TW202313121A - Her2靶向抗體-藥物結合物用於治療her2-低表現乳癌之用途 - Google Patents
Her2靶向抗體-藥物結合物用於治療her2-低表現乳癌之用途 Download PDFInfo
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Abstract
本發明提供HER2靶向抗體-藥物結合物於製備用於治療患有HER2-低表現乳癌之患者之藥劑中的用途。
Description
本發明係關於治療HER2-低表現乳癌之領域,及人類表皮生長因子受體2 (HER2)靶向抗體-藥物結合物於治療患有HER2-低表現乳癌之患者之用途。
人類表皮生長因子受體2 (HER2),亦稱作ERBB-2或原癌基因Neu,為藉由染色體17q12上之ERBB2 (HER2)基因編碼之酪胺酸蛋白激酶受體(Moasser M.M. The oncogene HER2: Its signaling and transforming functions and its role in human cancer pathogenesis. Oncogene. 2007;26: 6469-6487)。除了表皮生長因子受體(EGFR,ERBB-1)、人類表皮生長因子受體3 (HER3,ERBB-3)及人類表皮生長因子受體4 (HER4,ERBB-4)外,HER2亦為表皮生長因子受體家族之成員。因為HER2蛋白不具有用於配位體結合之細胞外區,所以無生長因子可直接結合至其。然而,其可與EGF受體家族之配位體結合成員形成異二聚體,從而增強激酶介導之下游信號(Iqbal N., Iqbal N. Human epidermal growth factor receptor 2 (HER2) in cancers: Overexpression and therapeutic implications. Mol. Biol. Int. 2014: 852748)。
HER2在胃腸道、呼吸道、生殖道、尿道、皮膚、乳房、胎盤等之上皮細胞膜上,以及在心肌及骨骼肌細胞上表現(Uhlen M等人,Proteomics. Tissue-based map of the human proteome. Science. 2015;347:1260419)。於胚胎組織中,HER2之表現程度一般高於對應正常成人組織中之表現程度(Press M.F.等人,Expression of the HER-2/neu proto-oncogene in normal human adult and fetal tissues. Oncogene. 1990 5(7):953-62)。HER2之過度表現可透過各種機制促進腫瘤發生,諸如乳癌、胃癌及肺癌。
乳癌為婦女中之常見惡性腫瘤。由於人們生活方式觀念及生態環境之變化,乳癌之發病率亦正在顯著增加。根據目前治療指導方針,一般將乳癌分類成HER2-陽性或HER2-陰性。HER2-陽性一般係指IHC 3+或IHC 2+/FISH+ (IHC:免疫組織化學檢測;FISH:螢光原位雜交檢測)。此外,存在HER2-低表現患者(IHC 2+/FISH陰性或IHC1+) (metastatictrialtalk.org/research-news/HER2-low-expressing-a-new-subcategory-of-HER2-negative-breast-cancer/)。根據臨床統計,超過50%之乳癌可為具有低HER2表現程度之乳癌(Tarantino P等人,HER2-low breast cancer: pathological and clinical landscape. J Clin Oncol. 2020;38(17):1951-1962。doi:10.1200/JCO.19.02488;Wolff A.C.等人,Human epidermal growth factor receptor 2 testing in breast cancer: American society of clinical oncology/college of american pathologists clinical practice guideline focused update. J. Clin. Oncol. 2018;36: 2105-2122。doi: 10.1200/JCO.2018.77.8738)。
抗體-藥物結合物(ADC)為藉由將單株抗體透過鍵聯單元共價結合至細胞毒性藥物而形成之分子。於抗體結合至癌細胞表面上之特定抗原後,細胞毒性藥物釋放至細胞中以發揮其效應。使用可裂解鍵聯單元,可將ADC工程改造以自靶細胞釋放至細胞外空間,使得可表現或可不表現ADC標靶抗原之周圍及旁觀者細胞可藉由攝取細胞毒性藥物而被殺死(Beck A.等人,Strategies and challenges for the next generation of antibody-drug conjugates. Nat. Rev. Drug Discov. 2017;16:315-337;Staudacher A.H., Brown M.P. Antibody drug conjugates and bystander killing: Is antigen-dependent internalisation required? Br. J. Cancer. 2017;117:1736-1742)。
目前,各種靶向HER2之抗體-藥物結合物已用於乳癌之臨床研究中(參見表1)。
表 1 :靶向 HER2 之 ADC 。
藥物名稱 | 全球最高研發狀態 | 最初研發公司 |
Fam-曲妥珠單抗(trastuzumab)德魯替康(deruxtecan) | 批准推出 (2019) | Daiichi Sankyo Co., Ltd. |
Ado-曲妥珠單抗恩坦辛(emtansine) | 批准推出(2013) | Genentech |
維迪西妥單抗(Disitamab Vedotin) | 應用於推出 | RemeGen Co., Ltd. |
TAA-013 | 3期臨床 | TOT Biopharm Co., Ltd. |
曲妥珠單抗多卡肼(duocarmazine) | 3期臨床 | Synthon |
BAT-8001 | 3期臨床 | Bio-Thera |
ARX-788 | 3期臨床 | Ambrx |
派特裡土單抗(Patritumab)德魯替康 | 2期臨床 | Daiichi Sankyo Co., Ltd. |
MRG-002 | 2期臨床 | Shanghai Miracogen Inc. |
A-166 | 2期臨床 | Sichuan Kelun Pharmaceutical Co., Ltd. |
曲妥珠單抗結合物 | 1期臨床 | Biointegrator |
抗HER2 ADC | 1期臨床 | Pfizer |
GQ-1001 | 1期臨床 | |
維迪西妥單抗 | 1期臨床 | CSPC Zhongqi Pharmaceutical Technology (Shijiazhuang) Co., Ltd. |
ZW-49 | 1期臨床 | Zymeworks Inc |
重組抗HER2人源化單株抗體-DM1 | 1期臨床 | Qilu Pharmaceutical Co., Ltd. |
ALT-P7 | 1期臨床 | Alteogen |
GB-251 | 1期臨床 | Genor Biopharma Co., Ltd. |
LCB14-0110 | 1期臨床 | Legochembio |
SHR-A1201 | 1期臨床 | Jiangsu Hengrui Pharmaceuticals Co., Ltd. |
重組抗HER2抗體-Tub114 | 1期臨床 | Hangzhou DAC Biotechnology Co., Ltd. |
抗HER2單株抗體-MCC-DM1結合物 | 1期臨床 | Shanghai Jiaolian Drug Research and Development Co., Ltd.; Shanghai Pharmaceuticals Holding Co., Ltd. |
RG-6148 | 1期臨床 | Roche |
然而,因為目前銷售之靶向HER2之藥物均針對HER2陽性患者,其不可有效用於治療HER2-低表現患者(IHC 2+/FISH陰性或IHC1+)。
自臨床資訊中所揭示之數據,僅利用DS-8201治療之HER2-低表現晚期或轉移性乳癌患者具有積極治療效應,其中客觀緩解率(ORR)為37.0%,中值反應持續時間為10.4個月,中值無進展生存期為11.1個月,及中值總生存期為29.4個月(95% CI,12.9至29.4) (www.onclive.com/view/trastuzumab-deruxtecan-is-active-in-HER2-low-expressing-breast-cancer)。
因此,此項技術中對組合物,諸如抗HER2抗體藥物結合物,此等組合物之用途及用於治療HER2-低表現乳癌之方法存在需求。
本文中引用之所有參考文獻(包含專利申請案、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)治療HER2-低表現乳癌患者之方法及用途。此等方法及用途至少部分基於大量臨床數據之深入分析。本發明出人意料地發現,ADC於治療HER2-低表現乳癌患者中產生意外技術效果。具體而言,RC48-ADC顯示於HER2-陽性及HER2-低表現患者子組中之一致治療功效。
於一個態樣中,本文中提供抗體-藥物結合物(ADC)於製備用於治療患有人類表皮生長因子受體2 (HER2)-低表現乳癌之患者之藥劑中的用途,其中該ADC具有通式Ab-(L-U)
n之結構,其中:Ab表示抗HER2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;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序列及/或該輕鏈可變區之CDR序列具有與維迪西妥單抗相同之CDR序列;其中該連接子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HER2抗體,及該連接位點為該抗HER2抗體之鏈間二硫鍵位點;且其中該細胞毒性分子U包括MMAE (單甲基澳瑞他汀E)。
於另一態樣中,本文中提供一種治療患有人類表皮生長因子受體2 (HER2)-低表現乳癌之患者之方法,其包括向該患者投與治療上有效量之抗體-藥物結合物(ADC),其中該ADC具有通式Ab-(L-U)
n之結構,其中:Ab表示抗HER2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;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序列及/或該輕鏈可變區之CDR序列具有與維迪西妥單抗相同之CDR序列;其中該連接子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HER2抗體,及該連接位點為該抗HER2抗體之鏈間二硫鍵位點;且其中該細胞毒性分子U包括MMAE (單甲基澳瑞他汀E)。
於可與上述態樣中之任一者組合之一些實施例中,該HER2-低表現乳癌患者為其HER2經檢測為免疫組織化學(IHC) 2+/螢光原位雜交(FISH)陰性或IHC1+之患者。於可與上述態樣或實施例中之任一者組合之一些實施例中,HER2於來自乳癌之樣品中經檢測為IHC 2+/FISH陰性或IHC1+。於可與上述態樣或實施例中之任一者組合之一些實施例中,HER2係使用免疫組織化學(IHC)分析及/或螢光原位雜交(FISH)分析檢測。
於可與上述態樣或實施例中之任一者組合之一些實施例中,該抗HER2抗體為鼠類、嵌合、人源化或全人類抗體。於可與上述態樣或實施例中之任一者組合之一些實施例中,該抗HER2抗體為IgG類別。於一些實施例中,該抗HER2抗體具有IgG1、IgG2或IgG4同型。
於可與上述態樣或實施例中之任一者組合之一些實施例中,該抗HER2抗體包含重鏈可變區(VH)及輕鏈可變區(VL),其中:(a)該VH包含包含胺基酸序列GYTFTDYY (SEQ ID NO:3)之CDR-H1,包含胺基酸序列VNPDHGDS (SEQ ID NO:4)之CDR-H2,及包含胺基酸序列ARNYLFDH (SEQ ID NO:5)之CDR-H3,且(b)該VL包含包含胺基酸序列QDVGTA (SEQ ID NO:6)之CDR-L1,包含胺基酸序列WAS (SEQ ID NO:7)之CDR-L2,及包含胺基酸序列HQFATYT (SEQ ID NO:8)之CDR-L3。
於可與上述態樣或實施例中之任一者組合之一些實施例中,該抗HER2抗體包含重鏈可變區(VH)及輕鏈可變區(VL),其中:(a)該VH包含包含胺基酸序列DYYIH (SEQ ID NO: 11)之CDR-H1,包含胺基酸序列RVNPDHGDSYYNQKFKD (SEQ ID NO: 12)之CDR-H2,及包含胺基酸序列ARNYLFDHW (SEQ ID NO: 13)之CDR-H3,且(b)該VL包含包含胺基酸序列KASQDVGTAVA (SEQ ID NO: 14)之CDR-L1,包含胺基酸序列WASIRHT (SEQ ID NO: 15)之CDR-L2,及包含胺基酸序列HQFATYT (SEQ ID NO: 8)之CDR-L3。
於可與上述態樣或實施例中之任一者組合之一些實施例中,該抗HER2抗體包含包含SEQ ID NO: 9之胺基酸序列之重鏈可變區(VH)及包含SEQ ID NO: 10之胺基酸序列之輕鏈可變區(VL)。
於可與上述態樣或實施例中之任一者組合之一些實施例中,該抗HER2抗體為人類IgG抗體。於可與上述態樣或實施例中之任一者組合之一些實施例中,該抗HER2抗體為人類IgG1、IgG2、IgG3或IgG4抗體。
於可與上述態樣或實施例中之任一者組合之一些實施例中,該抗體之重鏈之胺基酸序列示於SEQ ID NO:1中,及該抗體之輕鏈之胺基酸序列示於SEQ ID NO:2中。
於可與上述態樣或實施例中之任一者組合之一些實施例中,該ADC為維迪西妥單抗或其生物類似物。
於可與上述態樣或實施例中之任一者組合之一些實施例中,該ADC之平均藥物對抗體比率(DAR)值為2至7之任何數字。於可與上述態樣或實施例中之任一者組合之一些實施例中,該平均DAR值為4 ± 0.5。
於可與上述態樣或實施例中之任一者組合之一些實施例中,該乳癌為經藉由組織學及/或細胞學確立之浸潤性局部晚期或轉移性乳癌,且不可切除。
於可與上述態樣或實施例中之任一者組合之一些實施例中,該患者先前已接受一或多種先前治療。於一些實施例中,該一或多種先前治療選自化療藥物、靶向療法、免疫療法及內分泌療法。於可與上述態樣或實施例中之任一者組合之一些實施例中,該患者先前已接受紫杉烷(taxane)全身療法。於可與上述態樣或實施例中之任一者組合之一些實施例中,該患者先前已接受利用曲妥珠單抗或其生物類似物之全身療法至少一次。
於可與上述態樣或實施例中之任一者組合之一些實施例中,該藥劑或ADC係經鼻內、經皮下、經真皮內、經肌肉內或經靜脈內投與。
於可與上述態樣或實施例中之任一者組合之一些實施例中,該ADC係以每2週2.0 mg/kg之劑量投與。
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。藉由所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24日申請之中國申請案第202110565350.2號之優先權效益,其全文係以引用的方式併入本文中。
本發明提供靶向人類表皮生長因子受體2 (HER2)之抗體-藥物結合物,以及其用於治療HER2-低表現乳癌之方法及用途。本發明至少部分基於數據分析,該分析顯示,出人意料地,藉由本發明提供之靶向HER2之抗體-藥物結合物(ADC) (例如,維迪西妥單抗,即,RC48-ADC)顯示於HER2陽性及HER2-低表現患者子組中之一致治療功效。參見,本文中
實例 1。本文中所提供之抗體-藥物結合物、方法及用途極大地填補針對HER2-低表現乳癌之治療之臨床需求的短缺。因此,HER2-低表現乳癌患者亦可自本發明之抗體-藥物結合物(例如,RC48-ADC)、方法及用途顯著受益。
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, p3558 (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、Kabat、Chothia、AbM及Contact系統,其於此項技術中熟知。
如本發明中所用,術語「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。如本發明中所用,「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來製備,或可藉由使用重組DNA技術遺傳工程改造。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「鼠類抗體」為根據此項技術中之知識及技能製備之單株抗體。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融合瘤分離。於一些實施例中,鼠類抗體或其抗原結合片段可進一步包含鼠類κ或λ鏈或其變異體之輕鏈恆定區,或進一步包含鼠類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」為鼠類抗體之可變區與人類抗體之恆定區融合,及可降低藉由鼠類抗體誘導之免疫反應之抗體。當建立嵌合抗體時,首先建立分泌鼠類特異性單株抗體之融合瘤。然後,自鼠類融合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。於本發明之一實施例中,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。於本發明之另一實施例中,嵌合抗體之抗體重鏈進一步包含人類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。於一些實施例中,人類抗體之恆定區為人類IgG2或IgG4之重鏈恆定區。或者,可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。人源化抗體包含源自非人類抗體之CDR區而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,即藥物對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,產生最多8個游離巰基。因此,IgG抗體將具有最多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;及當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。
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 2 : 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 (IMGT 編號 ) 。
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 |
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(Kabat編號):
表 3 : 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 (Kabat 編號 ) 。
HCDR1: | DYYIH | SEQ ID NO: 11 |
HCDR2: | RVNPDHGDSYYNQKFKD | SEQ ID NO: 12 |
HCDR3: | ARNYLFDHW | SEQ ID NO: 13 |
LCDR1: | KASQDVGTAVA | SEQ ID NO: 14 |
LCDR2: | WASIRHT | SEQ ID NO: 15 |
LCDR3: | HQFATYT | SEQ ID NO: 8 |
於一些實施例中,該抗HER2抗體包含由
SEQ ID N O :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:11 至 15 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:11 至 15 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)抗體為鼠類、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
於一些實施例中,本發明之抗體-藥物結合物為維迪西妥單抗(例如,RC48-ADC),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該抗體;且平均DAR值為4 ± 0.5。
於一些實施例中,本發明中涉及(例如,用於根據本發明治療)之乳癌為HER2表現陽性乳癌,較佳地經藉由組織學及/或細胞學確立之浸潤性局部晚期或轉移性乳癌,且不可切除。
於一些實施例中,本發明中涉及(例如,根據本發明治療)之乳癌為HER2-低表現乳癌。因此,於一些實施例中,本發明中涉及(例如,根據本發明治療)之患者為HER2-低表現乳癌患者。於一些實施例中,根據本發明之HER2-低表現乳癌(例如,於患者中)經檢測為免疫組織化學(IHC) 2+/螢光原位雜交(FISH)陰性或IHC1+,例如,於來自乳癌之樣品中。於一些實施例中,根據本發明之HER2-低表現乳癌(例如,於患者中)經檢測為IHC 2+/FISH陰性或IHC1+,例如,於來自乳癌之樣品中。
於一些實施例中,HER2係使用此項技術中已知之任何適宜方法檢測及/或評估。例如,HER2可使用免疫組織化學(IHC)分析及/或螢光原位雜交(FISH)分析檢測及/或評估。以下提供可根據本發明使用之用於檢測及評估HER2之示例性方法。
HER2之檢測及評估可使用各種樣品/標本進行。例如,根據本發明使用之腫瘤樣品/標本之來源包括(但不限於):具有超過100個癌細胞之1)手術切除標本;2)活組織檢查標本;及/或3)細胞學標本。
根據本發明使用之樣品/標本可根據此項技術中之已知方法及技術處理,例如,使用下列步驟中之一或多者或所有:
(1)於分離後立即將標本浸漬至等於標本體積8至10倍之標準固定溶液中及使用10%中性緩衝福馬林固定劑固定(一些大的標本可需要切割及固定);
(2)在室溫下使用6至72小時之固定時間固定;及
(3)蠟塊包埋,例如,藉由及時更換組織脫水之試劑及浸蠟以確保充分脫水及浸蠟效果。
HER2之檢測可藉由FISH進行,例如,使用下列步驟中之一或多者或所有:
(1)選擇腫瘤組織之代表性蠟塊。藉由專業及技術人員切片,切片係完整、光滑、厚度均勻,而不影響刀痕褶皺之診斷(排除含有鈣化粒子及其他不可控因素之組織),切片厚度:4至5 μm;
(2)將組織切片使用下列方法中之任一者預處理:
方法 1 ( 手動操作 ):
a)於二甲苯中浸漬及脫蠟兩次,每次15分鐘,及然後在室溫下於100%乙醇中浸漬5分鐘,
b)在室溫下,各自於100%乙醇、85%乙醇及70%乙醇中再水化2分鐘,然後在室溫下於去離子水中浸漬3分鐘,
c)用90至93℃去離子水處理20分鐘,
d)將1 ml胃酶儲存溶液(200 mg/ mL)溶解於200 ml 0.01M HCl中以獲得胃酶工作溶液(1 mg/ml);將組織切片浸泡於胃酶工作溶液中及在37℃下培育15至30分鐘(時間取決於組織厚度,一般約20分鐘),
e)於藉由胃酶消化後,然後於去離子水中沖洗5分鐘,
f)在室溫下,各自於70%乙醇、85%乙醇及100%乙醇中脫水2分鐘,
g)於乾燥後,然後進行下列雜交變性。
方法 2 ( 全自動 ):
a)在室溫下浸泡於二甲苯中用於脫蠟兩次,各15分鐘,及然後於100%乙醇中浸漬兩次,各5分鐘,
b)將組織切片在室溫下乾燥,
c)初始化系統及選擇程序,根據儀器演算法填充試劑,
d)將乾燥載玻片組織面朝上放在玻璃架上,將其放入反應槽中,蓋上反應槽蓋,關閉機器蓋,及運行選定程序;
(3)使用下列步驟之雜交裝置變性雜交:
a)將10 µL探針混合物滴入載玻片雜交區域,立即覆蓋載玻片及用橡膠膠密封邊緣,
b)準備雜交機,共變異條件:75℃,5分鐘,雜交條件:37℃,16小時;(小心維持雜交儀中之濕度);
(4)使用下列步驟之載玻片沖洗(需要避光操作):
a)小心移除蓋玻片,在73℃下,將載玻片放入0.3% NP-40/2×SSC之溶液中,振盪1至3秒,洗滌2分鐘,
b)在室溫下於70%乙醇中沖洗3分鐘;
(5)使用下列步驟之複染:
a)於黑暗中自然乾燥載玻片;
b)將10 µL DAPI滴在雜交位點處及立即蓋上蓋玻片。放入黑暗中10至20分鐘,然後在螢光顯微鏡下利用適當濾波器組觀察載玻片。
例如,如上述產生之HER2 (例如)於FISH部分中之評估可使用此項技術中已知之任何適宜方法進行。例如,使用下列步驟中之一或多者或所有:
(a)在低放大倍數下觀察整個FISH部分以初步確定測試品質(諸如標本中之正常組織之正常細胞信號)及於HER2擴增中是否存在異質性;
(b)找到至少2個區域之浸潤性癌症及將至少20個浸潤性癌細胞計數。FISH不適用於具有太少細胞之微浸潤性病竈;
(c) IHC部分可用於測定可擴增之浸潤性癌症之區域;及
(d)透過特定通道濾波器在高放大倍數(60x或100x物鏡)下觀察HER2及CEPl7信號,及計算信號計數及比率。
於一些實施例中,HER2藉由FISH使用雙探針,例如,使用HER2及CEP17探針評估。參見,
圖 3。於一些實施例中,HER2之評估包括下列步驟中之一或多者或所有:
1.選擇具有一致核大小、完整核邊界、均勻4′6⁃二脒基⁃2⁃苯基吲哚(DAPI)染色、非重疊核及清晰信號之評價腫瘤細胞;及
2.將浸潤性癌症核中之至少20個二色信號隨機計數。當觀察到信號時,在任何時間根據情況調整顯微鏡之焦距,及精確觀察位於核之不同平面之信號以免錯過。
於一些實施例中,HER2係根據下列標準評估(亦參見
圖 3):
(1)組1,HER2/CEP17比率≥ 2.0及平均HER2副本數/細胞比率≥ 4.0:此情況被評價為FISH陽性。若許多HER2信號連接成簇,則可將其直接評價為FISH陽性。
(2)組2,HER2/CEP17比率≥ 2.0及平均HER2副本數/細胞比率< 4.0:針對此情況建議增加計數細胞之數目,及若結果保持相同,則將其評價為FISH陰性。
(3)組3,HER2/CEP17比率< 2.0,平均HER2副本數目/細胞比率≥ 6.0:針對此情況建議增加計數細胞之數目,及若結果保持不變,則將其評價為FISH陽性。
(4)組4,HER2/CEP17比率<2.0,平均HER2副本數/細胞比率≥4.0且<6.0:於此情況下,建議將至少20個樣品之核之信號重新計數,及若結果不同,則分析兩種結果。於此等情況下,結合IHC分數確定HER2狀態,及若IHC分數為3+,則認為HER2狀態為陽性。若IHC分數為0、1+或2+,則判斷HER2狀態為陰性。
(5)組5,HER2/CEP17比率<2.0,平均HER2副本數/細胞比率<4.0:此情況被評價為FISH陰性。
於一些實施例中,HER2可藉由IHC根據用於檢測乳癌中之HER2之2019指導方針來評估(
表 4)。
表 4.乳癌HER2之IHC評價標準。
評價標準 | IHC分數 | HER2表現評價 |
未觀察到染色或染色不完全,於≤10%浸潤性癌細胞中觀察到微弱膜染色。 | 0 | 陰性 |
於>10%之浸潤性癌細胞中檢測到微弱/幾乎不可察覺膜染色。 | 1+ | 陰性 |
於>10%之浸潤性癌細胞中觀察到弱至中等完全膜染色。 於≤10%之浸潤性癌細胞中觀察到強且完全膜染色。 | 2+ | 不確定,利用原位雜交進一步測試或更換標本。 |
於>10%之浸潤性癌細胞中觀察到強、完全且均勻膜染色。 | 3+ | 陽性 |
HER2藉由IHC之評價可涉及下列步驟中之一或多者或所有:
1.在低放大倍數下首先觀察完整部分以確定染色是否令人滿意及於HER2表現中是否存在異質性;
2.當評價時,讀取品質控制載玻片;細胞質及核染色應可忽略,及正常上皮不應顯示強細胞膜染色;
3.在評價期間忽略組織邊緣及差製備(例如,明顯被擠壓)之癌組織。
4.若腫瘤具有明顯異質性,則當解釋時單獨指定各評分水平之百分比。
5.若浸潤性癌症為評價期間之目標,若非浸潤性癌症部分具有過度表現之HER2 (2+或3+),則將其單獨指定。
6.若檢測到多個團塊或區段,則單獨報告結果。
於一些實施例中,涉及本發明(例如,根據本發明治療)之患者先前已接受一或多種先前治療,包括化療藥物、靶向療法、免疫療法及內分泌療法;較佳地,其先前已接受紫杉烷全身療法;或其先前已接受利用曲妥珠單抗或其生物類似物之全身療法至少一次。
於一些實施例中,本發明之抗體-藥物結合物或藥劑可經鼻內、經皮下、經真皮內、經肌肉內或經靜脈內投與。於一些實施例中,其以每2週2.0 mg/kg之劑量投與。
示例性實施例
以下提供本發明之示例性及非限制性實施例。
示例性實施例1:一種抗體-藥物結合物(ADC)於製備用於治療患有HER2-低表現乳癌之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;及
該細胞毒性分子U包括MMAE (單甲基澳瑞他汀E)。
示例性實施例2:如實施例1之用途,其中該HER2-低表現乳癌患者為其HER2經檢測為IHC 2+/FISH陰性或IHC1+之患者。
示例性實施例3:如實施例2之用途,其中該抗體為鼠類、嵌合、人源化或全人類抗體。
示例性實施例4:如實施例3之用途,其中該抗體為IgG,另外較佳地IgG1、IgG2及IgG4。
示例性實施例5:如實施例2之用途,其中該抗體之重鏈之胺基酸序列示於SEQ ID NO:1中,及該抗體之輕鏈之胺基酸序列示於SEQ ID NO:2中。
示例性實施例6:如實施例2之用途,其中該抗體-藥物結合物為維迪西妥單抗。
示例性實施例7:如實施例6之用途,其中該抗體-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;或更佳地,該平均DAR值為4 ± 0.5。
示例性實施例8:如實施例2之用途,其中該乳癌為經藉由組織學及/或細胞學確立之浸潤性局部晚期或轉移性乳癌,且不可切除。
示例性實施例9:如實施例2之用途,其中該患者先前已接受一或多種先前治療,包括化療藥物、靶向療法、免疫療法及內分泌療法。
示例性實施例10:如實施例8之用途,其中該患者先前已接受紫杉烷全身療法。
示例性實施例11:如實施例8之用途,其中該患者先前已接受利用曲妥珠單抗或其生物類似物之全身療法至少一次。
示例性實施例12:如實施例3之用途,其中該藥劑係經鼻內、經皮下、經真皮內、經肌肉內或經靜脈內投與。
示例性實施例13:如實施例3之用途,其中該抗體-藥物結合物係以每2週2.0 mg/kg之劑量投與。
實例
以下實例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 ADC) 於 HER2- 陽性及 HER2- 低表現晚期乳癌患者中之兩個臨床研究 (NCT02881138 ; NCT03052634) 之匯總分析。
此實例描述針對RC48-ADC於HER2-陽性或HER2-低表現晚期乳癌患者中之功效及安全性之兩個研究(C001 CANCER [NCT02881138]及C003 CANCER [NCT03052634])的匯總分析。
C001 CANCER (NCT02881138)為以3 + 3設計之利用HER2陽性患者之劑量遞增1期研究(0.5、1.0、1.5、2.0及2.5 mg/kg)。
C003 CANCER (NCT03052634)為Ib期研究,其中1.5、2.0、2.5 mg/kg劑量用於HER2-陽性子組中及2.0 mg/kg劑量用於IHC 2+/FISH-及IHC 1+ HER2-低表現子組二者中。C003 CANCER目前針對具有IHC 1+或更高之患者正在進行中。
進行針對RC48-ADC於HER2-陽性或HER2-低表現子組中之功效及安全性之此等兩個研究之匯總分析。
方法
HER2之檢測及評估係使用具有超過100個癌細胞之手術切除標本、活組織檢查標本或細胞學標本進行。
將標本藉由以下處理:
(1)於分離後立即將標本浸漬至等於標本體積8至10倍之標準固定溶液中及使用10%中性緩衝福馬林固定劑固定(將一些大的標本切割及固定);
(2)在室溫下使用6至72小時之固定時間固定;及
(3)蠟塊包埋,藉由及時更換組織脫水之試劑及浸蠟以確保充分脫水及浸蠟效果。
HER2之檢測係藉由螢光原位雜交(FISH)分析使用下列步驟進行:
(1)選擇腫瘤組織之代表性蠟塊。藉由專業及技術人員完成切片,切片係完整、光滑、厚度均勻,而不影響刀痕褶皺之診斷(排除含有鈣化粒子及其他不可控因素之組織),切片厚度:4至5 μm;
(2)將組織切片使用下列方法中之任一者預處理:
方法 1 ( 手動操作 ):
a)將切片於二甲苯中浸漬及脫蠟兩次,每次15分鐘,及然後在室溫下於100%乙醇中浸漬5分鐘,
b)在室溫下,將切片各自於100%乙醇、85%乙醇及70%乙醇中再水化2分鐘,然後在室溫下於去離子水中浸漬3分鐘,
c)將切片用90至93℃去離子水處理20分鐘,
d)將1 ml胃酶儲存溶液(200 mg/ mL)溶解於200 ml 0.01M HCl中以獲得胃酶工作溶液(1 mg/ml);將組織切片浸泡於胃酶工作溶液中及在37℃下培育15至30分鐘(時間取決於組織厚度,一般約20分鐘),
e)於藉由胃酶消化後,將切片於去離子水中沖洗5分鐘,
f)在室溫下,將切片各自於70%乙醇、85%乙醇及100%乙醇中脫水2分鐘,
g)於乾燥後,進行下列雜交變性。
方法 2 ( 全自動 ):
a)在室溫下,將切片浸泡於二甲苯中用於脫蠟兩次,各15分鐘,及然後於100%乙醇中浸漬兩次,各5分鐘,
b)將組織切片在室溫下乾燥,
c)初始化系統及選擇程序,根據儀器演算法填充試劑,
d)將乾燥載玻片組織面朝上放在玻璃架上,將其放入反應槽中,覆蓋反應槽,關閉機器蓋,及運行選定程序;
(3)使用下列步驟進行變性雜交:
a)將10 µL探針混合物滴入載玻片雜交區域,立即覆蓋載玻片及用橡膠膠密封邊緣,
b)準備雜交機,共變異條件:75℃,5分鐘,雜交條件:37℃,16小時;(小心維持雜交儀中之濕度);
(4)使用下列步驟將載玻片沖洗(需要避光操作):
a)小心移除蓋玻片,在73℃下,將載玻片放入0.3% NP-40/2×SSC之溶液中,振盪1至3秒,洗滌2分鐘,接著在室溫下於70%乙醇中沖洗3分鐘;
(5)使用下列步驟進行複染:
a)於黑暗中自然乾燥載玻片;
b)將10 µL DAPI滴在雜交位點處及立即蓋上蓋玻片,接著放入黑暗中10至20分鐘。在螢光顯微鏡下利用適當濾波器組觀察載玻片。
HER2之評估係使用下列步驟進行:
(a)在低放大倍數下觀察整個FISH部分以初步確定測試品質(諸如標本中之正常組織之正常細胞信號)及於HER2擴增中是否存在異質性;
(b)找到至少2個區域之浸潤性癌症及將至少20個浸潤性癌細胞計數。FISH不適用於具有太少細胞之微浸潤性病竈;
(c) IHC部分係用於測定可擴增之浸潤性癌症之區域;及
(d)透過特定通道濾波器在高放大倍數(60x或100x物鏡)下觀察HER2及CEPl7信號,及計算信號計數及比率。
HER2係藉由FISH使用雙探針如下評估(參見,
圖 3):
1.選擇具有一致核大小、完整核邊界、均勻4′6⁃二脒基⁃2⁃苯基吲哚(DAPI)染色、非重疊核及清晰信號之腫瘤細胞用於評價;及
2.將浸潤性癌症核中之至少20個二色信號隨機計數。當觀察到信號時,在任何時間根據情況調整顯微鏡之焦距,及精確觀察位於核之不同平面之信號以免錯過。
HER2係根據下列標準評估(亦參見
圖 3):
(1)組1,HER2/CEP17比率≥ 2.0及平均HER2副本數/細胞比率≥ 4.0:此情況被評價為FISH陽性。若許多HER2信號連接成簇,則可將其直接評價為FISH陽性。
(2)組2,HER2/CEP17比率≥ 2.0及平均HER2副本數/細胞比率< 4.0:針對此情況增加計數細胞之數目,及若結果保持相同,則將其評價為FISH陰性。
(3)組3,HER2/CEP17比率< 2.0,平均HER2副本數目/細胞比率≥ 6.0:針對此情況增加計數細胞之數目,及若結果保持不變,則將其評價為FISH陽性。
(4)組4,HER2/CEP17比率<2.0,平均HER2副本數/細胞比率≥4.0且<6.0:於此情況下,將至少20個樣品之核之信號重新計數,及若結果不同,則分析兩種結果。於此等情況下,結合IHC分數確定HER2狀態,及若IHC分數為3+,則認為HER2狀態為陽性。若IHC分數為0、1+或2+,則判斷HER2狀態為陰性。
(5)組5,HER2/CEP17比率<2.0,平均HER2副本數/細胞比率<4.0:此情況被評價為FISH陰性。
HER2係藉由IHC根據用於檢測乳癌中之HER2之2019指導方針評估(
表 5)。
表 5.乳癌HER2之IHC評價標準。
評價標準 | IHC 分數 | HER2 表現評價 |
未觀察到染色或染色不完全,於≤10%浸潤性癌細胞中觀察到微弱膜染色。 | 0 | 陰性 |
於>10%之浸潤性癌細胞中檢測到微弱/幾乎不可察覺膜染色。 | 1+ | 陰性 |
於>10%之浸潤性癌細胞中觀察到弱至中等完全膜染色。 於≤10%之浸潤性癌細胞中觀察到強且完全膜染色。 | 2+ | 不確定,利用原位雜交進一步測試或更換標本。 |
於>10%之浸潤性癌細胞中觀察到強、完全且均勻膜染色。 | 3+ | 陽性 |
HER2藉由IHC之評價係如下進行:
1.在低放大倍數下首先觀察完整部分以確定染色是否令人滿意及於HER2表現中是否存在異質性;
2.當評價時,讀取品質控制載玻片;細胞質及核染色應可忽略,及正常上皮不應顯示強細胞膜染色;
3.在評價期間忽略組織邊緣及差製備(例如,明顯被擠壓)之癌組織。
4.若腫瘤具有明顯異質性,則當解釋時單獨指定各評分水平之百分比。
5.若浸潤性癌症為評價期間之目標,若非浸潤性癌症部分具有過度表現之HER2 (2+或3+),則將其單獨指定。
6.若檢測到多個團塊或區段,則單獨報告結果。
結果
在數據截止日期(2020年12月31日),招募118名女性乳癌患者及用RC48-ADC治療。70名患者(59.3%)係HER2-陽性,及48名患者(40.7%)係HER2-低表現。在基線時,77名患者(65.3%)具有肝轉移,50名患者(42.4%)處於東部合作腫瘤學組(ECOG)性能狀態(PS) 1,及47名患者(39.8%)已接受3種先前化療方案。
於HER2-陽性子組中,針對1.5、2.0及2.5 mg/kg劑量之客觀緩解率(ORR)各自為22.2% (95%信賴區間[CI]:6.4%, 47.6%)、42.9% (95% CI: 21.8%, 66.0%)及40.0% (95% CI: 21.1%, 61.3%)。針對1.5、2.0及2.5 mg/kg隊組之中值無進展生存期(mPFS)為4.0個月(95% CI: 2.6, 7.6)、5.7個月(95% CI: 5.3, 8.4)及6.3個月(95% CI: 4.3, 8.8)。
於HER2-低表現子組中,ORR及mPFS各自為39.6% (95% CI: 25.8%, 54.7%)及5.7個月(95% CI: 4.1, 8.3)。IHC2+/FISH患者之ORR及mPFS各自為42.9% (15/35)及6.6個月(95% CI: 4.1, 8.5)。針對IHC1+患者,儘管COVID-19大流行造成一些患者延遲治療,但是ORR及mPFS各自達到30.8% (4/13)及5.5個月(95% CI: 2.7, 11.0)。
常見治療相關之不良事件(TRAE)係如下:AST增加(64.4%)、ALT增加(59.3%)、感覺遲鈍(58.5%)、白血球計數減少(48.3%)及嗜中性白血球計數減少(47.5%);及大多數處於等級1至2之嚴重度。嗜中性白血球計數減少3個等級之個體(16.9%)具有增加之γ麩胺醯基轉移酶(GGT;12.7%)且具有疲勞(11.9%),高於佔總群體之10%之TRAE。
結論
RC48-ADC顯示於HER2-陽性及HER2-低表現子組中之一致功效。此顯示與其他劑量水平相比,以2.0 mg/kg每2週一次(Q2W)之更有利效益-風險比。
本發明已藉由特定實例例示。然而,熟習此項技術者應瞭解,本發明不限於該等特定實施例。可於本發明之範圍內作出各種修改或變化,及可在不背離本發明之精神及範圍下將整篇本說明書提及之各種技術特徵彼此組合。此等修改及變化均於本發明之範圍內。
圖 1為單甲基澳瑞他汀E (MMAE)之結構之示意圖。
圖 2為本發明之一般結構式Ab-(L-U)
n之抗體-藥物結合物(ADC)在一組可能結合條件下(L透過巰基結合連接至抗體之一或多個鏈間二硫鍵位點)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,及「-L-U」之結構係如下:
圖 3為描述HER2雙探針原位雜交(ISH)試驗之評價標準之流程圖。
<![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> HER2靶向抗體-藥物結合物用於治療HER2-低表現乳癌之用途]]> <![CDATA[<130> 76168-20087.42]]> <![CDATA[<140> TW 111118596]]> <![CDATA[<141> 2022-05-18 ]]> <![CDATA[<150> CN 202110565350.2 ]]> <![CDATA[<151> 2021-05-24 ]]> <![CDATA[<160> 15]]> <![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 100 105 110 Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro 115 120 125 Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val 130 135 140 Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala 145 150 155 160 Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly 165 170 175 Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly 180 185 190 Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys 195 200 205 Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys 210 215 220 Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu 225 230 235 240 Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu 245 250 255 Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys 260 265 270 Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys 275 280 285 Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu 290 295 300 Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys 305 310 315 320 Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys 325 330 335 Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser 340 345 350 Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys 355 360 365 Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln 370 375 380 Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly 385 390 395 400 Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln 405 410 415 Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn 420 425 430 His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 435 440 445 <![CDATA[<210> 2]]> <![CDATA[<211> 212]]> <![CDATA[<212> PRT]]> <![CDATA[<213> ]]>人造序列 <![CDATA[<220> ]]> <![CDATA[<223> 合成構築體]]> <![CDATA[<400> 2]]> 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 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> 5]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人造序列]]> <![CDATA[<220> ]]> <![CDATA[<223> 合成構築體]]> <![CDATA[<400> 11]]> Asp Tyr Tyr Ile His 1 5 <![CDATA[<210> 12]]> <![CDATA[<211> 17]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人造序列]]> <![CDATA[<220> ]]> <![CDATA[<223> 合成構築體]]> <![CDATA[<400> 12]]> Arg Val Asn Pro Asp His Gly Asp Ser Tyr Tyr Asn Gln Lys Phe Lys 1 5 10 15 Asp <![CDATA[<210> 13]]> <![CDATA[<211> 9]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人造序列]]> <![CDATA[<220> ]]> <![CDATA[<223> 合成構築體]]> <![CDATA[<400> 13]]> Ala Arg Asn Tyr Leu Phe Asp His Trp 1 5 <![CDATA[<210> 14]]> <![CDATA[<211> 11]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人造序列]]> <![CDATA[<220> ]]> <![CDATA[<223> 合成構築體]]> <![CDATA[<400> 14]]> Lys Ala Ser Gln Asp Val Gly Thr Ala Val Ala 1 5 10 <![CDATA[<210> 15]]> <![CDATA[<211> 7]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人造序列]]> <![CDATA[<220> ]]> <![CDATA[<223> 合成構築體]]> <![CDATA[<400> 15]]> Trp Ala Ser Ile Arg His Thr 1 5
Claims (24)
- 一種抗體-藥物結合物(ADC)於製備用於治療患有人類表皮生長因子受體2 (HER2)-低表現乳癌之患者之藥劑中的用途,其中該ADC具有通式Ab-(L-U) n之結構,其中: Ab表示抗HER2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; 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序列及/或該輕鏈可變區之CDR序列具有與維迪西妥單抗(Disitamab vedotin)相同之CDR序列; 其中該連接子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HER2抗體,及該連接位點為該抗HER2抗體之鏈間二硫鍵位點;且 其中該細胞毒性分子U包括MMAE (單甲基澳瑞他汀(auristatin) E)。
- 如請求項1之用途,其中該HER2-低表現乳癌患者為其HER2經檢測為免疫組織化學(IHC) 2+/螢光原位雜交(FISH)陰性或IHC1+之患者。
- 如請求項2之用途,其中於來自該乳癌之樣品中HER2經檢測為IHC 2+/FISH陰性或IHC1+。
- 如請求項2或請求項3之用途,其中HER2係使用免疫組織化學(IHC)分析及/或螢光原位雜交(FISH)分析來檢測。
- 如請求項1至4中任一項之用途,其中該抗HER2抗體為鼠類、嵌合、人源化或全人類抗體。
- 如請求項5之用途,其中該抗HER2抗體為IgG類別。
- 如請求項6之用途,其中該抗HER2抗體具有IgG1、IgG2或IgG4同型。
- 如請求項1至7中任一項之用途,其中該抗HER2抗體包含重鏈可變區(VH)及輕鏈可變區(VL),其中: (a)該VH包含包含胺基酸序列GYTFTDYY (SEQ ID NO:3)之CDR-H1,包含胺基酸序列VNPDHGDS (SEQ ID NO:4)之CDR-H2,及包含胺基酸序列ARNYLFDH (SEQ ID NO:5)之CDR-H3,且 (b)該VL包含包含胺基酸序列QDVGTA (SEQ ID NO:6)之CDR-L1,包含胺基酸序列WAS (SEQ ID NO:7)之CDR-L2,及包含胺基酸序列HQFATYT (SEQ ID NO:8)之CDR-L3。
- 如請求項1至7中任一項之用途,其中該抗HER2抗體包含重鏈可變區(VH)及輕鏈可變區(VL),其中: (a)該VH包含包含胺基酸序列DYYIH (SEQ ID NO: 11)之CDR-H1,包含胺基酸序列RVNPDHGDSYYNQKFKD (SEQ ID NO: 12)之CDR-H2,及包含胺基酸序列ARNYLFDHW (SEQ ID NO: 13)之CDR-H3,且 (b)該VL包含包含胺基酸序列KASQDVGTAVA (SEQ ID NO: 14)之CDR-L1,包含胺基酸序列WASIRHT (SEQ ID NO: 15)之CDR-L2,及包含胺基酸序列HQFATYT (SEQ ID NO: 8)之CDR-L3。
- 如請求項1至9中任一項之用途,其中該抗HER2抗體包含包含SEQ ID NO: 9之胺基酸序列之重鏈可變區(VH)及包含SEQ ID NO: 10之胺基酸序列之輕鏈可變區(VL)。
- 如請求項1至10中任一項之用途,其中該抗HER2抗體為人類IgG抗體。
- 如請求項11之用途,其中該抗HER2抗體為人類IgG1、IgG2、IgG3或IgG4抗體。
- 如請求項1至12中任一項之用途,其中該抗體之重鏈之胺基酸序列示於SEQ ID NO:1中,及該抗體之輕鏈之胺基酸序列示於SEQ ID NO:2中。
- 如請求項1至12中任一項之用途,其中該ADC為維迪西妥單抗或其生物類似物。
- 如請求項1至14中任一項之用途,其中該ADC之平均藥物對抗體比率(DAR)值為2至7之任何數字。
- 如請求項15之用途,其中該平均DAR值為4 ± 0.5。
- 如請求項1至16中任一項之用途,其中該乳癌為經藉由組織學及/或細胞學確立之浸潤性局部晚期或轉移性乳癌,且不可切除。
- 如請求項1至17中任一項之用途,其中該患者先前已接受一或多種先前治療。
- 如請求項18之用途,其中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。
- 如請求項18或請求項19之用途,其中該患者先前已接受紫杉烷(taxane)全身療法。
- 如請求項18至20中任一項之用途,其中該患者先前已接受利用曲妥珠單抗(trastuzumab)或其生物類似物之全身療法至少一次。
- 如請求項1至21中任一項之用途,其中該藥劑係經鼻內、經皮下、經真皮內、經肌肉內或經靜脈內投與。
- 如請求項1至22中任一項之用途,其中該ADC係以每2週2.0 mg/kg之劑量投與。
- 一種治療患有人類表皮生長因子受體2 (HER2)-低表現乳癌之患者之方法,其包括向該患者投與治療上有效量之抗體-藥物結合物(ADC),其中該ADC具有通式Ab-(L-U) n之結構,其中: Ab表示抗HER2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; 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序列及/或該輕鏈可變區之CDR序列具有與維迪西妥單抗相同之CDR序列; 其中該連接子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HER2抗體,及該連接位點為該抗HER2抗體之鏈間二硫鍵位點;且 其中該細胞毒性分子U包括MMAE (單甲基澳瑞他汀E)。
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- 2022-05-18 EP EP22810435.2A patent/EP4346908A1/en active Pending
- 2022-05-18 CA CA3218663A patent/CA3218663A1/en active Pending
- 2022-05-18 AU AU2022283315A patent/AU2022283315A1/en active Pending
Also Published As
Publication number | Publication date |
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CN117750980A (zh) | 2024-03-22 |
IL308508A (en) | 2024-01-01 |
EP4346908A1 (en) | 2024-04-10 |
CA3218663A1 (en) | 2022-12-01 |
WO2022247708A1 (en) | 2022-12-01 |
KR20240021824A (ko) | 2024-02-19 |
AU2022283315A1 (en) | 2023-11-16 |
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