阿特珠單抗(Atezolizumab)、恩沃利單抗(Envafolimab)及RC98組成之群。
- 如以上請求項中任一項之用途或方法,其中該患者先前已接受一或多種先前治療,該一或多種先前治療選自由化療藥物、靶向療法、免疫療法及內分泌療法組成之群。
- 如以上請求項中任一項之用途或方法,其中該泌尿上皮癌患者選自由以下組成之群:患有不可手術切除之局部晚期泌尿上皮癌之患者、患有局部晚期或轉移性泌尿上皮癌之患者、患有HER2陽性泌尿上皮癌之患者、患有HER2陽性局部晚期或轉移性泌尿上皮癌之患者及不可耐受以鉑為主之化療之泌尿上皮癌患者。
- 如以上請求項中任一項之用途或方法,其中該泌尿上皮癌患者為患有不可切除局部晚期或轉移性泌尿上皮癌之患者。
- 如以上請求項中任一項之用途或方法,其中該泌尿上皮癌患者為針對不適合以順鉑為主之化療或已拒絕以順鉑為主之化療之患者。
- 如以上請求項中任一項之用途或方法,其中該泌尿上皮癌患者係為經化療後疾病已進展之患者。
- 如以上請求項中任一項之用途或方法,其中該泌尿上皮癌患者係為於完成新輔助或輔助以順鉑為主之化療之12個月內經歷疾病進展之患者。
- 如以上請求項中任一項之用途或方法,其中該藥劑經鼻內、經皮下、經真皮內、經肌肉內或經靜脈內投與。
- 如以上請求項中任一項之用途或方法,其中該ADC係以1.5 mg/kg或2.0 mg/kg之劑量投與。
- 如以上請求項中任一項之用途或方法,其中該ADC係每2週或14天投與。
- 如以上請求項中任一項之用途或方法,其中該抗體-藥物結合物及免疫檢查點抑制劑投與至該泌尿上皮癌患者會導致大於7.5個月之無進展生存期(progression-free survival;PFS)。
- 一種有效量之抗體-藥物結合物(ADC)及免疫檢查點抑制劑之用途,其係用於製造用於治療患者之泌尿上皮癌之包含該ADC之第一藥劑及包含該免疫檢查點抑制劑之第二藥劑, 其中該抗體-藥物結合物具有通式Ab-(L-U) n之結構,其中Ab表示抗-Her2 (人類表皮生長因子受體2)抗體;L表示連接子;U表示結合之細胞毒性分子;且n為1至8之整數,及表示鍵結至各抗體之細胞毒性分子之數目,且其中: 該抗體包含重鏈可變區及輕鏈可變區,其中該重鏈可變區之CDR及/或該輕鏈可變區之CDR具有與維迪西妥單抗相同之CDR序列; 該連接子L包括馬來醯亞胺基-己醯基-纈胺酸-瓜胺酸-對胺基苄氧基(mc-vc-pAB),其中該連接子藉助巰基結合共價連接至該抗體,及該連接位點為該抗體之鏈間二硫鍵位點; 該細胞毒性分子U包括MMAE (單甲基澳瑞他汀E);及 該免疫檢查點抑制劑為PD-1抗體或PD-L1抗體。
- 一種有效量之抗體-藥物結合物(ADC)於製造用於治療患者之泌尿上皮癌之藥劑中的用途,其中該ADC與免疫檢查點抑制劑組合使用, 其中該抗體-藥物結合物具有通式Ab-(L-U) n之結構,其中Ab表示抗-Her2 (人類表皮生長因子受體2)抗體;L表示連接子;U表示結合之細胞毒性分子;且n為1至8之整數,及表示鍵結至各抗體之細胞毒性分子之數目,且其中: 該抗體包含重鏈可變區及輕鏈可變區,其中該重鏈可變區之CDR及/或該輕鏈可變區之CDR具有與維迪西妥單抗相同之CDR序列; 該連接子L包括馬來醯亞胺基-己醯基-纈胺酸-瓜胺酸-對胺基苄氧基(mc-vc-pAB),其中該連接子藉助巰基結合共價連接至該抗體,及該連接位點為該抗體之鏈間二硫鍵位點; 該細胞毒性分子U包括MMAE (單甲基澳瑞他汀E);及 該免疫檢查點抑制劑為PD-1抗體或PD-L1抗體。
- 一種有效量之免疫檢查點抑制劑於製造用於治療患者之泌尿上皮癌之藥劑中的用途,其中該免疫檢查點抑制劑與抗體-藥物結合物組合使用, 其中該抗體-藥物結合物具有通式Ab-(L-U) n之結構,其中Ab表示抗Her2 (人類表皮生長因子受體2)抗體;L表示連接子;U表示結合之細胞毒性分子;且n為1至8之整數,及表示鍵結至各抗體之細胞毒性分子之數目,且其中: 該抗體包含重鏈可變區及輕鏈可變區,其中該重鏈可變區之CDR及/或該輕鏈可變區之CDR具有與維迪西妥單抗相同之CDR序列; 該連接子L包括馬來醯亞胺基-己醯基-纈胺酸-瓜胺酸-對胺基苄氧基(mc-vc-pAB),其中該連接子藉助巰基結合共價連接至該抗體,及該連接位點為該抗體之鏈間二硫鍵位點; 該細胞毒性分子U包括MMAE (單甲基澳瑞他汀E);及 該免疫檢查點抑制劑為PD-1抗體或PD-L1抗體。
- 一種醫藥組合物,其包含用於治療泌尿上皮癌之抗體-藥物結合物(ADC)與免疫檢查點抑制劑組合, 其中該抗體-藥物結合物具有通式Ab-(L-U) n之結構,其中Ab表示抗-Her2 (人類表皮生長因子受體2)抗體;L表示連接子;U表示結合之細胞毒性分子;且n為1至8之整數,及表示鍵結至各抗體之細胞毒性分子之數目,且其中: 該抗體包含重鏈可變區及輕鏈可變區,其中該重鏈可變區之CDR及/或該輕鏈可變區之CDR具有與維迪西妥單抗相同之CDR序列; 該連接子L包括馬來醯亞胺基-己醯基-纈胺酸-瓜胺酸-對胺基苄氧基(mc-vc-pAB),其中該連接子藉助巰基結合共價連接至該抗體,及該連接位點為該抗體之鏈間二硫鍵位點; 該細胞毒性分子U包括MMAE (單甲基澳瑞他汀E);及 該免疫檢查點抑制劑為PD-1抗體或PD-L1抗體。
- 一種醫藥組合物,其包含用於治療泌尿上皮癌之免疫檢查點抑制劑與抗體-藥物結合物(ADC)組合, 其中該抗體-藥物結合物具有通式Ab-(L-U) n之結構,其中Ab表示抗Her2 (人類表皮生長因子受體2)抗體;L表示連接子;U表示結合之細胞毒性分子;且n為1至8之整數,及表示鍵結至各抗體之細胞毒性分子之數目,且其中: 該抗體包含重鏈可變區及輕鏈可變區,其中該重鏈可變區之CDR及/或該輕鏈可變區之CDR具有與維迪西妥單抗相同之CDR序列; 該連接子L包括馬來醯亞胺基-己醯基-纈胺酸-瓜胺酸-對胺基苄氧基(mc-vc-pAB),其中該連接子藉助巰基結合共價連接至該抗體,及該連接位點為該抗體之鏈間二硫鍵位點; 該細胞毒性分子U包括MMAE (單甲基澳瑞他汀E);及 該免疫檢查點抑制劑為PD-1抗體或PD-L1抗體。
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