TWI767139B - 抗her2抗體藥物偶聯物在治療尿路上皮癌中的用途 - Google Patents
抗her2抗體藥物偶聯物在治療尿路上皮癌中的用途 Download PDFInfo
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- TWI767139B TWI767139B TW108130782A TW108130782A TWI767139B TW I767139 B TWI767139 B TW I767139B TW 108130782 A TW108130782 A TW 108130782A TW 108130782 A TW108130782 A TW 108130782A TW I767139 B TWI767139 B TW I767139B
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- antibody
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- urothelial carcinoma
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Abstract
本發明涉及抗HER2抗體藥物偶聯物(ADC)在製備用於治療尿路上皮癌的藥物中的用途。本發明所述的藥物對於尿路上皮癌特別是局部晚期或轉移性尿路上皮癌患者安全有效,能有效延長患者生存期。
Description
本發明涉及一種抗HER2(人類表皮生長因數受體2,human epidermal growth factor receptor 2)抗體藥物偶聯物在治療尿路上皮癌中的用途。
尿路上皮細胞癌(Urothelial carcinoma,UC;或稱移行細胞癌,Transitional cell carcinoma,TCC)是一種癌症類型,其通常存在於泌尿系統:腎、膀胱和附屬器官中。其為膀胱癌和輸尿管、尿道和臍尿管癌症的最常見類型。其為第二最常見的腎癌類型,占所有原發性腎臟惡性腫瘤的5-10%。
尿路上皮(也稱為過渡性上皮)是膀胱,輸尿管和尿道內側以及腎盂(尿液收集的腎臟部分)內襯。它由尿路上皮細胞或過渡細胞組成。這些細胞可以變成癌細胞,即稱為尿路上皮癌(或移行細胞癌)。
根據癌變細胞的侵入性,尿路上皮癌可以是非侵入性的(僅在膀胱的襯裡中)或侵入性的(生長到膀胱壁的其他層中)。其中,非侵入性尿路上皮癌僅在膀胱內膜中並且未在膀胱壁中更深地生長。在診斷時,50%-60%的尿路上皮癌患者的腫瘤為非侵入性的。非侵入性尿路上
皮癌的類型包括:非侵襲性扁平尿路上皮癌(也稱為原位癌);非侵襲性乳頭狀尿路上皮癌,高級別;非侵襲性乳頭狀尿路上皮癌,低度惡性;具有低惡性潛能的非侵襲性乳頭狀尿路上皮腫瘤發展成侵襲性癌症的可能性很小。
相比之下,侵入性尿路上皮癌從膀胱內膜生長到膀胱壁的較深層,例如結締組織(稱為固有層)和肌肉層(稱為肌層)。在診斷時,40%-50%的尿路上皮癌患者的腫瘤為侵襲性的。
理論上,尿路上皮癌可以從泌尿道的任何部位開始,包括但不限於腎盂、輸尿管、膀胱或尿道。
當相關腫瘤細胞未轉移時,手術切除治療為首選的治療方案,對於腫瘤已經轉移的患者,一般需要採取抗癌藥物治療,目前的一線療法是:吉西他濱和順鉑的聯合療法;而放射療法針對尿路上皮癌的效果並不理想,一般用作輔助治療的手段;當治療腎盂/輸尿管上皮中的癌時,可以使用BCG注射療法(導管注射牛結核桿菌)。
尿路上皮癌具有多中心,易復發的特點,對於腫瘤累及肌層的患者首選膀胱全切,且術後還需嚴格規律複查,因此,治療難度大,復發率高。(李學松,王剛,張騫編.泌尿外科病例精粹,北京大學醫學出版社,2017)。在術後早期(24小時內)作為一次性劑量或在外科手術後幾周作為六劑量方案將絲裂黴素(一種化療藥物)給予至膀胱中也是部分患者可選擇的治療方案。目前基於順鉑的化療仍然是轉移性UC患者的治療金標準,基於順鉑的化療的總體反應率(ORR)為60-70%,總生存期(OS)為14-15個月,5年生存率為13-15%,復發後的患者基
於鉑的化療,ORR約為15%,中位OS約為7個月。
在歐洲已批准長春氟寧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))。經單一藥劑療法測試,若干藥劑已顯示適中活性,且中值存活期為5至10個月(Yafi,F.A.等人,Current Oncol.18(1):e25-e34(2011))。在轉移性情況中,多西他賽(Docetaxel)作為緩解性選擇向移行細胞癌患者投與(NCCN 2014),且美國及加拿大(Canada)醫學界基於來自2期研究的證據認可多西他賽治療晚期疾病的方案(WO2016/064649A1)。
近年來,治療尿路上皮癌的新藥主要有:1.羅氏的Atezolizumab是2016年批准上市的首個抗PD-L1癌症免疫治療藥物,根據最新的Atezolizumab治療局部晚期或轉移性尿道膀胱癌三期臨床試驗(IMvigor211)試驗結果表明:Atezolizumab未滿足III期IMvigor211試驗的主要臨床終點,即改善局部晚期或轉移性尿路上皮癌(mUC)患者二線治療的總生存期(OS),在共234例患者(atezolizumab組116例,化療組118例)中,atezolizumab組的中位總生存期為11.1個月,化療組為10.6個月;該人群中可評估患者的確診客觀反應率分別為23%和22%,中位反應持續時間為15.9個月對8.3個月。
該人群的中位無進展生存期為2.4個月(對照為4.2個月),在意向治療人群的探索性分析中,12個月的總生存率資料:atezolizumab為39.2%,化療為32.4%;atezolizumab的中位總生存期為8.3個月,紫杉烷為7.5個月,長春氟寧為9.2個月。(The ASCO Post,IMvigor211 Trial:Atezolizumab vs Chemotherapy in Platinum-Treated Advanced Urothelial
Carcinoma,Matthew Stenger,9/17/2018)
此外,由於美國資料監測委員會觀測到使用Atezolizumab單一療法與基於鉑的化療療法相比,發現了PD-L1的低表達腫瘤患者的存活率下降的問題,因此在2018年6月,美國FDA發出了限制Atezolizumab(Tecentriq)在適合含順鉑化療的局部晚期或轉移性尿路上皮癌患者中使用的要求。要求在使用Atezolizumab前需先行檢測PD-L1表達水準。這進一步表明了Atezolizumab應用於治療尿路上皮癌的局限性。
2.百時美施貴寶公司的Nivolumab於2017年被FDA批准用於局部晚期或轉移性尿路上皮癌患者,Nivolumab是一種抗PD-1單克隆抗體,臨床資料顯示,Nivolumab的客觀緩解率(ORR)為19.6%,中位數總生存率為8.7個月,最常見嚴重不良事件包括:尿路感染,敗血症,腹瀉,小腸梗阻,以及總體健康狀況退化。最常見的不良反應包括疲勞,肌與骨骼疼痛,噁心,以及食欲減退。17%患者因不良反應停止Nivolumab治療,46%患者因不良反應延遲給藥。在臨床開展中,出現了3例患者由於肺炎或心血管衰竭導致與治療相關的死亡。
綜合以上內容來看,目前臨床階段的PD-L1/PD-1免疫治療藥物的主要問題是治療效果不佳,主要體現在客觀緩解率(ORR)和中位數總生存期等治療資料方面不理想,另一個主要問題是嚴重不良反應占比相對較高,例如:Nivolumab在相關臨床試驗中造成3例死亡病例。
3.強生公司旗下的楊森公司的erdafitinib在2018年被FDA授予突破性藥物資格,用於治療接受化療後病情進展且腫瘤中存在特定成
纖維細胞生長因數(FGFR)基因改變的局部晚期或轉移性尿路上皮癌患者的治療,該藥物屬於一種成纖維細胞生長因數受體(FGFR)酪氨酸激酶抑制劑;其二期臨床研究(BLC2001,NCT02365597)的結果顯示,erdafitinib治療的總緩解率為40%(完全緩解率3%,部分緩解率37%),中位無進展生存期為5.5個月,中位總生存期13.8個月,在總計99例患者中,7例患者因治療相關不良事件停止治療(https://www.jnj.com/media-center/press-releases/erdafitinib-phase-2-study-results-show-promise-in-the-treatment-of-metastatic-urothelial-cancer)。由於該藥的治療靶點是FGFR,因此,其僅適用於具有某些FGFR基因突變的尿路上皮癌患者,而FGFR僅在15%至20%的轉移性尿路上皮癌和40%至70%的非肌層浸潤性膀胱癌過表達(2018 ASCO Annual Meeting,Responses Found in Advanced Urothelial Carcinoma With FGFR Inhibitor)。
從目前的治療來看,晚期尿路上皮癌惡性程度高,預後差,特別是常規化療失敗後,治療手段有限,免疫治療僅能使部分患者獲益,而且可用的免疫治療抑制劑數量也極為有限,客觀緩解率不高,治療副作用較大,或者使用存在特定基因要求;目前患者能夠選擇的治療藥物並不多,因此,仍需要開發治療效果更為顯著、適用更廣的藥物,以滿足臨床的迫切需求。
本發明公開了一種治療尿路上皮癌的方法,所述方法包括向患者注射有效量的抗體藥物偶聯物(ADC),所述ADC為抗HER2抗體
偶聯細胞毒分子。所述細胞毒分子包括但不限於微管蛋白抑制劑或DNA損傷劑。所述微管蛋白抑制劑包括但不限於海兔毒素(dolastatin)及奧瑞他汀(auristatin)類細胞毒分子,美登素(maytansine)類細胞毒分子;所述DNA損傷劑包括但不限於卡奇黴素(calicheamicin)類、倍癌黴素(duocarmycin)類、安麯黴素類衍生物PBD(pyrrolobenzodiazepine,吡咯並苯並二氮雜)、喜樹堿類衍生物SN-38。所述奧瑞他汀(auristatin)類細胞素分子包括但不限於單甲基澳瑞他汀E(monomethyl auristatin E;MMAE)、單甲基澳瑞他汀F(monomethyl auristatin F;MMAF)、和澳瑞他汀F(auristatin F;AF)或它們的衍生物,所述美登素類細胞毒分子包括但不限於DM1、DM3、DM4或它們的衍生物(抗體藥物偶聯物的彈頭分子研究進展,胡馨月等,中國醫藥生物技術,2017年12月,第12卷第6期)(美登素類抗體藥物偶聯物研究進展,周磊等,中國新藥雜誌2016年第25卷第22期,第2521-2530頁)。所述細胞毒分子還可以是瓢菌素(amanitins)、蒽環類物(anthracyclines)、漿果赤黴素(baccatins)、喜樹堿(camptothecins)、西馬多丁(cemadotins)、秋水仙堿(colchicines)、秋水仙胺(colcimids)、考布他汀(combretastatins)、隱菲辛(cryptophycins)、圓皮海綿內酯(discodermolides)、多烯紫杉醇(docetaxel)、阿黴素(doxorubicin)、棘黴素(echinomycins)、艾榴塞洛素(eleutherobins)、埃博黴素(epothilones)、雌莫司汀(estramustines)、偏端黴素(lexitropsins)、美登素(maytansines)、氨甲蝶呤(methotrexate)、紡錘菌素(netropsins)、嘌呤黴素(puromycins)、根瘤菌素(rhizoxins)、紫杉烷(taxanes)、微管蛋白裂解素(tubulysins)、或
長春花生物鹼(vinca alkaloids)。所述細胞毒分子不限於上述類別,包括所有可用於ADC的藥物。
本發明的另一個方面是提供了一種抗體藥物偶聯物(ADC)在製備用於治療膀胱癌的藥物中的用途;所述抗體藥物偶聯物包含結合HER2的抗體或其功能性片段,其中所述抗體包含重鏈可變區和輕鏈可變區,其中(i)所述重鏈可變區包含三個CDR區,其中所述CDR區的氨基酸序列分別具有如SEQ ID NO:1、2和3所示的氨基酸序列;和(ii)所述輕鏈可變區包含三個CDR區,其中所述CDR區的氨基酸序列分別具有如SEQ ID NO:4、5和6所示的氨基酸序列。所述抗體還可以是與上述CDR限定的抗體競爭性結合相同或相近表位的抗體。
本發明中,術語“抗體”可以包括全長抗體或與HER2結合、反應性相關、或複合的抗體片段。抗體可以是任何蛋白質、類蛋白質分子、或多肽,其與尋求治療性修飾的細胞群的一部分結合、複合、或反應。所述抗體可為嵌合抗體或其功能活性片段、人源化抗體或其功能活性片段、人類抗體或其功能活性片段。亦可為上述物種以外的其他物種的抗體或其其功能活性片段,例如:小鼠抗體或其功能活性片段、大鼠抗體或其功能活性片段、羊抗體或其功能活性片段、兔子抗體或其功能活性片段。抗體可為多克隆抗體或單克隆抗體。於一些實施例中,抗體可為雙特異性抗體。此外,抗體也可為功能性活性片段、抗體的衍生物或類似物。“功能性”代表所述片段、衍生物或類似物可辨認相同的抗原,辨認衍生自抗原的片段、衍生物或類似物的抗體,例如但不限於:F(ab’)2、Fab、Fab’、Fv片段及抗體的重鏈及輕鏈二聚體、或其任何
最小片段像是Fvs或單鏈抗體(SCAs)。此外,抗體可為抗體的融合蛋白。抗體也可包括經修飾或未經修飾(亦即,通過任何分子的共價連接)的類似物和衍生物,只要這樣的共價連接允許抗體保留其抗原結合免疫特異性。例如但不限於:抗體的類似物和衍生物,包括經過進一步修飾,例如:糖基化、乙醯化、聚乙二醇化、磷酸化、醯胺化、通過已知的保護/阻隔基衍生化、蛋白酶切割、連接至細胞抗體單元或其他蛋白質等。可利用已知技術實現任何大量的化學修飾,包括但不限於特異性化學切割、乙醯化、甲醯化、衣黴素存在下的代謝合成等。此外,類似物或衍生物可包括一種或多種非天然氨基酸。在一些實施例中,抗體可在與Fc受體作用的氨基酸殘基中具有修飾(例如:取代、刪除、或增加)。另一方面,所述抗體藥物偶聯物具有通式Ab-(L-U)n的結構,其中Ab表示所述的抗體或其功能性片段,L表示接頭;U表示偶聯的細胞毒分子,n為1至8的整數,代表每一抗體上結合的治療劑的分子數量。
本發明的接頭優選馬來醯亞胺基-己醯基-纈氨酸-瓜氨酸-p-氨基苄氧基(Maleimido-Caproyl-Valine-Citrulline-p-Aminobenzyloxy,mc-vc-pAB)和馬來醯亞胺基己醯基(Maleimidocaproyl,mc)。
本發明的接頭也可選擇三甘氨酸肽接頭(triglycyl peptide linker),該接頭是近年來開發的用於ADC藥物偶聯物的新接頭。(Rajeeva Singh et al,A New Triglycyl Peptide Linker for Antibody-Drug Conjugates (ADCs)with Improved Targeted Killing of Cancer Cells,MCT-16-002,Published June 2016.),此外,也可以選擇葡萄糖醛酸接頭(glucuronide-tubulysin)(Patrick J.Burke et al,Glucuronide-linked antibody-tubulysin conjugates display activity in MDR+ and heterogeneous tumor models,Molecular Cancer Therapeutics,2018)。
另一方面,其中所述抗體或其功能性片段衍生自在2013年08月22日以保藏編號CGMCC No.8102保藏於中國微生物菌種保藏管理委員會普通微生物中心的雜交瘤所分泌的抗體。
另一方面,其中所述抗體是人源化抗體,優選地所述抗體是在2013年11月06日以保藏編號CCTCC C2013170保藏于中國典型培養物保藏中心的CHO細胞所分泌的抗體。
在一個實施例中,所使用的抗體藥物偶聯物名稱為RC48-mc-vc-pAB-MMAE,符合通式Ab-(L-U)n的結構,RC48(一種人源化的抗HER2單克隆抗體)通過連接子mc-vc-pAB偶聯MMAE,偶聯數量為1-8個不等,包括偶聯1個,2個,3個,4個,5個,6個,7個,8個或為偶聯1-8個MMAE數量不等的抗體藥物偶聯物的組合。
本發明中,所述尿路上皮癌為無法接受手術切除的局部進展尿路上皮癌、局部晚期或轉移性尿路上皮癌、HER2(人類表皮生長因數受體2,也稱之為ErbB-2、c-erbB2或HER2/neu)陽性尿路上皮癌、HER2陽性局部晚期或轉移性尿路上皮癌。
本發明中所述藥物可通過鼻內、皮下、皮內、肌內或靜脈內施用。
所述藥物還包括藥學上可接受的載體;所述藥物優選為凍幹劑或液體製劑;所述載體包括穩定劑、保護劑、緩衝液、凍幹保護劑、活性保護劑、表面活性劑、吸附載體、吸收促進劑中的一種或多種。
圖1:純化人重組蛋白HER2-ECD的SDS-PAGE圖,經考馬斯亮藍染色。每孔上樣量為10μg。
圖2:表示cRC48(嵌合抗體),RC48(人源化抗體)的SDS-PAGE分析圖,抗體每孔上樣量為2μg。
圖3:顯示了通過ELISA實驗測定的人源化抗體RC48的HER2-ECD的結合親和力,並計算出結合親和力常數Kd。本實驗中Herceptin和cRC48作為對照。
圖4A:表示用流式細胞術分析抗HER2人源化抗體RC48結合HER2+細胞SK-BR3,BT474,HER2-細胞MDA-MB468的能力。
圖4B:顯示流式細胞術分析不同抗體濃度下抗HER2抗體結合BT474細胞表面抗原的能力。抗HER2抗體包括Herceptin,cRC48,RC48。共分析
了5×104個細胞。
圖5:表示RC48只對HER2表現出特異性結合親和力,而對EGFR,HER3,HER4沒有結合。
圖6:受試者編號01001療效示意圖
患者基本情況:女,57歲,右腎盂癌術後,多發肺轉移。病理診斷尿路上皮癌,HER2 IHC 3+;
圖7:受試者編號01003療效示意圖
患者基本情況:女,45歲,右腎盂癌術後,腹腔淋巴結轉移。病理診斷尿路上皮癌,HER2 IHC 3+。
圖8:受試者編號01007療效示意圖
患者基本情況:男,63歲,膀胱癌術後,右腎盂癌術後,肺轉移,肝轉移,頸部淋巴結轉移,縱隔轉移,多發骨轉移。病理診斷尿路上皮癌,,HER2 IHC 3+;
實施例1.鼠源單克隆抗體mRC48的製備與序列分析
1、HER2抗原的表達和純化
編碼HER2-ECD(氨基酸Thr23至Thr652,GenBank登錄號為M11730)的cDNA片段通過PCR克隆到pcDNA3(Invitrogen公司)表達載體上。
具體方法為:通過RT-PCR方法從HER2+SKBR3細胞株(ATCC號:HTB-30)中獲得HER2-ECD編碼區的cDNA(試劑盒採用Promega公司的ImProm-IITM Reverse Transcription System逆轉錄系統)。
引物為:P1:5’CGGGATCCTGCCACCAGCTGTGCGCC(SEQ ID NO:7),P2:5’GCTCTAGA TCAGTTGATGGGGCAAGGCT(SEQ ID NO:8),底線序列分別為引入的BamHI、XbaI酶切位點,以反轉錄的HER2-ECD的cDNA為範本用上述引物進行PCR擴增,擴增條件是:94℃變性30s,60℃退火30s,72℃延伸1分鐘,迴圈30次,最後72℃延伸10分鐘。然後將PCR片段回收,用BamHI和XbaI酶(NEB)進行酶切,與pcDNA3載體連接。HER2-ECD的C末端加入了一個多聚組
氨酸標籤以方便純化。用構建的DNA表達載體轉染HEK293細胞(美國ATCC),利用Ni-NTA親和層析(Qiagen)從細胞培養液中純化His-標記的可溶性蛋白HER2-ECD。SDS-PAGE及考馬斯亮藍染色表明純化的HER2-ECD蛋白具有95%以上的同質性,結果見圖1。可溶性的HER2-ECD以單體形式出現,相對分子量約為75kDa,比計算的分子量(71kDa)稍大,表明蛋白在HEK293細胞中進行了糖基化。將純化得到的HER2-ECD蛋白進一步濃縮,並轉移到無菌pH7.4的PBS緩衝液中,用於隨後的體內和體外分析。
2、雜交瘤細胞的生產與篩選
使用上述製備的HER2-ECD作為抗原免疫小鼠,製備單克隆抗體。免疫反應、雜交瘤細胞融合和初篩都按照標準步驟(參考文獻:WHO Technical Report Series,No.822,1992 Annex 3)進行。0.25ml HER2-ECD蛋白(50-100μg)和0.25ml弗氏完全佐劑(Difco Lab)等體積混合均勻後免疫4只Balb/c小鼠(購自上海斯萊克實驗動物有限責任公司),間隔2周後進行第2次注射,用弗氏不完全佐劑(Difco Lab),抗原量為25-50μg/0.5ml/只小鼠,間隔3周後進行第3次注射,注射劑量同第2次,第3次注射後10天取血。用酶聯免疫吸附試驗(ELISA)檢測小鼠的血清,將血清中抗HER2抗體滴度最大的2只小鼠的脾臟取出,然後與骨髓瘤細胞P3X63Ag8(ATCC CRL-1580)融合。將融合細胞稀釋到10塊96孔板上,根據與HER2-ECD的結合能力用ELISA方法進行初篩。在典型的ELISA實驗中,用HER2-ECD(0.2-1μg/ml)包被Nunc Maxisorb 96孔板,然後用梯度稀釋的小鼠血清或雜交瘤上清液(100μL)孵育。鼠源的抗HER2抗體用辣根過氧化物酶偶聯的山羊F(ab')2抗鼠IgG Fc特異的二抗(Invitrogen公司)進行檢測。
用ELISA法對400個雜交瘤細胞株的上清液進行篩選,其中36個表現出強的HER2-ECD結合力。選擇HER2結合能力最強的十株雜交瘤細胞,通過有限稀釋方法篩選亞克隆雜交瘤細胞株。通過懸浮亞克隆雜交瘤細胞株培養,蛋白純化,用ELISA確定HER2的結合親和力,用流式細胞儀(BD FACS Calibur)來進一步測試上述抗體對自然表達在人乳腺癌細胞株表面的HER2的結合能力(更詳細的描述見實施例4)。最終通過序列分析確定了一株雜交瘤細胞系mRC48(鼠源IgG1k),它具有強的HER2結合能力。所述雜交瘤細胞mRC48在2013年08月22日以保藏編號No.8102保藏於中國微生物菌種保藏管理委員會普通微
生物中心(轉為按照布達佩斯條約之保藏的日期為2013年10月29日)。
3、抗HER2雜交瘤細胞克隆mRC48的序列分析
上述雜交瘤細胞克隆mRC48重鏈和輕鏈的可變區根據說明書利用商業試劑盒SMARTTM RACE cDNA Amplification Kit(Clontech公司)快速擴增5’末端進行測序。
用RNApure Tissue Kit(北京康威世紀生物科技有限公司)從雜交瘤細胞中提取總RNA,使用SMARTTM RACE cDNA Amplification Kit進行總RNA的反轉錄,以總RNA為範本,利用試劑盒中的引物,加入反轉錄酶SMARTScribeTM Reverse Transcriptase,按照試劑盒提供的步驟進行反轉錄獲得RACE-Ready第一鏈cDNA,然後進行兩輪PCR,第一輪PCR以獲得的cDNA為範本,試劑盒中提供的UPM為5’端引物,3’端引物為mRC48-VL-1/mRC48-VH-1。PCR反應條件為:94℃預變性5min;25個擴增迴圈(94℃變性30s,68℃退火30s,72℃延伸2min);最後72℃延伸10min。
第二輪PCR,以第一輪PCR的產物為範本,以試劑盒中提供的NUP為5’端引物,3’端引物為mRC48-VL-2/mRC48-VH-2,PCR反應條件為:94℃預變性5min;25個擴增迴圈(94℃變性30s,68℃退火30s,72℃延伸2min);72℃延伸10min。這樣既獲得上述雜交瘤細胞克隆mRC48重鏈和輕鏈的可變區。
具體引物序列如下:mRC48-VL-1:5’-GTTGGTGCAGCATCAGCCCGTT-3’(SEQ ID NO.9)
mRC48-VL-2:5’-GTTCACTGCCATCAATCTTCCAC-3’(SEQ ID NO.10)
mRC48-VH-1:5’-GCCAGTGGATAGACAGATGG-3’(SEQ ID NO.11)
mRC48-VH-2:5’-AGGTCACTGTCACTGGCTCAG-3’(SEQ ID NO.12)
PCR產物通過瓊脂糖凝膠電泳進行純化,並亞克隆到pCR2.1TOPO克隆載體上(Invitrogen公司)。通過PCR,獲得10個獨立克隆的質粒DNA,進而用M13正向和反向引物測序。DNA序列分析
表明,這10個克隆都具有編碼相同VH或VL多肽的cDNA。互補決定區(CDR)的氨基酸序列通過Kabat編碼表定義,並在表1中列出。序列比較分析表明,抗HER2 mRC48的CDR與已知的HER2抗體包括Herceptin(曲妥珠單抗)有顯著區別。
實施例2.抗HER2單克隆抗體mRC48的人源化(源引自CN105008398A中相應方法)
通過移植輕鏈或重鏈CDR到人的IgG1κ框架區來人源化鼠抗HER2單克隆抗體mRC48。
設計了人源化RC48抗體的輕鏈可變區(RC48-VL),以及人源化RC48抗體的重鏈可變區(RC48-VH),從而組合成為人源化抗HER2抗體:RC48。RC48-VH的整體序列與人IgG1VH基因的相似性分別84%。RC48抗體包含輕鏈可變區RC48-VL和重鏈可變區RC48-VH。
人源化抗HER2單克隆抗體RC48通過CDR移植的方法獲得,重鏈或輕鏈可變區是由南京金斯瑞生物科技有限公司直接合成,合成的可變區包括Kozak共有序列、起始密碼子,重鏈或輕鏈信號肽,人源框架區和鼠源CDR,可變區與人IgG1k恒定區是通過重疊延伸PCR的方法連接成完整片段。
重疊延伸PCR的引物是:重鏈VH1:5 CGCGGATCC GCCGCCACCATGGGATGGAGCT3′(SEQ ID NO:13)
VH2:5GATGGGCCCTTGGTGCTAGCGGAGCTCACTGTCACCAGTGTT3(SEQ ID NO:14)
CH1:5 GCTAGCACCAAGGGCCCATC 3(SEQ ID NO:15)
CH2:5 CCGGAATTCTTTACCGGGAGACAGGGAGA 3(SEQ ID NO:16)
輕鏈:VL1:5 CGCGGATCC GCCGCCACCATGGACATGAGGGT 3(SEQ ID NO:17)
VL2:5 GATGGTGCAGCCACAGTACGCTTTATCTCAACTTTTG T 3 AC3(SEQ ID NO:18)
CL1:5 CGTACTGTGGCTGCACCAT 3(SEQ ID NO:19)
CL2:5 CCGGAATTCACACTCTCCCCTGTTGAAGC 3(SEQ ID NO:20)
對於重鏈的擴增,首先以合成的可變區為範本,以VH1和VH2為引物,人IgG1κ重鏈恒定區為範本,以CH1和CH2為引物,分別擴增重鏈的可變區、恒定區,擴增條件均是:94℃變性30s,60℃退火30s,72℃延伸1分鐘,迴圈30次,最後72℃延伸10分鐘。再以兩次的PCR產物為範本,VH1和CH2為引物,擴增RC48的重鏈序列。擴增條件均是:94℃變性30s,60℃退火30s,72℃延伸2分鐘,迴圈30次,最後72℃延伸10分鐘。
對於輕鏈的擴增,首先以合成的可變區為範本,以VL1和VL2為引物,以人IgG1κ輕鏈恒定區為範本,以CL1和CL2為引物,分別擴增輕鏈的可變區、恒定區,擴增條件均是:94℃變性30s,60℃退火30s,72℃延伸1分鐘,迴圈30次,最後72℃延伸10分鐘。再以兩次的PCR產物為範本,VL1和CL2為引物,擴增輕鏈序列。擴增條件均是:94℃變性30s,60℃退火30s,72℃延伸2分鐘,迴圈30次,最後72℃延伸10分鐘。
因此,得到了人源化抗HER2單克隆抗體RC48,其中RC48包含人IgG1κ重鏈恒定區和重鏈可變區RC48-VH,以及人IgG1κ輕鏈恒定區和輕鏈可變區RC48-VL。
人-鼠嵌合抗體cRC48也是通過相同的方法獲得,將鼠的可變區
和人IgG1k恒定區通過重疊延伸PCR的方法連接成完整片段。
將上述擴增得到的各片段分別亞克隆到表達載體pcDNA3.0上。將構建的不同質粒轉染到懸浮CHO細胞(Invitrogen)中,以產生不同的重組抗體,並利用Protein A進行純化和後續的特徵分析。嵌合的抗-HER2 RC48(被稱為cRC48)是由鼠-人嵌合cRC48重鏈和輕鏈組成。RC48包括人源化重鏈RC48-VH和人源化輕鏈RC48-VL。cRC48和RC48都能夠表達,從CHO細胞上清液中收集所述抗體,經Protein A進行純化,在還原與非還原條件下用SDS-PAGE分析(見圖2)。如上所述分泌RC48抗體的CHO細胞(即轉染了人IgG1κ重鏈恒定區和重鏈可變區RC48-VH,以及人IgG1κ輕鏈恒定區和輕鏈可變區RC48-VL的CHO細胞)在2013年11月06日以保藏編號C2013170保藏于中國典型培養物保藏中心。
實施例3.抗HER2 RC48抗體的表徵分析
用ELISA法測定cRC48(嵌合抗體)和RC48抗體(人源化抗體)的HER2-結合親和力常數(Kd),具體方法可見實施例1,即以可溶性HER2-ECD蛋白包被96孔板,之後與稀釋的抗體(Herceptin和嵌合cRC48作為對照)一起孵育,對於與HER2-ECD相關的抗體(所有形式的人IgG1κ)用HRP-偶聯的羊F(ab’)2抗-人IgG Fc-特異性二抗進行檢測(invitrogen)。繪製結合曲線並進一步用單一位元點特異性結合非線性方程(Journal of Immunological Methods,270:155-162,2002),為每一個抗HER2抗體計算表面結合親和力常數(Kd)值(圖3中展示的是由3次獨立的ELISA實驗得出的一條典型HER2-結合曲線)。ELISA試驗結果見圖3。
從3次獨立的測定試驗可知,與cRC48(平均親和常數77pM)和Herceptin(平均親和常數97pM)相比,RC48(人源化抗體)有顯著提高的HER2-ECD結合親和力,平均親和常數為44pM,結果見表2。
實施例4.RC48(人源化抗體)與HER2的結合力
RC48抗體與HER2的結合親和力試驗
利用流式細胞儀來檢測人乳腺癌細胞內源表達的HER2與人源化抗HER2抗體RC48的結合力,結果見圖3。用6μg對照組人IgG、Herceptin、cRC48、RC48分別與兩種HER2+細胞系人乳腺癌細胞SK-BR-3、BT474以及HER2-細胞MDA-MB468(2×107個細胞)共同孵育,冰上孵育30-45分鐘。用4ml冷的PBS充分洗滌2次之後,細胞表面結合的抗體通過偶聯R-PE的山羊抗人IgG Fc(15μl,25μg/mL)特異性二抗檢測,然後利用流式細胞儀(BDFACSCalibur)進行分析。對照組人IgG1沒有檢測出與上述三種癌症細胞的結合。相比而言,Herceptin、cRC48、RC48與兩種HER2陽性細胞強烈結合,但與HER2陰性細胞不結合,這說明這種結合是HER2特異性的(如圖4a所示)。通過比較同種對照組的平均螢光強度發現,與Herceptin和cRC48相比,RC48表現出更高的結合親和力。通過滴定抗HER2抗體的濃度,以及流式細胞術中分析的細胞數目,得出基於細胞的抗HER2的抗體與細胞表面HER2的結合曲線,結果見圖4b。人源化的抗HER2抗體RC48表現出明顯的結合親和力,與BT474細胞表面HER2結合親和力Kd為4nM,Herceptin、cRC48分別為10nM和5nM,結果見表3:
2)抗原結合特異性試驗
用ELISA方法測定Herceptin、cRC48、RC48結合不同的表面抗原EGFR、HER2、HER3、HER4的能力。ELISA方法見實施例1。分別用抗原EGFR、HER2、HER3、HER4包被96孔板,每孔上樣量為20ng,用不同的抗HER2抗體進行孵育,即Herceptin、cRC48、RC48抗體,然後用辣根過氧化物酶偶聯的羊F(ab′)2抗鼠IgG Fc特異的二抗(Invitrogen公司)進行檢測。結果見圖5,結果表明Herceptin、cRC48、RC48抗體與EGFR、HER3、HER4幾乎無結合力,而與HER2有強的結合力,說明Herceptin、RC48對HER2的結合有高度的特異性。
實施例5.抗體偶聯物的製備
單克隆抗體RC48的純化
經Protein A從CHO細胞培養液中捕獲得到RC48的單克隆抗體,SDS-PAGE電泳及SEC分析純度達到95%以上。用30KD膜包將所獲抗體蛋白超濾透析到PBS緩衝液中,濃縮,用紫外吸光光度計標定濃度,用於後續的偶聯反應。
2)單克隆抗體RC48與藥物分子的偶聯
用PBS緩衝液分別配製還原劑和保護劑如下:1~20mmol/L TCEP(Tris-2-carboxyethyl-phosphine)、1~20mmol/LDTPA(Diethylene
triamine pentacetate acid)母液,還原劑用量根據所需偶聯率不同可在一定濃度範圍內添加,與一定濃度單克隆抗體(如:5~30mg/ml)按照一定體積比(如1:1)混合,TCEP與抗體的終濃度摩爾比0.5~6.0::1,於25℃攪拌反應2h。用DTNB法於412nm檢測自由巰基濃度,與抗體的摩爾比計算自由巰基個數。TCEP還原可重複性好,還原後自由巰基數可以達到1.0-8.0。
TCEP還原後抗體可直接進行後續偶聯。配製一定濃度(10mM)藥物(vc-MMAE、vc-MMAF、mc-MMAF)(購自上海皓元化學科技有限公司)溶於25%的DMSO(dimethyl sulfoxide,二甲亞碸),按照藥物與巰基的摩爾比0.3~2.8:1緩慢加藥,於25℃攪拌反應2h。用DTNB法於412nm檢測自由巰基濃度(接近0),Sephadex G-25純化除去殘餘未反應藥物以及DMSO等游離小分子,SDS-PAGE電泳、反相高效液相(R-HPLC)巰水高效液相(HIC-HPLC)法檢測偶聯情況。
實施例6.抗體藥物偶聯物親和力的測定
ELISA法測親和力
用重組蛋白HER2-ECD(濃度為0.5mg/ml)包被ELISA板,2℃-8℃過夜。洗板機洗板3次。3%BSA-PBST溶液封閉,37度2h。洗板機洗板3次。加樣:用PBST溶液稀釋標線從1000ng/ml起梯度稀釋11個點,100μl/孔,37度2h。洗板機洗板3次。用PBST溶液稀釋二抗(山羊抗人IgG-Fc-HRP)5000倍。加入TMB顯色液顯色,室溫避光顯色8-10分鐘。用2M H2SO4終止試驗,酶標儀450/655nm處讀數。結果見表4。
由結果可知,RC48-VC-MMAE(即RC48-mc-vc-pAB-MMAE)、RC48-VC-MMAF、RC48-MC-MMAF的HER2-ECD親和力與T-DM1相當。
實施例7.單藥治療HER2陽性局部晚期或轉移性尿路上皮癌的有效性和安全性實驗
本實驗的目的是評價單藥治療HER2陽性局部晚期或轉移性尿路上皮癌的有效性和安全性。所使用的抗體藥物偶聯物為RC48-mc-vc-pAB-MMAE,RC48通過連接子mc-vc-pAB偶聯MMAE,偶聯數量為1-8個不等。
其中對於受試者的選擇標準為:年齡:18歲(最小年齡)至80歲(最大年齡)
其中入選標準為:1.自願同意參與研究並簽署知情同意書;2.男性或女性,年齡大於等於18歲且小於60歲;3.預期生存期大於等於12周;4.具有病理學確診的無法接受手術完全切除的局部進展或轉移性膀胱尿路上皮癌;5.受試者確診為無法手術切除的局部進展或轉移性疾病後接受過至少一線全身化療後出現疾病進展或不能耐受;6.至少具有RECIST 1.1標準規定的可測量病灶;7.中心實驗室確認的HER2表達陽性;8. ECOG體力狀況0或1分;9.足夠的心、骨髓、肝、腎功能;10.對於女性受試者:應為手術絕育、絕經後的患者,或同意在研究治療期間和研究治療期結束後6個月內至少採用一種經醫學認可的避孕措施(如宮內節育器,避孕藥或避孕套);男性受試者應同意在研究治療期間和研究治療期結束後6個月內至少採用一種經醫學認可的避孕措施(如避孕套、禁欲等);11.願意且能夠遵從試驗和隨訪程式安排。
同時,排除標準為:1.已知對重組人源化抗HER2單抗-MMAE偶聯劑藥物及其組分過敏者;2.研究治療開始前4周內接受過其他抗腫瘤治療;3.既往接受過重組人源化抗HER2單抗-MMAE偶聯劑藥物;4.研究給藥開始前4周內進行過大型手術且未完全恢復;
5.研究給藥開始前4周內接種過活疫苗或計畫在研究期間接受任何疫苗;6.其他可能影響方案依從性或干擾結果解釋的嚴重的、無法控制的伴隨疾病;7.研究給藥開始前5年內患有其他惡性腫瘤;8.患有中樞神經系統轉移和/或癌性腦膜炎;9.有在過去2年內需要系統治療的活動性自身免疫性疾病;10.既往接受過異體造血幹細胞移植或實體器官移植;11.伴有臨床症狀或需要對症處理的大量胸水或腹水;12.妊娠或哺乳期婦女;13. HIV檢測結果陽性;14.活動性乙型肝炎或丙型肝炎患者;15.活動性結核病史;16.患有任何其它疾病,代謝異常,體格檢查異常或實驗室檢查異常,根據研究者判斷,有理由懷疑患者具有不適合使用研究藥物的某種疾病或狀態,或者將會影響研究結果的解讀,或者使患者處於高風險的情況;17.估計患者參加本臨床研究的依從性不足。
具體實驗方法:
本研究將納入既往接受過至少一線全身化療失敗或不能耐受的局部晚期或轉移性尿路上皮癌受試者,且具有可測量病灶,一般情況及器官功能良好。所有受試者送檢腫瘤組織病理切片至中心實驗室檢測確認HER2表達陽性,其陽性定義為免疫組化(IHC)為2+或3+(無論螢光原位雜交[FISH]檢測結果)。
本研究中HER2免疫組化(IHC)的結果判定依據中國《乳腺癌HER2檢測指南(2014版)》中的HER2判讀標準。具體如表5所示。
表5中國《乳腺癌HER2檢測指南(2014版)》中的HER2判讀標準。
符合所有研究人群標準的受試者接受RC48-ADC治療(2.0mg/kg,靜脈滴注,每2週一次),每6周進行療效評價,直至發生疾病進展、不可耐受毒性或主動退出。研究的主要終點指標為獨立評估的客觀緩解率(ORR),次要研究終點為無進展生存期、總生存期以及治療的安全性。
研究結果:
該研究於2017年12月啟動,截至2018年7月31日,共入組18例受試者接受治療,其中男性15例,女性3例,中位年齡63歲。原發病灶包括膀胱(50.0%)、腎盂(27.8%)和輸尿管(22.2%),主要的轉移部位為肺、肝以及淋巴結轉移。16例(88.9%)既往接受過一線鉑類治療。受試者腫瘤HER2表達經中心實驗室確認的免疫組化(IHC)結果為11例(61.1%)IHC2+,7例(38.9%)IHC3+。
18例受試者中有13例受試者進行了療效評估,部分緩解(PR)10例(4例已確認PR(連續兩次評效為PR稱為確認PR)。根據RECIST
標準“當每一個受試者符合部分或者完全緩解標準而且在隨後的時間點(一般是四周後)再次做療效確認後才能認為是完全或者部分緩解”,即受試者連續兩次評效為PR,稱為確認PR。其他6例還未到再次療效確認時間點,目前僅完成一次確認),客觀緩解率(ORR)為76.9%(10/13),疾病控制率(DCR)(13例療效評估者中10例PR,2例疾病穩定(SD))為92.3%(12/13)。目前受試者最長治療時間超過7個月。獲得疾病緩解的受試者中,7例(53.8%)接受過紫杉類藥物治療,4例(30.8%)接受過PD-1/PD-L1治療。
18例受試者中,有16例接受了安全性評估,安全性評估中最常見的治療相關不良反應(TRAEs)為ALT升高(50.0%,1-2級)、感覺減退(50.0%,1-2級)和白細胞計數降低(50.0%,1-2級);3級的TRAE為中性粒細胞計數下降(12.5%,3級)。無藥物相關嚴重不良事件(SAE)發生。
下方為部分病例直觀治療效果描述:
1.患者01001:女,57歲,右腎盂癌術後,多發肺轉移。病理診斷尿路上皮癌,HER2 IHC 3+;根據圖6可以看出:經過長達12周的治療,其位於右肺下葉的腫瘤病灶經過6周、12周的治療後,腫瘤病灶從54×31mm縮小到37×23mm,縮小了49%。
2.患者01003,女,45歲,右腎盂癌術後,腹腔淋巴結轉移。病理診斷尿路上皮癌,HER2 IHC 3+;根據圖7可以看出:通過6周的治療,其位於右腰大肌旁的腫瘤病灶從56×48mm縮小到33×22mm,縮小了72.9%。
3.患者01007,男,63歲,膀胱癌術後,右腎盂癌術後,肺轉移,肝轉移,頸部淋巴結轉移,縱隔轉移,多發骨轉移。病理診斷尿路上皮癌,,HER2 IHC 3+;
根據圖8可以看出:位於左上肺葉、肝轉移、縱隔淋巴結的腫瘤病灶經過為期6周的治療,病灶處的腫瘤面積均有明顯的縮小。左上肺葉從45×36mm縮小到28×22mm,減少61.9%,肝轉移處從38×32mm縮小到25×21mm,減少56.8%,縱隔淋巴結從29×15mm縮小到18×7mm,減少71.03%。
以上臨床資料及直觀病理檢測均表明本發明的抗HER2單抗-MMAE偶聯劑藥物具有非常顯著的治療效果;通過與目前的上市藥物對比,也可以看出:其明顯優於目前已經被歐盟和美國批准的同類藥物,例如:羅氏的Atezolizumab三期臨床資料顯示ORR僅為23%,百時美施貴寶公司的Nivolumab的ORR僅為19.6%,而楊森公司的erdafitinib僅針對具有某些FGFR基因突變的尿路上皮癌患者,反觀本發明的重組人源化抗HER2單抗-MMAE偶聯劑藥物的ORR為76.9%,疾病控制率(DCR)為92.3%,明顯優於目前上市的同類藥物,並且副作用也明顯小於同類藥物,未發生任何嚴重不良反應(SAE),針對的患者更為廣泛,為急需治療的尿路上皮癌患者提供了另一種選擇;由此可見,本發明的抗HER2抗體偶聯物在治療尿路上皮癌中有著極佳的應用前景,能夠有效改善,甚至逆轉患者的疾病發展進程,取得了預料不到的技術效果。
<110> 荣昌生物制药(烟台)有限公司
<120> 抗HER2抗体药物偶联物在治疗尿路上皮癌中的用途
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Claims (7)
- 一種抗體藥物偶聯物(ADC)在製備用於治療尿路上皮癌的藥物中的用途,所述抗體藥物偶聯物具有通式Ab-(L-U)n的結構,其中Ab表示抗HER2(人表皮生長因數受體2)抗體或其功能性片段,L表示接頭;U表示偶聯的細胞毒分子,n為1至8的整數,代表每一抗體上結合的治療劑的分子數量,其中:所述抗體或其功能性片段包含重鏈可變區和輕鏈可變區:(i)所述重鏈可變區包含三個CDR區,其中所述CDR區的氨基酸序列分別具有如SEQ ID NO:1、2和3所示的氨基酸序列;和(ii)所述輕鏈可變區包含三個CDR區,其中所述CDR區的氨基酸序列分別具有如SEQ ID NO:4、5和6所示的氨基酸序列;所述接頭包括馬來醯亞胺基-己醯基-纈氨酸-瓜氨酸-p-氨基苄氧基(Maleimido-Caproyl-Valine-Citrulline-p-Aminobenzyloxy,mc-vc-pAB);所述細胞毒分子包括MMAE(單甲基耳抑素肽E)。
- 根據請求項1所述的用途,其中所述抗體或其功能性片段為鼠源、嵌合或人源化的。
- 根據請求項1或2所述的用途,其中所述抗體或其功能性片段衍生自在2013年08月22日以保藏編號CGMCC No.8102保藏於中國微生物菌種保藏管理委員會普通微生物中心的雜交瘤所分泌的抗體。
- 根據請求項1或2所述的用途,其中所述抗體是在2013年11月06日以保藏編號CCTCC C2013170保藏於中國典型培養物保藏中心的CHO細胞所分泌的抗體。
- 根據請求項1或2所述的用途,所述尿路上皮癌為無法接受手術切除的局部進展尿路上皮癌、局部晚期或轉移性尿路上皮癌、HER2(人表皮生長因數受體2)陽性尿路上皮癌、HER2(人表皮生長因數受體2)陽性局部晚期或轉移性尿路上皮癌。
- 根據請求項1或2所述的用途,所述藥物還包括藥學上可接受的載體;所述藥物優選為凍幹劑或液體製劑;所述載體包括穩定劑、保護劑、緩衝液、凍幹保護劑、活性保護劑、表面活性劑、吸附載體、 吸收促進劑中的一種或多種。
- 根據請求項1或2所述的用途,所述藥物可通過鼻內、皮下、皮內、肌內或靜脈內施用。
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TW108130782A TWI767139B (zh) | 2018-08-29 | 2019-08-28 | 抗her2抗體藥物偶聯物在治療尿路上皮癌中的用途 |
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US (1) | US20200289663A1 (zh) |
EP (1) | EP3845252A4 (zh) |
JP (2) | JP7105304B2 (zh) |
KR (3) | KR20240033092A (zh) |
CN (1) | CN111655295B (zh) |
AU (2) | AU2019330680A1 (zh) |
BR (1) | BR112020010856A8 (zh) |
CA (1) | CA3077260C (zh) |
RU (1) | RU2750817C1 (zh) |
SG (1) | SG11202009130XA (zh) |
TW (1) | TWI767139B (zh) |
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US20200289663A1 (en) * | 2018-08-29 | 2020-09-17 | Remegen, Ltd | Use of anti-her2 antibody-drug conjugate in treating urothelial carcinoma |
BR112023023398A2 (pt) * | 2021-05-21 | 2024-01-23 | Remegen Co Ltd | Usos de um conjugado anticorpo-droga em combinação com um inibidor de checkpoint imune e de uma quantidade eficaz de conjugado anticorpo-droga e um inibidor de checkpoint imune, método para tratar um paciente com câncer urotelial, e, composição farmacêutica |
TW202313121A (zh) * | 2021-05-24 | 2023-04-01 | 中國大陸商榮昌生物製藥(煙臺)股份有限公司 | Her2靶向抗體-藥物結合物用於治療her2-低表現乳癌之用途 |
CN115925954A (zh) * | 2022-12-28 | 2023-04-07 | 广州誉衡生物科技有限公司 | 抗-pd-1抗体及其在制备治疗尿路上皮癌患者的药物中的用途 |
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Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2015074528A1 (zh) * | 2013-11-19 | 2015-05-28 | 烟台荣昌生物工程有限公司 | 抗her2抗体及其缀合物 |
US20170209594A1 (en) * | 2015-06-25 | 2017-07-27 | Immunomedics, Inc. | Synergistic effect of anti-trop-2 antibody-drug conjugate in combination therapy for triple-negative breast cancer when used with microtubule inhibitors or parp inhibitors |
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---|---|---|---|---|
CA2837167A1 (en) * | 2011-05-27 | 2012-12-06 | Ambrx, Inc. | Compositions containing, methods involving, and uses of non-natural amino acid linked dolastatin derivatives |
CN103319599B (zh) * | 2013-05-27 | 2015-02-18 | 上海交联药物研发有限公司 | 一种抗人ErbB2抗体—美登木素偶联物及其应用 |
EP3868379A1 (en) * | 2014-05-22 | 2021-08-25 | Byondis B.V. | Site-specific conjugation of linker drugs to antibodies and resulting adcs |
TW201625304A (zh) | 2014-10-24 | 2016-07-16 | 美國禮來大藥廠 | 泌尿上皮癌之療法 |
ES2789500T5 (es) * | 2015-05-29 | 2023-09-20 | Hoffmann La Roche | Procedimientos terapéuticos y de diagnóstico para el cáncer |
CN107029244B (zh) * | 2016-02-04 | 2021-04-27 | 浙江昭华生物医药有限公司 | 抗her2抗体-药物偶联物及其应用 |
US20180282402A1 (en) * | 2016-11-30 | 2018-10-04 | Atyr Pharma, Inc. | Anti-hrs antibodies and combinaton therapies for treating cancers |
CN107789631B (zh) * | 2017-11-03 | 2021-03-16 | 合肥瀚科迈博生物技术有限公司 | 抗人ErbB2双表位抗体-药物偶联物及其应用 |
US20200289663A1 (en) * | 2018-08-29 | 2020-09-17 | Remegen, Ltd | Use of anti-her2 antibody-drug conjugate in treating urothelial carcinoma |
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Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2015074528A1 (zh) * | 2013-11-19 | 2015-05-28 | 烟台荣昌生物工程有限公司 | 抗her2抗体及其缀合物 |
US20170209594A1 (en) * | 2015-06-25 | 2017-07-27 | Immunomedics, Inc. | Synergistic effect of anti-trop-2 antibody-drug conjugate in combination therapy for triple-negative breast cancer when used with microtubule inhibitors or parp inhibitors |
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Title |
---|
Bladder Cancer. 2018 Jul 30;4(3):247-259. * |
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AU2022252734A1 (en) | 2022-11-03 |
CA3077260C (en) | 2023-03-07 |
JP7105304B2 (ja) | 2022-07-22 |
WO2020042941A1 (zh) | 2020-03-05 |
RU2750817C1 (ru) | 2021-07-05 |
EP3845252A1 (en) | 2021-07-07 |
BR112020010856A8 (pt) | 2023-03-07 |
KR20200134268A (ko) | 2020-12-01 |
EP3845252A4 (en) | 2022-06-15 |
JP2022130744A (ja) | 2022-09-06 |
TW202023626A (zh) | 2020-07-01 |
KR20230051318A (ko) | 2023-04-17 |
US20200289663A1 (en) | 2020-09-17 |
CN111655295B (zh) | 2024-05-28 |
SG11202009130XA (en) | 2020-10-29 |
AU2019330680A1 (en) | 2020-04-23 |
JP7470154B2 (ja) | 2024-04-17 |
JP2021504427A (ja) | 2021-02-15 |
CN111655295A (zh) | 2020-09-11 |
KR20240033092A (ko) | 2024-03-12 |
KR102520974B1 (ko) | 2023-04-17 |
CA3077260A1 (en) | 2020-03-05 |
TW202310877A (zh) | 2023-03-16 |
BR112020010856A2 (pt) | 2021-03-09 |
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