TW202102546A - 密蛋白抗體及其應用 - Google Patents
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Abstract
本公開涉及抗Claudin18.2抗體及其應用。具體地,本發明涉及一種抗Claudin18.2抗體;包含所述抗Claudin18.2抗體CDR的鼠源抗體、嵌合抗體、人源化抗體及其抗原結合片段,以及其作為藥物的用途。特別地,本公開涉及一種抗Claudin18.2抗體在製備用於治療Claudin18.2陽性疾病或病症的藥物中的用途。
Description
本申請要求2019年4月1日提交的中國專利申請201910257853.6的優先權,其全部內容藉由引用併入此處。
本公開涉及抗體藥物領域。具體地,本公開涉及Claudin18.2抗體以及其應用。
這裡的陳述僅提供與本公開有關的背景信息,而不必然地構成現有技術。
密蛋白18(Claudin-18,CLDN18)是一種在人類中由Claudin18基因編碼的蛋白質,屬於細胞緊密連接蛋白家族。Claudin-18可以控制層細胞之間的分子流動。
Claudin-18蛋白結構中包括四個跨膜區域、兩個細胞外環,其N末端和C末端在胞漿內。Claudin-18具有兩個剪接變體,分別為Claudin 18.1和Claudin 18.2,兩者序列之間僅在第一個細胞外環有八個胺基酸的差異。Claudin 18.1和Claudin 18.2的表現分佈有所不同,Claudin 18.1在正常肺的細胞中選擇性表現,Claudin 18.2在正常細胞中表現高度受限,但在多種腫瘤(胃癌、肺癌和
胰腺癌等)中頻繁異位激活和過表現。Claudin18.2被認為是胃癌和其他癌症類型的潛在治療靶點,此靶點的發現也為胃癌的治療提供了一種新的選擇。
本公開提供一種抗Claudin18.2抗體。
在一些實施方案中,如前所述抗Claudin18.2抗體,其包含重鏈可變區和輕鏈可變區,其中:
i)該重鏈可變區包含與如SEQ ID NO:3所示的重鏈可變區相同序列的HCDR1、HCDR2和HCDR3,該輕鏈可變區包含與如SEQ ID NO:4所示的輕鏈可變區相同序列的LCDR1、LCDR2和LCDR3;或
ii)該重鏈可變區包含與如SEQ ID NO:5所示的重鏈可變區相同序列的HCDR1、HCDR2和HCDR3,該輕鏈可變區包含與如SEQ ID NO:6所示的輕鏈可變區相同序列的LCDR1、LCDR2和LCDR3。在一些實施方案中,如前所述抗Claudin18.2抗體,其包含重鏈可變區和輕鏈可變區,其中:
iii)該重鏈可變區包含分別如SEQ ID NO:9、SEQ ID NO:10和SEQ ID NO:11所示的HCDR1、HCDR2和HCDR3,該輕鏈可變區包含分別如SEQ ID NO:12、SEQ ID NO:13和SEQ ID NO:14所示的LCDR1、LCDR2和LCDR3;或
iv)該重鏈可變區包含分別如SEQ ID NO:15、SEQ ID NO:16和SEQ ID NO:17所示的HCDR1、HCDR2和HCDR3,該輕鏈可變區包含分別如SEQ ID NO:18、SEQ ID NO:19和SEQ ID NO:20所示的LCDR1、LCDR2和LCDR3。
本領域技術人員應當理解,項目編號,例如i)、ii)、a)、b)等,其目的僅在於使所列舉的技術方案或要素更加清晰、有條理,但是對跟隨
其後的技術方案或要素不具有任何方面的約束性。當使用相同的項目編號時,不代表跟隨其後的技術方案或要素是相同的。
在一些實施方案中,如前所述抗Claudin18.2抗體,其中該抗Claudin18.2抗體是鼠源抗體、嵌合抗體或人源化抗體。
在一些實施方案中,如前所述抗Claudin18.2抗體,其包含重鏈可變區和輕鏈可變區,其中:
(v)該重鏈可變區與SEQ ID NO:3或24所示的重鏈可變區有至少90%、92%、94%、95%、96%、97%、98%、99%、100%同一性,和該輕鏈可變區與SEQ ID NO:4或21所示輕鏈可變區有至少90%、92%、94%、95%、96%、97%、98%、99%、100%同一性;或
(vi)該重鏈可變區與SEQ ID NO:5或31所示重鏈可變區有至少90%、92%、94%、95%、96%、97%、98%、99%、100%同一性,和該輕鏈可變區與SEQ ID NO:6或28所示輕鏈可變區有至少90%、92%、94%、95%、96%、97%、98%、99%、100%同一性。
在一些實施方案中,如前所述抗Claudin18.2抗體,其包含重鏈可變區和輕鏈可變區,其中:
(1)該重鏈可變區胺基酸序列如SEQ ID NO:3所示或與其有至少90%同一性,和該輕鏈可變區胺基酸序列如SEQ ID NO:4所示或與其有至少90%同一性;
(2)該重鏈可變區胺基酸序列如SEQ ID NO:24所示或與其有至少90%同一性,和該輕鏈可變區胺基酸序列如SEQ ID NO:21所示或與其有至少90%同一性;
(3)該重鏈可變區胺基酸序列如SEQ ID NO:5所示或與其有至少90%同一性,和該輕鏈可變區胺基酸序列如SEQ ID NO:6所示或與其有至少90%同一性;或
(4)該重鏈可變區胺基酸序列如SEQ ID NO:31所示或與其有至少90%同一性,和該輕鏈可變區胺基酸序列如SEQ ID NO:28所示或與其有至少90%同一性。
在一些實施方案中,如前所述抗Claudin18.2抗體,其中該抗Claudin18.2抗體為人源化抗體,該人源化抗體包含來源自人抗體的框架區或其框架區變體,該框架區變體為在人抗體的輕鏈框架區和/或重鏈框架區上分別具有至多10個胺基酸的回復突變。
在一些實施方案中,該人抗體的重鏈框架區與胺基酸序列SEQ ID NO:24所示重鏈可變區的框架區相同,或該人抗體的輕鏈可變區與胺基酸序列SEQ ID NO:21所示輕鏈可變區的框架區相同;或該人抗體的重鏈框架區與胺基酸序列SEQ ID NO:31所示重鏈可變區的框架區相同,或該人抗體的輕鏈可變區與胺基酸序列SEQ ID NO:28所示輕鏈可變區的框架區相同。
在一些實施方案中,較佳地,該框架區變體包含選自以下(a)或(b)所述的突變:
(a)該輕鏈可變區中包含22S、85I或87H中的一個或更多個胺基酸回復突變,和/或該重鏈可變區中包含選自48I、82T和69M中的一個或更多個胺基酸回復突變;或
(b)該輕鏈可變區中包含選自4L和22S一個或更多個胺基酸回復突變,和/或該重鏈可變區中包含38K、40R、48I、66K、67A、69L、71L和73K中的一個或更多個胺基酸回復突變。
在一些實施方案中,如前所述抗Claudin18.2抗體,該框架區變體包含選自以下(a-1)或(b-1)所述的突變:
(a-1)該輕鏈可變區中包含22S、85I和87H的胺基酸回復突變,和該重鏈可變區中包含48I和82T的胺基酸回復突變;或
(b-1)該輕鏈可變區中包含選自4L的胺基酸回復突變。
在一些實施方案中,如前所述抗Claudin18.2抗體,其中:
(vii)該重鏈可變區序列如SEQ ID NO:3所示和該輕鏈可變區序列如SEQ ID NO:4所示;或
(viii)該重鏈可變區序列如SEQ ID NO:24、25、26或27所示和該輕鏈可變區序列如SEQ ID NO:21、22或23所示;或
(ix)該重鏈可變區序列如SEQ ID NO:5所示和該輕鏈可變區序列如SEQ ID NO:6所示;或
(x)該重鏈可變區序列如SEQ ID NO:31、32、33或34所示和該輕鏈可變區序列如SEQ ID NO:28、29或30所示。
在一些實施方案中,如前所述抗Claudin18.2抗體,其中:該抗Claudin18.2抗體或其抗原結合片段,其包含如下所示的重鏈可變區和輕鏈可變區:
(xi)該重鏈可變區序列如SEQ ID NO:31所示和該輕鏈可變區序列如SEQ ID NO:29所示;或
(xii)該重鏈可變區序列如SEQ ID NO:26所示和該輕鏈可變區序列如SEQ ID NO:23所示。
在一些實施方案中,如前所述抗Claudin18.2抗體,其中:輕鏈可變區和重鏈可變區可以為如下表格所示的輕重鏈可變區的組合:
在一些實施方案中,如前所述抗Claudin18.2抗體,其中該抗體進一步包含抗體恆定區。在一些具體的實施方案中,該抗體的重鏈恆定區選自人IgG1、IgG2、IgG3和IgG4恆定區及其變體,該抗體的輕鏈恆定區選自人抗體κ和λ鏈恆定區及其變體。在一些具體的實施方案中,該抗體包含序列如SEQ ID NO:7所示的重鏈恆定區和序列如SEQ ID NO:8所示的輕鏈恆定區。在一些具體的實施方案中,該抗體包含:與SEQ ID NO:35或42所示胺基酸序列具有至少90%、92%、94%、95%、96%、97%、98%、99%、100%同一性的重
鏈,和與SEQ ID NO:36或39所示胺基酸序列有至少90%、92%、94%、95%、96%、97%、98%、99%、100%同一性的輕鏈;或
與SEQ ID NO:37或49所示胺基酸序列具有至少90%、92%、94%、95%、96%、97%、98%、99%、100%同一性的重鏈,和/或與SEQ ID NO:38或46所示胺基酸序列有至少90%、92%、94%、95%、96%、97%、98%、99%、100%同一性的輕鏈。
在一些實施方案中,如前所述抗Claudin18.2抗體,其包含:
(c)序列如SEQ ID NO:35所示的重鏈和/或序列如SEQ ID NO:36所示的輕鏈;
(d)序列如SEQ ID NO:42、43、44或45所示的重鏈和/或序列如SEQ ID NO:39、40或41所示的輕鏈;
(e)序列如SEQ ID NO:37所示的重鏈和/或序列如SEQ ID NO:38所示的輕鏈;或
(f)序列如SEQ ID NO:49、50、51或52所示的重鏈和/或序列如SEQ ID NO:46、47或48所示的輕鏈。
在一些實施方案中,如前所述抗Claudin18.2抗體,該抗體與前述的抗Claudin18.2抗體或其抗原結合片段競爭性結合人Claudin18.2。
在一些實施方案中,如前所述抗Claudin18.2抗體,其包含:
胺基酸序列如SEQ ID NO:44所示的重鏈,和序列如SEQ ID NO:41所示的輕鏈;或
胺基酸序列如SEQ ID NO:49所示的重鏈,和序列如SEQ ID NO:47所示的輕鏈。
本公開的另一方面還提供一種核酸分子,其編碼如前所述的抗Claudin18.2抗體。
本公開的另一方面還提供一種表現載體,其包含如前所述的核酸分子。
本公開的另一方面還提供一種宿主細胞,其包含如如前所述的核酸分子或如前所述的表現載體,較佳該細胞為細菌細胞、真菌細胞、昆蟲動物細胞或哺乳動物細胞。
本公開的另一方面還提供一種抗體藥物偶聯物,其為由根據如前所述的抗Claudin18.2抗體與細胞毒性藥物偶聯形成的抗體藥物偶聯物。
本公開的另一方面還提供一種抗體藥物偶聯物,其包含或由以下組成:共價結合有細胞毒性藥物的前述抗Claudin18.2抗體。
在一些實施方案中,本公開提供一種如前所述的Claudin18.2抗體的製備方法。
在一些實施方案中,本公開提供一種如前所述的Claudin18.2抗體藥物偶聯物的製備方法。
在一些實施方案中,本公開提供一種醫藥組成物,其含有治療有效量的根據如前所述的抗Claudin18.2抗體,或根據如前所述的核酸分子,或如前所述的抗體藥物偶聯物,以及一種或更多種藥學上可接受的載體、稀釋劑、緩衝劑或賦形劑。
在一些實施方案中,本公開提供一種用於免疫檢測或測定Claudin18.2的方法,該方法包括用如前所述的抗Claudin18.2抗體接觸待測樣本的步驟。
在一些實施方案中,本公開提供如前所述的抗Claudin18.2抗體在製備免疫檢測人Claudin18.2的試劑中的用途。
在一些實施方案中,本公開提供一種用於免疫檢測或測定Claudin18.2的如前所述的抗Claudin18.2抗體。
在一些實施方案中,本公開提供一種試劑盒,其包含根據如前所述的抗Claudin18.2抗體。
在一些實施方案中,本公開提供如前所述的抗Claudin18.2抗體,或如前所述的核酸分子,或如前所述的抗體藥物偶聯物或如前所述的醫藥組成物在製備用於治療癌症或腫瘤的藥物中的用途,其中該癌症或腫瘤較佳Claudin18.2陽性癌症或惡性腫瘤,更佳頭和頸鱗狀細胞癌、頭和頸癌、腦癌、神經膠質瘤、多形性成膠質細胞瘤、神經母細胞瘤、中樞神經系統癌、神經內分泌腫瘤、咽喉癌、鼻咽癌、食管癌、甲狀腺癌、惡性胸膜間皮瘤、肺癌、乳腺癌、肝癌、肝細胞瘤、肝細胞癌、肝膽癌、胰腺癌、胃癌、胃腸道癌、腸癌、結腸癌、結腸直腸癌、腎癌、透明細胞腎細胞癌、卵巢癌、子宮內膜癌、子宮頸癌、膀胱癌、前列腺癌、睾丸癌、皮膚癌、黑色素瘤、白血病、淋巴瘤、骨癌、軟骨肉瘤、骨髓瘤、多發性骨髓瘤、骨髓異常增生綜合症、骨髓增生性腫瘤、鱗狀細胞癌、尤因氏肉瘤、全身性輕鏈澱粉樣變性和梅克爾細胞癌;該淋巴瘤選自:何傑金淋巴瘤、非何傑金淋巴瘤、彌漫性大B-細胞淋巴瘤、濾泡性淋巴瘤、原發性縱隔大B-細胞淋巴瘤、套細胞淋巴瘤、小淋巴細胞性淋巴瘤、富含T-細胞/組織細胞的大B-細胞淋巴瘤和淋巴漿細胞性淋巴瘤,該肺癌選自:非小細胞肺癌和小細胞肺癌,該白血病選自:慢性髓細胞樣白血病、急性髓細胞樣白血病、淋巴細胞白血病、成淋巴細胞性白血病、急性成淋巴細胞性白血病、慢性淋巴細胞性白血病和髓樣細胞白血病。
在一些實施方案中,本公開提供一種治療與Claudin18.2相關的疾病的方法,該方法包括向受試者施用治療有效量的如前所述的抗Claudin18.2抗體,或如前所述的核酸分子,或如前所述的抗體藥物偶聯物或如前所述的醫藥組成物,其中該疾病較佳為癌症或腫瘤;更佳的Claudin18.2陽性癌症或惡性腫瘤,更佳選自:頭和頸鱗狀細胞癌、頭和頸癌、腦癌、神經膠質瘤、多形性
成膠質細胞瘤、神經母細胞瘤、中樞神經系統癌、神經內分泌腫瘤、咽喉癌、鼻咽癌、食管癌、甲狀腺癌、惡性胸膜間皮瘤、肺癌、乳腺癌、肝癌、肝細胞瘤、肝細胞癌、肝膽癌、胰腺癌、胃癌、胃腸道癌、腸癌、結腸癌、結腸直腸癌、腎癌、透明細胞腎細胞癌、卵巢癌、子宮內膜癌、子宮頸癌、膀胱癌、前列腺癌、睾丸癌、皮膚癌、黑色素瘤、白血病、淋巴瘤、骨癌、軟骨肉瘤、骨髓瘤、多發性骨髓瘤、骨髓異常增生綜合症、骨髓增生性腫瘤、鱗狀細胞癌、尤因氏肉瘤、全身性輕鏈澱粉樣變性和梅克爾細胞癌。更佳的,該淋巴瘤選自:何傑金淋巴瘤、非何傑金淋巴瘤、彌漫性大B-細胞淋巴瘤、濾泡性淋巴瘤、原發性縱隔大B-細胞淋巴瘤、套細胞淋巴瘤、小淋巴細胞性淋巴瘤、富含T-細胞/組織細胞的大B-細胞淋巴瘤和淋巴漿細胞性淋巴瘤,該肺癌選自:非小細胞肺癌和小細胞肺癌,該白血病選自:慢性髓細胞樣白血病、急性髓細胞樣白血病、淋巴細胞白血病、成淋巴細胞性白血病、急性成淋巴細胞性白血病、慢性淋巴細胞性白血病和髓樣細胞白血病。
在一些實施方案中,該治療有效量為單位劑量的組成物中含有0.1mg至3000mg或1mg至1000mg如前所述的抗Claudin18.2抗體或如前所述的抗體藥物偶聯物。
在一些實施方案中,本公開提供一種用於治療與Claudin18.2相關的疾病如前所述的抗Claudin18.2抗體,或如前所述的核酸分子,或如前所述的抗體藥物偶聯物或如前所述的醫藥組成物,其中該疾病較佳為癌症或腫瘤;更佳的Claudin18.2陽性癌症或惡性腫瘤,更佳選自:頭和頸鱗狀細胞癌、頭和頸癌、腦癌、神經膠質瘤、多形性成膠質細胞瘤、神經母細胞瘤、中樞神經系統癌、神經內分泌腫瘤、咽喉癌、鼻咽癌、食管癌、甲狀腺癌、惡性胸膜間皮瘤、肺癌、乳腺癌、肝癌、肝細胞瘤、肝細胞癌、肝膽癌、胰腺癌、胃癌、胃腸道癌、腸癌、結腸癌、結腸直腸癌、腎癌、透明細胞腎細胞癌、卵巢癌、子
宮內膜癌、子宮頸癌、膀胱癌、前列腺癌、睾丸癌、皮膚癌、黑色素瘤、白血病、淋巴瘤、骨癌、軟骨肉瘤、骨髓瘤、多發性骨髓瘤、骨髓異常增生綜合症、骨髓增生性腫瘤、鱗狀細胞癌、尤因氏肉瘤、全身性輕鏈澱粉樣變性和梅克爾細胞癌。更佳的,該淋巴瘤選自:何傑金淋巴瘤、非何傑金淋巴瘤、彌漫性大B-細胞淋巴瘤、濾泡性淋巴瘤、原發性縱隔大B-細胞淋巴瘤、套細胞淋巴瘤、小淋巴細胞性淋巴瘤、富含T-細胞/組織細胞的大B-細胞淋巴瘤和淋巴漿細胞性淋巴瘤,該肺癌選自:非小細胞肺癌和小細胞肺癌,該白血病選自:慢性髓細胞樣白血病、急性髓細胞樣白血病、淋巴細胞白血病、成淋巴細胞性白血病、急性成淋巴細胞性白血病、慢性淋巴細胞性白血病和髓樣細胞白血病。
在一些實施方案中,該癌症為胃癌、食道癌、肺癌、胰腺癌。
在一些實施方案中,如前所述抗體、抗體藥物偶聯物可以在Claudin18.2高表現、中表現、低表現的如前所述癌症中發揮治療作用。
本公開提供的Claudin18.2抗體及抗體藥物偶聯物具有與細胞表面抗原良好的親和力,良好的細胞內吞效率和很強的腫瘤抑制效率,並且具有更寬的藥物應用窗口,適於臨床的藥物應用。
第1圖:在細胞水平上,人源化抗體與人Claudin18.2結合的FACS檢測結果。
第2圖:人源化抗體的NUGC4細胞內吞實驗。
第3A圖至第3C圖:在不同Claudin18.2表現程度的NUGC4細胞中,抗體的ADCC效應檢測。第3A圖為抗體在野生型NUGC4細胞(Claudin18.2低表現)中的ADCC效應檢測;第3B圖為抗體在Claudin18.2中
等表現NUGC4細胞中的ADCC效應檢測;第3C圖為抗體在Claudin18.2高表現NUGC4細胞中的ADCC效應檢測。
為了更容易理解本公開,以下具體定義了某些技術和科學術語。除非在本文中另有明確定義,本文使用的所有其它技術和科學術語都具有本公開所屬領域的一般技術人員通常理解的含義。
本公開所用胺基酸三字母代碼和單字母代碼如J.biol.chem,243,p3558(1968)中所述。
術語“細胞毒性藥物”是指抑制或防止細胞的功能和/或引起細胞死亡或破壞的物質。包括毒素、化療藥物等能用於殺傷細胞的化合物。
術語“毒素”是指能夠對細胞的生長或增殖產生有害效果的任何物質,可以是來自細菌、真菌、植物或動物的小分子毒素及其衍生物,包括喜樹鹼類衍生物如伊沙替康,美登木素生物鹼及其衍生物(CN101573384)如DM1、DM3、DM4、奧利斯他汀F(AF)及其衍生物,如MMAF、MMAE、3024(WO 2016/127790 A1,化合物7)、白喉毒素、外毒素、蓖麻毒蛋白(ricin)A鏈、相思豆毒蛋白(abrin)A鏈、蒴蓮根毒素(modeccin)、α-帚麯黴素(sarcin)、油桐(Aleutites fordii)毒蛋白、香石竹(dianthin)毒蛋白、美洲商陸(Phytolaca americana)毒蛋白(PAPI、PAPII和PAP-S)、苦瓜(Momordica charantia)抑制物、麻瘋樹毒蛋白(curcin)、巴豆毒蛋白(crotin)、肥皂草(sapaonaria officinalis)抑制物、白樹毒蛋白(gelonin)、絲林黴素(mitogellin)局限麯黴素(restrictocin)、酚黴素(phenomycin)、依諾黴素(enomycin)和單端孢菌素(trichothecenes)。
術語“化療藥物”是可用於治療腫瘤的化合物。該定義還包括起調節、降低、阻斷或抑制可促進癌生長的激素效果作用的抗激素劑,且常常是系統或全身治療的形式。它們自身可以是激素。化療藥物實例包括烷化劑,如噻替哌(thiotepa);環磷醯胺(cyclosphamide)(CYTOXANTM);烷基磺酸脂如白消安(busulfan),英丙舒凡(improsulfan)和哌泊舒凡(piposulfan);氮丙啶(aziridine)如苯並多巴(benaodopa)、卡波醌(carboquone)、美妥替哌(meturedopa)和尿烷亞胺(uredopa);氮丙啶和甲基蜜胺(methylamelamine)包括六甲蜜胺(altretamine)、三亞胺嗪(triethylenemelamine)、三亞乙基磷醯胺、三亞乙基硫代磷醯胺和三羥甲基蜜胺(trimethylolomelamine);氮芥(nitrogen mustards)如苯丁酸氮芥、萘氮芥、膽磷醯胺(cholophosphamide)、雌氮芥(estramustine)、異環磷醯胺(ifosfamide)、氮芥(mechlorethamine)、鹽酸氧氮芥;左旋苯丙胺酸氮芥(melphalan)、新氮芥(novembichin)、膽甾醇苯乙酸氮芥、松龍苯芥(prednimustine)、曲磷胺(trofosfamide)、尿嘧啶氮芥;亞硝基脲(nitrosureas)如亞硝基脲氮芥(carmustine)、氯脲菌素(chlorozotocin)、福莫司汀(fotemustine)、洛莫司汀(lomustine)、尼莫司汀(nimustine)、雷莫司汀(ranimustine);抗生素如阿克拉黴素、放線菌素、安麯黴素(authramycin)、重氮絲胺酸、博來黴素、放線菌素C(cactinomycin)、加利車黴素(calicheamicin)、卡拉黴素(carabicin)、洋紅黴素(chromomycin)、嗜癌素(carzinophilin)、色黴素、放線菌素D、柔紅菌素(daunorubicin)、地托比星(detorubicin)、6-重氮-5-氧-L-正亮胺酸、阿黴素(doxorubicin)、表阿黴素(epirubicin)、依索比星(esorubicin)、伊達比星(idarubicin)、發波黴素(rmarcellomycin)、絲裂黴素、黴酚酸、諾加黴素(nogalamycin)、橄欖黴素(olivomycin)、培洛黴素(peplomycin)、泊非黴素(potfiromycin)、嘌呤黴素、三鐵阿黴素(quelamycin)、羅多比星
(rodorubicin)、鏈黑菌素;鏈脲黴素(streptozocin)、殺結核菌素、烏苯美司(ubenimex)、淨司他丁(zinostatin)、佐柔比星(zorubicin);抗代謝藥如胺甲蝶吟、5-氟尿嘧啶(5-FU);葉酸類似物如二甲葉酸(denopterin)、胺甲蝶呤、蝶羅呤、三甲曲沙(trimetrexate);喋吟類似物氟達拉濱(fludarabine)、6-巰基蝶呤、硫咪蝶呤、硫鳥蝶呤;嘧啶類似物如安西他濱(ancitabine)、阿紮胞苷(azacitidine)、6-氮尿苷、卡莫氟(carmofur)、阿糖胞苷、雙脫氧尿苷、去氟氧尿苷(doxitluridine)、依諾他濱(enocitabine)、氟尿苷、5-FU;雄激素類如二甲睾酮(calusterone)、丙酸甲雄烷酮(dromostanolong propionate)、環硫雄醇(epitiostanol)、美雄胺(mepitiostane)、睾內酯(testolactone);抗腎上腺類如胺魯米特(aminoglutethimide)、米托坦(mitotane)、曲洛司坦(trilostane);葉酸補充劑如亞葉酸(frolinic acid);醋葡內脂;醛磷醯胺糖苷(aldophosphamideglycoside);胺基乙醯丙酸(aminolevulinic acid);安吖啶(amsacrine);倍曲布昔(bestrabucil);比生群(biasntrene);依達曲沙(edatraxate);地佛法明(defofamine);秋水仙胺;地吖醌(diaziquone);依佛米辛(elfomithine);依利醋銨(elliptinium acetate);依託格魯(etoglucid);硝酸鎵;羥基脲;香菇多糖(lentinan);氯尼達明(lonidamine);米托胍腙(mitoguazone);米托蒽醌(mitoxantrone);莫哌達醇(mopidamol);硝呋旦(nitracrine);噴司他丁(pintostatin);蛋胺氮芥(phenamet);吡柔比星(pirarubicin);鬼臼樹酸(podophyllinic acid);2-乙基醯肼;丙卡巴肼(procarbazine);PSK®;雷佐生(razoxane);西索菲蘭(sizofiran);鍺螺胺(spirogermanium);細交鏈孢菌酮酸;三亞胺醌;2,2',2"-三氯二乙胺(trichlorrotriethylamine);烏拉坦(urethan);長春鹼醯胺;達卡巴嗪(dacarbazine);甘露醇氮芥;二溴甘露醇(mitobronitol);二溴衛矛醇;哌溴烷坑(pipobroman);加胞嘧啶(gacytosine);阿拉伯糖苷("Ara-C");
環磷醯胺;噻替哌(thiotepa);紫杉烷、如紫杉醇(TAXOL®,Bristol-Myers Squibb Oncology,Princeton,NJ)和多西紫杉醇(docetaxel)(TAXOTERE®,Rhone-Poulenc Rorer,Antony,France);苯丁酸氮芥;吉西他濱(gemcitabine);6-硫代鳥嘌呤;巰基嘌呤;胺甲蝶呤;鉑類似物如順鉑和卡鉑;長春花鹼;鉑;依託泊甙(etoposide)(VP-16);異環磷航膠;絲裂黴素C;米托蒽醌;長春新鹼;長春瑞賓(vinorelbine);新黴醯胺(navelbine);諾肖林(novantrone);替尼泊甙(teniposide);柔紅黴素;胺基蝶呤;希羅達(xeloda);伊拜磷酸鹽(ibandronate);CPT-11;拓撲異構酶抑制劑RFS2000;二氟甲基鳥胺酸(DMFO);維甲酸埃斯黴素(esperamicins);卡培他濱(capecitabine);以及上述任何物質的可藥用鹽、酸或衍生物。此定義還包括能調節或抑制激素對腫瘤的作用的抗激素製劑、如抗雌激素製劑包括他莫昔芬(tamoxifen)、雷洛昔芬(raloxifene)、芳香酶抑制劑4(5)-咪唑、4-羥基他莫昔芬、曲沃昔芬(trioxifene)、雷洛昔芬(keoxifene)、LY117018、奧那斯酮(onapristone)、和托瑞米芬(Fareston);和抗雄激素製劑如氟他胺(flutamide)、尼魯米特(nilutamide)、比卡魯胺(bicalutamide)、亮丙瑞林(leuprolide)和戈舍瑞林(goserelin);和上述任何物質的可藥用鹽、酸或衍生物。
本公開所述的“抗體”指免疫球蛋白,完整抗體是由兩條相同的重鏈和兩條相同的輕鏈藉由鏈間二硫鍵連接而成的四肽鏈結構。免疫球蛋白重鏈恆定區的胺基酸組成和排列順序不同,故其抗原性也不同。據此,可將免疫球蛋白分為五類,或稱為免疫球蛋白的同種型,即IgM、IgD、IgG、IgA和IgE,其相應的重鏈分別為μ鏈、δ鏈、γ鏈、α鏈、和ε鏈。同一類Ig根據其鉸鏈區胺基酸組成和重鏈二硫鍵的數目和位置的差別,又可分為不同的亞類,如IgG可分為IgG1、IgG2、IgG3、IgG4。輕鏈藉由恆定區的不同分為κ鏈或λ鏈。五類Ig中每類Ig都可以有κ鏈或λ鏈。
抗體重鏈和輕鏈靠近N端的約110個胺基酸的序列變化很大,為可變區(Fv區);靠近C端的其餘胺基酸序列相對穩定,為恆定區。可變區包括3個高變區(HVR)和4個序列相對保守的骨架區(FR)。3個高變區決定抗體的特異性,又稱為互補性決定區(CDR)。每條輕鏈可變區(VL)和重鏈可變區(VH)由3個CDR區4個FR區組成,從胺基端到羧基端依次排列的順序為:FR1、CDR1、FR2、CDR2、FR3、CDR3、FR4。輕鏈的3個CDR區指LCDR1、LCDR2、和LCDR3;重鏈的3個CDR區指HCDR1、HCDR2和HCDR3。
本公開的抗體包括鼠源抗體、嵌合抗體和人源化抗體。
術語“鼠源抗體”在本公開中為根據本領域知識和技能製備的針對人Claudin18.2的單株抗體。製備時用Claudin18.2或其表位作為抗原注射試驗對象,然後分離表現具有所需序列或功能特性的抗體的融合瘤。在本公開一個較佳的實施方案中,所述的鼠源抗Claudin18.2抗體或其抗原結合片段,可進一步包含鼠源κ、λ鏈或其變體的輕鏈恆定區,或進一步包含鼠源IgG1、IgG2、IgG3或其變體的重鏈恆定區。
術語“嵌合抗體(chimeric antibody)”,是將鼠源性抗體的可變區與人抗體的恆定區融合而成的抗體,可以減輕鼠源性抗體誘發的免疫應答反應。建立嵌合抗體,要先建立分泌鼠源性特異性單抗的融合瘤,然後從鼠融合瘤細胞中選殖可變區基因,再根據需要選殖人抗體的恆定區基因,將鼠可變區基因與人恆定區基因連接成嵌合基因後插入表現載體中,最後在真核系統或原核系統中表現嵌合抗體分子。在本公開一個較佳的實施方案中,該嵌合抗體的抗體輕鏈進一步包含人源κ、λ鏈或其變體的輕鏈恆定區。該Claudin18.2嵌合抗體的抗體重鏈進一步包含人源IgG1、IgG2、IgG3、IgG4或其變體的重鏈恆定區,較佳包含人源IgG1、IgG2或IgG4重鏈恆定區,或者使用胺基酸突變
(例如L234A和/或L235A突變,和/或S228P突變)的IgG1、IgG2或IgG4變體。
術語“人源化抗體(humanized antibody)”,也稱為CDR移植抗體(CDR-grafted antibody),是指將非人物種的CDR序列移植到人的抗體可變區框架,即不同類型的人種系抗體框架序列中產生的抗體。可以克服嵌合抗體由於攜帶大量異源蛋白成分,從而誘導的異源性反應。此類構架序列可以從包括種系抗體基因序列的公共DNA數據庫或公開的參考文獻獲得。如人重鏈和輕鏈可變區基因的種系DNA序列可以在“VBase”人種系序列數據庫(在因特網www.mrccpe.com.ac.uk/vbase可獲得),以及在Kabat,E.A.等人,1991 Sequences of Proteins of Immunological Interest,第5版中找到。為避免免疫原性下降的同時,引起的活性下降,可對該人抗體可變區框架序列進行最少反向突變或回復突變,以保持活性。本公開的人源化抗體也包括進一步由酵母菌展示對CDR進行親和力成熟突變後的人源化抗體。
在本公開一個的實施方案中,該抗體或其抗原結合片段,可進一步包含人源或鼠源κ、λ鏈或其變體的輕鏈恆定區,或進一步包含人源或鼠源IgG1、IgG2、IgG3、IgG4或其變體的重鏈恆定區;較佳包含人源IgG1、IgG2或IgG4重鏈恆定區,或者使用胺基酸突變(例如L234A和/或L235A突變、和/或S228P突變)的IgG1、IgG2或IgG4變體。
本公開中所述人抗體的重鏈恆定區和人抗體的輕鏈恆定區的“變體”是指現有技術已公開的來源於人的不改變抗體可變區結構和功能的重鏈恆定區或輕鏈恆定區的變體。示例性變體包括對重鏈恆定區進行定點改造和胺基酸替換的IgG1、IgG2、IgG3或IgG4重鏈恆定區變體;具體替換如現有技術已知的YTE突變、L234A和/或L235A突變、S228P突變、和/或獲得knob-into-
hole結構的突變(使抗體重鏈具有knob-Fc和hole-Fc組合),這些突變已被證實使得抗體具有新的性能,但不改變抗體可變區的功能。
“人抗體”(HuMAb)、“人源抗體”、“全人抗體”、“完全人抗體”可以互換使用,可以是源於人的抗體或者是從一種轉基因生物體中獲得的抗體,該轉基因生物體經“改造”以響應於抗原刺激而產生特異性人抗體,並且可以藉由本領域已知的任何方法產生。在某些技術中,將人重鏈和輕鏈基因座元件引入到源於胚胎幹細胞系的細胞株中,這些細胞株中的內源性重鏈和輕鏈基因座遭到靶向破壞。轉基因生物可以合成對人抗原特異的人抗體,並且該生物可以用於產生分泌人抗體的融合瘤。人抗體還可以是一種抗體,其中重鏈和輕鏈是由源於一個或更多個人DNA來源的核苷酸序列編碼的。完全人抗體還可以藉由基因或染色體轉染方法以及噬菌體展示技術來構建,或者由體外活化的B細胞構建,所有的這些都是本領域已知的。
術語“全長抗體”、“完整抗體”、“完全抗體”和“全抗體”在本文中可互換使用,指基本上完整形式的抗體,與下文定義的抗原結合片段相區分。該術語特別指在輕鏈和重鏈中包含恆定區的抗體。本公開“抗體”包含“全長抗體”及其抗原結合片段。
在一些實施方案中,本公開的全長抗體包括由以下表中輕重鏈可變區組合中的輕鏈可變區與輕鏈恆定區連接和重鏈可變區與重鏈恆定區連接後所形成的全長抗體。本領域技術人員可以根據實際需要選擇不同的抗體來源的輕鏈恆定區、重鏈恆定區,例如人抗體來源的輕鏈恆定區和重鏈恆定區。
術語抗體的“抗原結合片段”或“功能片段”是指保持特異性結合抗原(例如,Claudin18.2)的能力的一個或更多個片段。已顯示可利用全長抗體的片段來進行抗體的抗原結合功能。術語抗體的“抗原結合片段”中包含的結合片段的實例包括(i)Fab片段,由VL、VH、CL和CH1結構域組成
的單價片段;(ii)F(ab')2片段,包含藉由鉸鏈區上的二硫橋連接的兩個Fab片段的二價片段,(iii)由VH和CH1結構域組成的Fd片段;(iv)由抗體的單臂的VH和VL結構域組成的Fv片段;(v)dsFv,由VH和VL經鏈間二硫鍵形成的抗原結合片段;(vi)包含scFv、dsFv、Fab等片段的雙抗體、雙特異性抗體和多特異性抗體。此外,雖然Fv片段的兩個結構域VL和VH,藉由合成的接頭連接它們,從而使得其能夠產生為其中VL和VH區配對形成單價分子的單個蛋白質鏈(稱為單鏈Fv(scFv);參見,例如,Bird等人(1988)Science242:423-426;和Huston等人(1988)Proc.Natl.Acad.Sci USA85:5879-5883)。此類單鏈抗體也包括在術語抗體的“抗原結合片段”中。使用本領域技術人員已知的常規技術獲得此類抗體片段,並且以與對於完整抗體的方式相同的方式就功用性篩選片段。可藉由重組DNA技術或藉由酶促或化學斷裂完整免疫球蛋白來產生抗原結合部分。抗體可以是不同同種型的抗體,例如,IgG(例如,IgG1、IgG2、IgG3或IgG4亞型)、IgA1、IgA2、IgD、IgE或IgM抗體。
Fab是藉由用木瓜蛋白酶相同活性的酶處理IgG抗體分子所獲得的片段中具有抗原結合活性的抗體片段。
F(ab')2是藉由用酶胃蛋白酶相同活性的酶消化IgG,而獲得的具有抗原結合活性的抗體片段。
Fab'是藉由切割上述F(ab')2而獲得的具有抗原結合活性的抗體片段。
此外,可以藉由將編碼Fab'片段的DNA插入到表現載體中,並將載體導入到宿主中來生產所述Fab'。
術語“單鏈抗體”、“單鏈Fv”或“scFv”意指包含藉由接頭連接的抗體重鏈可變結構域(或區域;VH)和抗體輕鏈可變結構域(或區域;
VL)的分子。此類scFv分子可具有通用結構:NH2-VL-接頭-VH-COOH或NH2-VH-接頭-VL-COOH。可用於本公開的其他接頭由以下文獻描述,例如但不限於:Holliger等人(1993)Proc.Natl.Acad.Sci.USA 90:6444-6448;Alfthan等人(1995),Protein Eng.8:725-731;Choi等人(2001),Eur.J.Immuno 1.31:94-106;Hu等人(1996),Cancer Res.56:3055-3061;Kipriyanov等人(1999),J.Mol.Biol.293:41-56和Roovers等人(2001),Cancer Immumol.。
雙抗體是其中scFv或Fab被二聚體化的抗體片段,是具有二價抗原結合活性的抗體片段。在二價抗原結合活性中,兩個抗原可以是相同或不同的。
雙特異性抗體和多特異性抗體是指能結合兩個或多個抗原或抗原決定簇的抗體。
dsFv是藉由將其中每個VH和VL中的一個胺基酸殘基被半胱胺酸殘基取代的多肽經由半胱胺酸殘基之間的二硫鍵相連而獲得的。可以按照已知方法(例如Protein Engineering,7,697(1994))基於抗體的三維結構預測來選擇被半胱胺酸殘基取代的胺基酸殘基。
術語“胺基酸差異”或“胺基酸突變”是指相較於原蛋白質或多肽,變體蛋白質或多肽存在胺基酸的改變或突變,包括在原蛋白質或多肽的基礎上發生1個、2個、3個或更多個胺基酸的插入、缺失或替換。
術語“抗體框架”或“FR區”,是指可變結構域VL或VH的一部分,其用作該可變結構域的抗原結合環(CDR)的支架。從本質上講,其是不具有CDR的可變結構域。
術語“互補決定區”、“CDR”或“高變區”是指抗體的可變結構域內主要促成抗原結合的6個高變區之一。通常,每個重鏈可變區中存在三個CDR(HCDR1、HCDR2、HCDR3),每個輕鏈可變區中存在三個CDR
(LCDR1、LCDR2、LCDR3)。可以使用各種公知方案中的任何一種來確定CDR的胺基酸序列邊界,包括“Kabat”編號規則(參見Kabat等(1991),“Sequences of Proteins of Immunological Interest”,第5版,Public Health Service,National Institutes of Health,Bethesda,MD)、“Chothia”編號規則(參見Al-Lazikani等人,(1997)JMB 273:927-948)和ImMunoGenTics(IMGT)編號規則(Lefranc M.P.,Immunologist,7,132-136(1999);Lefranc,M.P.等,Dev.Comp.Immunol.,27,55-77(2003)等。例如,對於經典格式,遵循Kabat規則,該重鏈可變域(VH)中的CDR胺基酸殘基編號為31-35(HCDR1)、50-65(HCDR2)和95-102(HCDR3);輕鏈可變域(VL)中的CDR胺基酸殘基編號為24-34(LCDR1)、50-56(LCDR2)和89-97(LCDR3)。遵循Chothia規則,VH中的CDR胺基酸編號為26-32(HCDR1)、52-56(HCDR2)和95-102(HCDR3);並且VL中的胺基酸殘基編號為26-32(LCDR1)、50-52(LCDR2)和91-96(LCDR3)。藉由組合Kabat和Chothia兩者的CDR定義,CDR由人VH中的胺基酸殘基26-35(HCDR1)、50-65(HCDR2)和95-102(HCDR3)和人VL中的胺基酸殘基24-34(LCDR1)、50-56(LCDR2)和89-97(LCDR3)構成。遵循IMGT規則,VH中的CDR胺基酸殘基編號大致為26-35(CDR1)、51-57(CDR2)和93-102(CDR3),VL中的CDR胺基酸殘基編號大致為27-32(CDR1)、50-52(CDR2)和89-97(CDR3)。遵循IMGT規則,抗體的CDR區可以使用程序IMGT/DomainGap Align確定。
術語“表位”或“抗原決定簇”是指抗原上被免疫球蛋白或抗體所結合的部位(例如,Claudin18.2分子上的特定部位)。表位通常以獨特的空間構象包括至少3、4、5、6、7、8、9、10、11、12、13、14或15個連續或非
連續的胺基酸。參見,例如,Epitope Mapping Protocols in Methods in Molecular B iology,第66卷,G.E.Morris,Ed.(1996)。
術語“特異性結合”、“選擇性結合”、“選擇性地結合”和“特異性地結合”是指抗體對預先確定的抗原上的表位的結合。通常,抗體以大約小於10-8M,例如大約小於10-9M、10-10M、10-11M、10-12M或更小的親和力(KD)結合。
術語“KD”是指特定抗體-抗原相互作用的解離平衡常數。通常,本公開的抗體以小於大約10-7M,例如小於大約10-8M或10-9M的解離平衡常數(KD)結合Claudin18.2或其表位,例如,在本公開中抗體與細胞表面抗原的親和力採用FACS法測定KD值。
當術語“競爭”用於競爭相同表位的抗原結合蛋白的情況中時,意指在抗原結合蛋白之間競爭,其藉由以下測定法來測定:在該測定法中,待檢測的抗原結合蛋白(例如抗體或其功能片段)防止或抑制(例如降低)參考抗原結合蛋白(例如配體或參考抗體)與共同抗原(例如Claudin18.2抗原或其片段)的特異性結合。眾多類型的競爭性結合測定可用於確定一種抗原結合蛋白是否與另一種競爭,這些測定例如:固相直接或間接放射免疫測定(RIA)、固相直接或間接酶免疫測定(EIA)、夾心競爭測定(參見例如Stahli等,1983,Methodsin Enzymology 9:242-253);固相直接生物素-親和素EIA(參見例如Kirkland等,1986,J.Immunol.137:3614-3619)、固相直接標記測定、固相直接標記夾心測定(參見例如Harlow和Lane,1988,Antibodies,A Laboratory Manual(抗體,實驗室手冊),Cold Spring Harbor Press);用I-125標記物的固相直接標記RIA(參見例如Morel等,1988,Molec.Immunol.25:7-15);固相直接生物素-親和素EIA(參見例如Cheung,等,1990,Virology176:546-552);和直接標記的RIA(Moldenhauer等,1990,
Scand.J.Immunol.32:77-82)。通常該測定法涉及使用結合荷有未標記的檢測抗原結合蛋白及標記的參考抗原結合蛋白任一種的固態表面或細胞的純化的抗原。藉由測量在所測抗原結合蛋白存在下結合固態表面或細胞的標記的量來測量競爭性抑制。通常所測抗原結合蛋白過量存在。由競爭性測定(競爭抗原結合蛋白)鑒定的抗原結合蛋白包括:結合與參考抗原結合蛋白同一表位的抗原結合蛋白;和結合充分接近參考抗原結合蛋白的結合表位的鄰近表位的抗原結合蛋白,所述兩個表位在空間上互相妨礙發生結合。在本文實施例中提供關於用於測定競爭性結合的方法的其它詳細資料。通常當競爭的抗原結合蛋白過量存在時,其將抑制(例如降低)至少40-45%、45-50%、50-55%、55-60%、60-65%、65-70%、70-75%或75%或更多參考抗原結合蛋白與共同抗原的特異性結合。在某些情況下,結合被抑制至少80-85%、85-90%、90-95%、95-97%或97%或更多。
本文中使用的術語“核酸分子”是指DNA分子和RNA分子。核酸分子可以是單鏈或雙鏈的,較佳是雙鏈DNA或單鏈mRNA或修飾的mRNA。當將核酸與另一個核酸序列置於功能關係中時,核酸是“有效連接的”。例如,如果啟動子或增強子影響編碼序列的轉錄,那麼啟動子或增強子有效地連接至該編碼序列。
胺基酸序列“同一性”指在比對胺基酸序列時(必要時引入間隙),以達成最大序列同一性百分比,且不將任何保守性取代視為序列同一性的一部分,第一序列中與第二序列中的胺基酸殘基同一的胺基酸殘基的百分比。為測定胺基酸序列同一性百分比,比對可以藉由屬於本領域技術的範圍內的多種方式來實現,例如使用公開可得到的計算機軟體,諸如BLAST、BLAST-2、ALIGN、ALIGN-2或Megalign(DNASTAR)軟體。本領域技術人員
可確定適用於測量比對的參數,包括在所比較的序列全長上達成最大比對所需的任何算法。
術語“表現載體”是指能夠運輸已與其連接的另一個核酸的核酸分子。在一個實施方案中,載體是“質粒”,其是指可將另外的DNA區段連接至其中的環狀雙鏈DNA環。在另一個實施方案中,載體是病毒載體,其中可將另外的DNA區段連接至病毒基因組中。本文中公開的載體能夠在已引入它們的宿主細胞中自主複製(例如,具有細菌的複製起點的細菌載體和附加型哺乳動物載體)或可在引入宿主細胞後整合入宿主細胞的基因組,從而隨宿主基因組一起複製(例如,非附加型哺乳動物載體)。
現有技術中熟知生產和純化抗體和抗原結合片段的方法,如冷泉港的抗體實驗技術指南,5-8章和15章。例如,鼠可以用人Claudin18.2或其片段免疫,所得到的抗體能被覆性、純化,並且可以用常規的方法進行胺基酸測序。抗原結合片段同樣可以用常規方法製備。發明所述的抗體或抗原結合片段用基因工程方法在非人源的CDR區加上一個或更多個人源FR區。人FR種系序列可以藉由比對IMGT人類抗體可變區種系基因數據庫和MOE軟體,從ImMunoGeneTics(IMGT)的網站http://imgt.cines.fr得到,或者從免疫球蛋白雜誌,2001ISBN012441351上獲得。
術語“宿主細胞”是指已向其中引入了表現載體的細胞。宿主細胞可包括細菌、微生物、植物或動物細胞。易於轉化的細菌包括腸桿菌科(enterobacteriaceae)的成員,例如大腸桿菌(Escherichia coli)或沙門氏菌(Salmonella)的菌株;芽孢桿菌科(Bacillaceae)例如枯草芽孢桿菌(Bacillus subtilis);肺炎球菌(Pneumococcus);鏈球菌(Streptococcus)和流感嗜血菌(Haemophilus influenzae)。適當的微生物包括釀酒酵母(Saccharomyces
cerevisiae)和畢赤酵母(Pichia pastoris)。適當的動物宿主細胞系包括CHO(中國倉鼠卵巢細胞系)、293細胞和NS0細胞。
本公開的抗體或抗原結合片段可用常規方法製備和純化。比如,編碼重鏈和輕鏈的cDNA序列,可以選殖並重組至表現載體。重組的免疫球蛋白表現載體可以穩定地轉染宿主細胞。作為一種更推薦的現有技術,哺乳動物類表現系統會導致抗體的糖基化,特別是在Fc區的高度保守N端位點。藉由表現與人Claudin18.2特異性結合的抗體得到穩定的純株。陽性的純株在生物反應器中擴大培養以生產抗體。分泌了抗體的培養液可以用常規技術純化。比如,用含調整過的緩衝液的A或G Sepharose FF管柱進行純化。洗去非特異性結合的組分。再用pH梯度法沖提結合的抗體,用SDS-PAGE檢測抗體片段,收集。抗體可用常規方法進行過濾濃縮。可溶的混合物和多聚體,也可以用常規方法去除,比如分子篩、離子交換。得到的產物需立即冷凍,如-70℃,或者凍幹。
“施用”、“給予”和“處理”當應用於動物、人、實驗受試者、細胞、組織、器官或生物流體時,是指外源性藥物、治療劑、診斷劑或組成物與動物、人、受試者、細胞、組織、器官或生物流體的接觸。“施用”、“給予”和“處理”可以指例如治療、藥物代謝動力學、診斷、研究和實驗方法。細胞的處理包括試劑與細胞的接觸,以及試劑與流體的接觸,其中該流體與細胞接觸。“施用”、“給予”和“處理”還意指藉由試劑、診斷、結合組成物或藉由另一種細胞體外和離體處理例如細胞。“處理”當應用於人、獸醫學或研究受試者時,是指治療處理、預防或預防性措施,研究和診斷應用。
“治療”意指給予患者內用或外用治療劑,例如包含本公開的任一種抗體或抗原結合片段的組成物,該患者具有一種或多種疾病症狀,而已知該治療劑對這些症狀具有治療作用。通常,在受治療患者或群體中以有效緩解
一種或多種疾病症狀的量給予治療劑,以誘導這類症狀退化或抑制這類症狀發展到任何臨床右測量的程度。有效緩解任何具體疾病症狀的治療劑的量(也稱作“治療有效量”)可根據多種因素變化,例如患者的疾病狀態、年齡和體重,以及藥物在患者產生需要療效的能力。藉由醫生或其它專業衛生保健人士通常用於評價該症狀的嚴重性或進展狀況的任何臨床檢測方法,可評價疾病症狀是否已被減輕。儘管本公開的實施方案(例如治療方法或製品)在緩解每個目標疾病症狀方面可能無效,但是根據本領域已知的任何統計學檢驗方法如Student t檢驗、卡方檢驗、依據Mann和Whitney的U檢驗、Kruskal-Wallis檢驗(H檢驗)、Jonckheere-Terpstra檢驗和Wilcoxon檢驗確定,其在統計學顯著數目的患者中應當減輕目標疾病症狀。
“保守修飾”或“保守置換或取代”是指具有類似特徵(例如電荷、側鏈大小、疏水性/親水性、主鏈構象和剛性等)的其它胺基酸置換蛋白中的胺基酸,使得可頻繁進行改變而不改變蛋白的生物學活性。本領域技術人員知曉,一般而言,多肽的非必需區域中的單個胺基酸置換基本上不改變生物學活性(參見例如Watson等(1987)Molecular Biology of the Gene,The Benjamin/Cummings Pub.Co.,第224頁,(第4版))。另外,結構或功能類似的胺基酸的置換不大可能破環生物學活性。示例性保守取代於下表“示例性胺基酸保守取代”中陳述。
“有效量”或“有效劑量”指指獲得任一種或多種有益的或所需的治療結果所必需的藥物、化合物或醫藥組成物的量。對於預防用途,有益的或所需的結果包括消除或降低風險、減輕嚴重性或延遲病症的發作,包括病症、其併發症和在病症的發展過程中呈現的中間病理表型的生物化學、組織學和/或行為症狀。對於治療應用,有益的或所需的結果包括臨床結果,諸如減少各種本公開靶抗原相關病症的發病率或改善所述病症的一個或更多個症狀,減少治療病症所需的其它藥劑的劑量,增強另一種藥劑的療效,和/或延緩患者的本公開靶抗原相關病症的進展。
“外源性”指根據情況在生物、細胞或人體外產生的物質。
“內源性”指根據情況在細胞、生物或人體內產生的物質。
“同一性”是指兩個多核苷酸序列之間或兩個多肽之間的序列相似性。當兩個比較序列中的位置均被相同鹼基或胺基酸單體亞基佔據時,例如如果兩個DNA分子的每一個位置都被腺嘌呤佔據時,那麼該分子在該位置是同源的。兩個序列之間的同一性百分率是兩個序列共有的匹配或同源位置數除以比較的位置數×100的函數。例如,在序列最佳比對時,如果兩個序列中的10個位置有6個匹配或同源,那麼兩個序列為60%同源;如果兩個序列中的100個位置有95個匹配或同源,那麼兩個序列為95%同源。通常,當比對兩個序列時進行比較以給出最大百分比同一性。例如,可以藉由BLAST算法執行比較,其中選擇算法的參數以在各個參考序列的整個長度上給出各個序列之間的最大匹配。以下參考文獻涉及經常用於序列分析的BLAST算法:BLAST算法(BLAST ALGORITHMS):Altschul,S.F.等人,(1990)J.Mol.Biol.215:403-410;Gish,W.等人,(1993)Nature Genet.3:266-272;Madden,T.L.等人,(1996)Meth.Enzymol.266:131-141;Altschul,S.F.等人,(1997)Nucleic
Acids Res.25:3389-3402;Zhang,J.等人,(1997)Genome Res.7:649-656。其他如NCBI BLAST提供的常規BLAST算法也為本領域技術人員所熟知。
本文使用的表述“細胞”、“細胞系”和“細胞培養物”可互換使用,並且所有這類名稱都包括後代。因此,“轉化體”和“轉化細胞”包括原代受試細胞和由其衍生的培養物,而不考慮傳代數目。還應當理解的是,由於故意或非有意的突變,所有後代在DNA含量方面不可能精確相同。包括具有與最初轉化細胞中篩選的相同的功能或生物學活性的突變後代。在意指不同名稱的情況下,其由上下文清楚可見。
“分離的”指分子基本上不含其他生物分子,例如核酸、蛋白質、脂質、碳水化合物或其他材料,例如細胞碎片和生長培養基。通常,術語“分離的”並不意圖指完全不存在這些材料或不存在水、緩衝液或鹽,除非它們以顯著干擾如本文所述的化合物的實驗或治療用途的量存在。
“視需要”或“視需要地”意味著隨後所描述地事件或環境可以但不必發生,該說明包括該事件或環境發生或不發生的場合。
“醫藥組成物”表示含有一種或多種本文所述化合物或其生理學上/可藥用的鹽或前體藥物與其他化學組分的混合物,該其他組分例如生理學/可藥用的載體和賦形劑。醫藥組成物的目的是促進對生物體的給藥,利於活性成分的吸收進而發揮生物活性。
術語“藥學上可接受的載體”指適合用於製劑中用於遞送抗體或抗原結合片段的任何無活性物質。載體可以是抗黏附劑、黏合劑、包衣、崩解劑、充填劑或稀釋劑、防腐劑(如抗氧化劑、抗菌劑或抗真菌劑)、增甜劑、吸收延遲劑、潤濕劑、乳化劑、緩衝劑等。合適的藥學上可接受的載體的示例包括水、乙醇、多元醇(例如甘油、丙二醇、聚乙二醇等)右旋糖、植物油
(例如橄欖油)、鹽水、緩衝液、緩衝的鹽水和等滲劑例如糖、多元醇、山梨糖醇和氯化鈉。
此外,本公開包括用於治療與目標抗原(例如Claudin18.2)陽性細胞相關的疾病的藥劑,該藥劑包含本公開的抗Claudin18.2抗體或其抗原結合片段作為活性成分。
本公開中與Claudin18.2相關的疾病沒有限制,只要它是與Claudin18.2相關的疾病即可,例如,本公開的分子誘導的治療反應包括:(1)藉由結合人類Claudin18.2,阻遏Claudin18.2與其受體/配體的結合,或(2)殺傷過表現Claudin18.2的腫瘤細胞。因此,當處於適於治療應用的製備物和製劑中時,本公開的分子對這樣一些人是非常有用的,他們患有腫瘤或癌症,較佳黑色素瘤、結腸癌、乳腺癌、肺癌、胃癌、腸癌、腎癌、非小細胞肺癌、膀胱癌等。
此外,本公開涉及用於免疫檢測或測定目標抗原(例如Claudin18.2)的方法、用於免疫檢測或測定目標抗原(例如Claudin18.2)的試劑、用於免疫檢測或測定表現目標抗原(例如Claudin18.2)的細胞的方法和用於診斷與目標抗原(例如Claudin18.2)陽性細胞相關的疾病的診斷劑,其包含本公開的特異性識別目標抗原(例如人Claudin18.2)並與胞外區的胺基酸序列或其三維結構結合的抗體或抗體片段作為活性成分。
在本公開中,用於檢測或測定目標抗原(例如Claudin18.2)的量的方法可以是任何已知方法。例如,它包括免疫檢測或測定方法。
免疫檢測或測定方法是使用標記的抗原或抗體檢測或測定抗體量或抗原量的方法。免疫檢測或測定方法的實例包括放射性物質標記的免疫抗體方法(RIA)、酶免疫測定法(EIA或ELISA)、螢光免疫測定法(FIA)、發光免疫測定法、蛋白質免疫印跡法、物理化學方法等。
上述與Claudin18.2陽性細胞相關的疾病可以藉由用本公開的抗體或抗體片段檢測或測定表現Claudin18.2的細胞來診斷。
為了檢測表現多肽的細胞,可以使用已知的免疫檢測方法,並較佳使用免疫沉澱法、螢光細胞染色法、免疫組織染色法等。此外,可以使用利用FMAT8100HTS系統(Applied Biosystem)的螢光抗體染色法等。
在本公開中,對用於檢測或測定目標抗原(例如Claudin18.2)的待測樣品沒有特別限制,只要它具有包含表現目標抗原(例如Claudin18.2)的細胞的可能性即可,例如組織細胞、血液、血漿、血清、胰液、尿液、糞便、組織液或培養液。
根據所需的診斷方法,含有本公開的單株抗體或其抗體片段的診斷劑還可以含有用於執行抗原-抗體反應的試劑或用於檢測反應的試劑。用於執行抗原-抗體反應的試劑包括緩衝劑、鹽等。用於檢測的試劑包括通常用於免疫檢測或測定方法的試劑,例如識別該單株抗體、其抗體片段或其結合物的標記的第二抗體和與該標記對應的受質等。
在以上說明書中提出了本發明一種或多種實施方式的細節。雖然可使用與本文所述類似或相同的任何方法和材料來實施或測試本發明,但是以下描述較佳的方法和材料。藉由說明書和申請專利範圍,本發明的其他特點、目的和優點將是顯而易見的。在說明書和申請專利範圍中,除非上下文中有清楚的另外指明,單數形式包括複數指代物的情況。除非另有定義,本文使用的所有技術和科學術語都具有本發明所屬領域普通技術人員所理解的一般含義。說明書中引用的所有專利和出版物都藉由引用納入。提出以下實施例是為了更全面地說明本發明的較佳實施方式。這些實施例不應以任何方式理解為限制本發明的範圍,本發明的範圍由申請專利範圍限定。
實施例
實施例1:構建高表現Claudin18.2的細胞株
用Lipofectamine 3000轉染試劑,將pCDH-hClaudin18.2慢病毒表現載體質粒與pVSV-G,pCMV-dR8.91慢病毒系統包裝載體轉染至病毒包裝細胞293T中;收集含有病毒的培養基上清,過濾並進行超高速離心;使用濃縮後的病毒感染人胃印戒細胞癌細胞株NUGC4,經puromycin篩選兩至三週,再進行FACS單細胞分選。
根據腫瘤IHC評分來區分Claudin18.2表現程度。與腫瘤IHC評分為3分的腫瘤Claudin18.2表現水平相當的細胞為高表現細胞,與腫瘤IHC評分為2分的腫瘤Claudin18.2表平水平相當的細胞為中等表現細胞。根據藉由FACS檢測慢病毒感染的NUGC4細胞表面的Claudin18.2表現,挑選出Claudin18.2表現量高的NUGC4/hClaudin18.2單株細胞株。同時藉由FACS檢測野生型NUGC4細胞表面的Claudin18.2表現,挑選出Claudin18.2表現量中等的NUGC4純株細胞株,野生型NUGC4為Claudin18.2低表現量細胞。
將挑選出的單株細胞株擴大培養,凍存備庫以便後續實驗。
Claudin18.2序列Genbank:NP_001002026:(SEQ ID NO:1)
Claudin18.2 DNA序列:(SEQ ID NO:2)
實施例2:抗人claudin18.2單株抗體產生
1 免疫
藉由免疫小鼠產生抗人Claudin18.2單株抗體。
實驗用SJL白小鼠,雌性,6-8週齡(北京維通利華實驗動物技術有限公司,動物生產許可證號:SCXK(京)2012-0001)。飼養環境:SPF級。小鼠購進後,實驗室環境飼養1週,12/12小時光/暗週期調節,溫度20-25℃;濕度40-60%。將已適應環境的小鼠按以下方案免疫。免疫抗原為huClaudin18.2-HEK293細胞(轉染人Claudin18.2質粒的HEK-293穩轉細胞株)。
免疫方案:首次免疫細胞前,用TiterMax® Gold Adjuvant(Sigma Cat No.T2684)0.1ml/隻注射小鼠腹膜內(IP);半小時後每隻小鼠腹膜內(IP)注射0.1ml生理鹽水稀釋至1×108/ml濃度的細胞液。細胞吹散均勻後進行接種,時間為第0、14、28、42、56天。於第21、35、49、63天取血,用ELISA方法確定小鼠血清中的抗體滴度。在第4-5次免疫以後,選擇血清中抗體滴度高並且滴度趨於平臺的小鼠進行脾細胞融合。在進行脾細胞融合前3天加強免疫,腹膜內(IP)注射1×107細胞。
2 脾細胞融合
採用PEG介導的融合步驟將脾淋巴細胞與骨髓瘤細胞Sp2/0細胞(ATCC® CRL-8287TM)進行融合得到融合瘤細胞。融合瘤細胞以0.5-1×106/ml的密度用完全培養基(含20% FBS、1×HAT、1×OPI的IMDM培養基)重新懸浮,100μl/孔種於96孔板中,37℃,5%CO2孵育3-4天後,補充HAT完全培養基100μl/孔,繼續培養3-4天至形成純株。去除上清,加入200μl/孔的HT完全培養基(含20%FBS、1×HT和1×OPI的IMDM培養基),37℃,5%CO2培養3天後進行ELISA檢測。
3 融合瘤細胞篩選
根據融合瘤細胞生長密度,用結合ELISA方法檢測培養上清。選擇與huClaudin18.2-HEK293細胞結合能力強,同時與HEK293細胞沒有結合的細胞,及時進行擴增凍存;經過二到三次亞選殖直至獲得單細胞純株。
每次亞選殖細胞均需進行細胞結合實驗。藉由以上實驗篩選得到融合瘤純株,用無血清細胞培養法進一步製備抗體,按純化實例純化抗體,供在檢測例中使用。
實施例3:鼠源抗體的人源化
挑選出體外活性高的單株融合瘤細胞株mAb1901,mAb1902;選殖其中的單株抗體序列,再進行人源化、重組表現和活性評價。
從融合瘤中選殖序列的過程如下。收集對數生長期融合瘤細胞,用Trizol(Invitrogen,15596-018)提取RNA(按照試劑盒說明書步驟)並進行反轉錄(PrimeScriptTM Reverse Transcriptase,Takara,cat # 2680A)。將反轉錄得到的cDNA採用mouse Ig-Primer Set(Novagen,TB326 Rev.B 0503)進行PCR擴增,送測序公司測序。得到的DNA序列對應的胺基酸序列SEQ ID NO:3-6所示:
mAb1901鼠源重鏈可變區(SEQ ID NO:3)
mAb1901鼠源輕鏈可變區(SEQ ID NO:4)
mAb1902鼠源重鏈可變區(SEQ ID NO:5)
mAb1902鼠源輕鏈可變區(SEQ ID NO:6)
上述鼠源重鏈可變區和輕鏈可變區,分別與下述人IgG1抗體的重鏈恆定區和人源κ輕鏈恆定區連接,形成嵌合抗體ch1901和ch1902。
恆定區選自以下序列:
人IgG1抗體的重鏈恆定區:(SEQ ID NO:7)
人源κ輕鏈恆定區:(SEQ ID NO:8)
RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC。
如本領域許多文獻公示的方法,對鼠源單株抗體進行人源化。簡言之,使用人恆定結構域替代親本(鼠源抗體)恆定結構域,根據鼠源抗體和人抗體的同源性選擇人種系抗體序列,進行CDR移植。本發明選擇活性好的候選分子進行人源化,結果如下。
1.鼠源抗體的CDR區
表4中VH/VL CDR的胺基酸殘基由Kabat編號系統確定並注釋。
鼠源抗體的CDR序列如表4所述:
2.選擇人種系FR區序列
在所獲得的鼠源抗體VH/VLCDR典型結構的基礎上,將重、輕鏈可變區序列與抗體Germline數據庫比較,獲得同源性高的人種系模板。其中人類種系輕鏈框架區來自人κ輕鏈基因。
2.1 mAb1901的人源化改造和回復突變設計
選擇適當的人抗體種系,對mAb1901鼠源抗體進行人源化改造,將鼠源抗體mAb1901的CDR區移植到選擇的人源化模板上,得到人源化
可變區,其人源化重鏈可變區序列為SEQ ID NO:24和輕鏈可變區序列為SEQ ID NO:21;再與IgG恆定區重組,形成完整抗體。同時,對人源化抗體的V區中FR區進行回復突變,示例性回復突變方式及組合如下:
*表格中所有胺基酸位置編號為Kabat編號規則的編號,重鏈可變區的N82T中,82為Kabat規則的第82A位。
上表中對應重鏈可變區可與SEQ ID NO:7所示的人IgG1重鏈恆定區連接形成全長抗體的重鏈,輕鏈可變區與SEQ ID NO:8所示的人κ輕鏈恆定區連接形成全長抗體的輕鏈。在其他實施方案中,重鏈可變區和輕鏈可變區也可與其他重鏈恆定區和輕鏈恆定區分別連接形成全長抗體。
2.2 mAb1902的人源化改造和回復突變設計
選擇適當的人抗體種系,對mAb1902鼠源抗體進行人源化改造,將鼠源抗體mAb1902的CDR區移植到選擇的人源化模板上,得到人源化可變區,其人源化重鏈可變區序列為SEQ ID NO:31和輕鏈可變區序列為SEQ ID NO:28;再與IgG恆定區重組,形成完整抗體。同時,對人源化抗體的V區中FR區進行回復突變,示例性回復突變方式及組合如下:
上表中對應重鏈可變區與SEQ ID NO:7所示的人IgG1重鏈恆定區連接形成全長抗體的重鏈,輕鏈可變區與SEQ ID NO:8所示的人κ輕鏈恆定區連接形成全長抗體的輕鏈。
示例性的,抗體全長序列如下:
嵌合抗體ch1901:
ch1901重鏈:(SEQ ID NO:35)
ch1901輕鏈(SEQ ID NO:36)
嵌合抗體ch1902:
ch1902重鏈(SEQ ID NO:37)
ch1902輕鏈(SEQ ID NO:38)
全長抗體輕重鏈序列如下所示:
全長抗體輕重鏈序列如下所示:
本公開陽性對照抗體為IMAB-362(來自WO2016166122)
IMAB-362重鏈(SEQ ID NO:53)
IMAB-362輕鏈(SEQ ID NO:54)
用常規的基因選殖、重組表現的方法分別選殖、表現、純化上述抗體。
體外活性生物學評價
測試例1:Cell水平ELISA結合實驗
基於細胞的ELISA實驗被用來檢測Claudin18.2抗體的結合特性。將穩轉表現Claudin18.2的NUGC4細胞培養於96孔細胞板(Corning,3599)中,待生長至90%密度時加入4%多聚甲醛固定細胞1小時,用PBST緩衝液(pH 7.4 PBS含0.05% Tween-20)洗板3次後,加入用PBS稀釋的5%脫脂牛奶(光明脫脂奶粉)封閉液200μl/孔,37℃孵育箱孵育2.5小時或4℃放置過夜(16-18小時)進行封閉。封閉結束後,棄去封閉液,並用PBST緩衝液洗板3次後,加入50μl/孔用樣品稀釋液(pH7.4 PBS含1%脫脂乳)稀釋的不同濃度待測抗體,放於37℃孵育箱孵育2小時。孵育結束後用PBST洗板5次,加入100μl/孔用樣品稀釋液稀釋的HRP標記的羊抗入二抗(Jackson Immuno Research,109-035-003),37℃孵育1小時。用PBST洗板6次後,加入50μl/孔TMB顯色受質(KPL,52-00-03),於室溫孵育10-15min,加入50μl/孔 1M H2SO4終止反應,用MD Versa Max TM酶標儀在450nm處讀取吸收值,計算Claudin18.2抗體對Claudin18.2的結合EC50值(結果見下表)。
測試例2:抗體細胞水平結合實驗
將穩轉表現Claudin18.2的NUGC4細胞用FACS緩衝液(2%胎牛血清(Gibco,10099141)pH7.4 PBS(Sigma,P4417-100TAB))製備成1×106/ml的細胞懸液,100μl/孔加入96孔圓底板(Corning,3795)中。離心去除上清後加入50μl/孔用FACS緩衝液稀釋的不同濃度待測Claudin18.2抗體,放於4℃冰箱中避光孵育1小時。以FACS緩衝液300g離心洗滌3次後,加入工作濃度的Alexa Fluor 488包被的抗人IgG(H+L)(invitrogen,A-11013),放於4℃冰箱中避光孵育40分鐘。以FACS緩衝液300g離心洗滌3次後,在BD FACS CantoII流式細胞儀上檢測幾何平均數螢光強度,計算Claudin18.2抗體對穩轉表現Claudin18.2的NUGC4細胞的結合EC50值,結果見第1圖。
測試例3:抗體內吞實驗
將預標記了DyLight 488 NHS Ester(thermofisher,46403)的待測Claudin18.2抗體,以5μg/ml終濃度加入1×106/ml穩轉表現Claudin18.2的NUGC4細胞中,放於冰上避光孵育1小時,以預冷的FACS緩衝液(pH7.4 PBS,2%胎牛血清)離心洗滌3次,去上清後加入預熱的完全培養基,放入37℃ 5% CO2細胞培養箱。分別在0、0.5、1、2、4小時後取出細胞,放置於冰上避光保存。待樣品全部收集後,300g低溫離心去除上清,加入沖提緩衝液(pH1.7 0.05M甘胺酸,0.1M氯化鈉)後,室溫孵育7分鐘,以FACS緩衝液300g離心洗滌1次,在BD FACS CantoII流式細胞儀上檢測幾何平均數螢光強度,計算Claudin18.2抗體對穩轉表現Claudin18.2的NUGC4細胞的內吞效率。結果顯示(見第2圖),人源化抗體具有良好的細胞內吞效率。
測試例4:基於流式細胞技術測定抗體親和力
實驗當天收集HEK293/hClaudin18.2細胞於U底96孔板中,每孔1×105至2×105個細胞。加入起始濃度5μg/ml,2×梯度稀釋(12個濃度點)的
Claudin18.2抗體,4℃孵育1小時,陽性對照為IMAB362,同時設置不加抗體的陰性對照。離心去除抗體,再加入100μl/孔FITC抗人IgG Fc抗體(200×),4℃避光孵育30分鐘,用PBS+2%FBS清洗兩遍後準備進行流式細胞檢測。啟動BD FACS CantoII,預熱完成後打開BD FACSDiva軟體,建立一個新的實驗,檢測HEK293/hClaudin18.2陰性對照樣品,調節FSC及SSC電壓至適當的數值並保存。根據QuantumTM FITC-5 MESF Kit說明書,分別檢測空白樣品B及標準曲線1,調節FITC電壓至適當的數值並保存。在保存的電壓下檢測U底96孔板中的樣品,記錄數據。使用Flowjo軟體分析實驗數據得到Geo Mean數值,根據QuantumTM FITC-5 MESF Kit說明書擬合MESF-Geo Mean標準曲線,根據FITC抗人IgG Fc抗體的濃度螢光值計算出與HEK293/hClaudin18.2細胞結合的Claudin18.2抗體的莫耳濃度及游離抗體濃度,利用Scatchard作圖法計算抗體的Bmax和解離常數KD。結果見表15.
測試例5:抗體的ADCC效應評價
消化各種NUGC4細胞(高中低表現Claudin18.2),1000rpm離心後,重新懸浮計數。將細胞以3×105細胞/ml的密度重新懸浮在添加10% FBS(新西蘭超低IgG胎牛血清,Gibco,1921005PJ)的無酚紅RPMI 1640中(Gibco,11835-030)。在96孔板(Corning,3903)中,每孔加入25μl細胞(7500個/孔)。將抗體稀釋在上述無酚紅培養基中,配製成3×的抗體稀釋液,向細胞板中加入25μl/孔的抗體。在37℃、5% CO2培養箱中孵育0.5小時。
收集效應細胞(FcrR3A-V158-NFAT-RE-Jurkat細胞),1000rpm離心後,重新懸浮計數。將細胞以3×106細胞/ml的密度重新懸浮在添加10%FBS(新西蘭超低IgG胎牛血清)的無酚紅RPMI 1640中,在實驗板中每孔加入25μl細胞(7.5×104個細胞/孔)。在37℃、5% CO2培養箱中孵育6小時。
向實驗板的每個孔中加入75μl/孔的Bright-Glo(Promega,E2610),用酶標儀(PerkinElmer,VITOR3)檢測化學發光(luminescence)。
結果顯示(見表16和第3A圖至第3C圖),在低中高不同程度Claudin18.2表現的NUGC4細胞中,抗體h1901-11和h1902-5均顯示出很強的ADCC活性。
<110> 江蘇恆瑞醫藥股份有限公司
上海恆瑞醫藥有限公司
<120> 密蛋白抗體及其應用
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<211> 261
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<221> 基因
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<221> 結構域
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<221> 結構域
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<400> 8
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<221> 結構域
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<400> 9
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<212> PRT
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<221> 結構域
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<221> 結構域
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<210> 12
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> 結構域
<223> mAb1901 LCDR1
<400> 12
<210> 13
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
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<221> 結構域
<223> mAb1901 LCDR2
<400> 13
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<221> 結構域
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<212> PRT
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<221> 結構域
<223> mAb1902 HCDR1
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<210> 16
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<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> 結構域
<223> mAb1902 HCDR2
<400> 16
<210> 17
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> 結構域
<223> mAb1902 HCDR3
<400> 17
<210> 18
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> 結構域
<223> mAb1902 LCDR1
<400> 18
<210> 19
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> 結構域
<223> mAb1902 LCDR2
<400> 19
<210> 20
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<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> 結構域
<223> mAb1902 LCDR3
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<210> 21
<211> 113
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> 結構域
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<210> 22
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<213> 人工序列(Artificial Sequence)
<220>
<221> 結構域
<223> VL2
<400> 22
<210> 23
<211> 113
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> 結構域
<223> VL3
<400> 23
<210> 24
<211> 120
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> 結構域
<223> VH1
<400> 24
<210> 25
<211> 120
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> 結構域
<223> VH2
<400> 25
<210> 26
<211> 120
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> 結構域
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<400> 26
<210> 27
<211> 120
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> 結構域
<223> VH4
<400> 27
<210> 28
<211> 113
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> 結構域
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<400> 28
<210> 29
<211> 113
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> 結構域
<223> VL12
<400> 29
<210> 30
<211> 113
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> 結構域
<223> VL13
<400> 30
<210> 31
<211> 118
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> 結構域
<223> VH11
<400> 31
<210> 32
<211> 118
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> 結構域
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<400> 32
<210> 33
<211> 118
<212> PRT
<213> 人工序列(Artificial Sequence)
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<221> 結構域
<223> VH13
<400> 33
<210> 34
<211> 118
<212> PRT
<213> 人工序列(Artificial Sequence)
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<221> 結構域
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<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> 鏈
<223> ch1901重鏈
<400> 35
<210> 36
<211> 220
<212> PRT
<213> 人工序列(Artificial Sequence)
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<221> 鏈
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<211> 448
<212> PRT
<213> 人工序列(Artificial Sequence)
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<221> 鏈
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<211> 220
<212> PRT
<213> 人工序列(Artificial Sequence)
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<221> 鏈
<223> L2
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<211> 220
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<213> 人工序列(Artificial Sequence)
<220>
<221> 鏈
<223> L3
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<213> 人工序列(Artificial Sequence)
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<400> 43
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<213> 人工序列(Artificial Sequence)
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<223> H3
<400> 44
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<213> 人工序列(Artificial Sequence)
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<221> 鏈
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<400> 45
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<213> 人工序列(Artificial Sequence)
<220>
<221> 鏈
<223> L11
<400> 46
<210> 47
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<213> 人工序列(Artificial Sequence)
<220>
<221> 鏈
<223> L12
<400> 47
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<213> 人工序列(Artificial Sequence)
<220>
<221> 鏈
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<400> 48
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<213> 人工序列(Artificial Sequence)
<220>
<221> 鏈
<223> H11
<400> 49
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<213> 人工序列(Artificial Sequence)
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<221> 鏈
<223> H12
<400> 50
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<213> 人工序列(Artificial Sequence)
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<400> 51
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<213> 人工序列(Artificial Sequence)
<220>
<221> 鏈
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<210> 53
<211> 448
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> 鏈
<223> IMAB-362重鏈
<400> 53
<210> 54
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Claims (17)
- 一種抗Claudin18.2抗體,其包含重鏈可變區和輕鏈可變區,其中:i)該重鏈可變區包含與如SEQ ID NO:3所示的重鏈可變區相同序列的HCDR1、HCDR2和HCDR3,該輕鏈可變區包含與如SEQ ID NO:4序列所示的輕鏈可變區相同序列的LCDR1、LCDR2和LCDR3;或ii)該重鏈可變區包含與如SEQ ID NO:5所示的重鏈可變區相同序列的HCDR1、HCDR2和HCDR3,該輕鏈可變區包含與如SEQ ID NO:6所示的輕鏈可變區相同序列的LCDR1、LCDR2和LCDR3。
- 如申請專利範圍第1項所述的抗Claudin18.2抗體,其包含重鏈可變區和輕鏈可變區,其中:iii)該重鏈可變區包含分別如SEQ ID NO:9、SEQ ID NO:10和SEQ ID NO:11所示的HCDR1、HCDR2和HCDR3,該輕鏈可變區包含分別如SEQ ID NO:12、SEQ ID NO:13和SEQ ID NO:14所示的LCDR1、LCDR2和LCDR3;或iv)該重鏈可變區包含分別如SEQ ID NO:15、SEQ ID NO:16和SEQ ID NO:17所示的HCDR1、HCDR2和HCDR3,該輕鏈可變區包含分別如SEQ ID NO:18、SEQ ID NO:19和SEQ ID NO:20所示的LCDR1、LCDR2和LCDR3。
- 如申請專利範圍第1或2項所述的抗Claudin18.2抗體,其是鼠源抗體、嵌合抗體或人源化抗體。
- 如申請專利範圍第1至3項中任一項所述的抗Claudinl8.2抗體,其包含重鏈可變區和輕鏈可變區,其中:v)該重鏈可變區,其胺基酸序列與SEQ ID NO:3或24具有至少90%同一性,和該輕鏈可變區,其胺基酸序列與SEQ ID NO:4或21具有至少90%同一性;或vi)該重鏈可變區,其胺基酸序列與SEQ ID NO:5或31具有至少90%同一性,和該輕鏈可變區,其胺基酸序列與SEQ ID NO:6或28具有至少90%同一性;較佳地:1)該重鏈可變區,其胺基酸序列如SEQ ID NO:3所示或與其有至少90%同一性,和該輕鏈可變區,其胺基酸序列如SEQ ID NO:4所示或與其有至少90%同一性;2)該重鏈可變區,其胺基酸序列如SEQ ID NO:24所示或與其有至少90%同一性,和該輕鏈可變區,其胺基酸序列如SEQ ID NO:21所示或與其有至少90%同一性;3)該重鏈可變區,其胺基酸序列如SEQ ID NO:5所示或與其有至少90%同一性,和該輕鏈可變區,其胺基酸序列如SEQ ID NO:6所示或與其有至少90%同一性;或4)該重鏈可變區,其胺基酸序列如SEQ ID NO:31所示或與其有至少90%同一性,和該輕鏈可變區,其胺基酸序列如SEQ ID NO:28所示或與其有至少90%同一性。
- 如申請專利範圍第4項所述的抗Claudin18.2抗體,其為人源化抗體,該人源化抗體包含來源自人抗體的框架區或其框架區變體,該框架區變體在人抗體的輕鏈框架區和/或重鏈框架區上分別具有1至10個回復突變;較佳地,該框架區變體包含選自以下a)或b)所述的突變:a)該輕鏈可變區中包含選自22S、85I和87H中的一個或更多個回復突變,和/或該重鏈可變區中包含選自48I、82T和69M中的一個或更多個回復突變;或b)該輕鏈可變區中包含選自4L和22S一個或更多個回復突變,和/或該重鏈可變區中包含選自38K、40R、48I、66K、67A、69L、71L和73K中的一個或更多個回復突變;更佳地,該框架區變體包含選自以下a-1)或b-1)所述的突變:a-1)該輕鏈可變區中包含22S、85I和87H的回復突變,和該重鏈可變區中包含48I和82T的回復突變;或b-1)該輕鏈可變區中包含4L的回復突變;重鏈可變區的82T中,82為Kabat規則的第82A位。
- 如申請專利範圍第3項所述的抗Claudin18.2抗體,其包含如下所示的重鏈可變區和輕鏈可變區:vii)該重鏈可變區序列如SEQ ID NO:3所示和該輕鏈可變區序列如SEQ ID NO:4所示;或viii)該重鏈可變區序列如SEQ ID NO:24、25、26或27所示和該輕鏈可變區序列如SEQ ID NO:21、22或23所示;或ix)該重鏈可變區序列如SEQ ID NO:5所示和該輕鏈可變區序列如SEQ ID NO:6所示;或x)該重鏈可變區序列如SEQ ID NO:31、32、33或34所示和該輕鏈可變區序列如SEQ ID NO:28、29或30所示;較佳地,該抗Claudin18.2抗體或其抗原結合片段,其包含如下所示的重鏈可變區和輕鏈可變區:xi)該重鏈可變區序列如SEQ ID NO:31所示和該輕鏈可變區序列如SEQ ID NO:29所示;或xii)該重鏈可變區序列如SEQ ID NO:26所示和該輕鏈可變區序列如SEQ ID NO:23所示。
- 如申請專利範圍第1至6項中任一項所述的抗Claudin18.2抗體,其進一步包含重鏈恆定區和輕鏈恆定區;較佳地,該重鏈恆定區選自人IgG1、IgG2、IgG3和IgG4恆定區及其變體,較佳地,該輕鏈恆定區選自人抗體κ和λ鏈恆定區及其變體;更佳地,該抗Claudin18.2抗體包含SEQ ID NO:7所示的重鏈恆定區和SEQ ID NO:8所示的輕鏈恆定區;最佳地,該抗Claudin18.2抗體包含:與SEQ ID NO:35或42具有至少90%同一性的重鏈,和與SEQ ID NO:36或39具有至少90%同一性的輕鏈;或與SEQ ID NO:37或49具有至少90%同一性的重鏈,和與SEQ ID NO:38或46具有至少90%同一性的輕鏈。
- 如申請專利範圍第1至7項中任一項所述的抗Claudin18.2抗體,其包含:c)SEQ ID NO:35所示的重鏈和SEQ ID NO:36所示的輕鏈;d)SEQ ID NO:42、43、44或45所示的重鏈和SEQ ID NO:39、40或41所示的輕鏈;e)SEQ ID NO:37所示的重鏈和SEQ ID NO:38所示的輕鏈;或f)SEQ ID NO:49、50、51或52所示的重鏈和SEQ ID NO:46、47或48所示的輕鏈。
- 如申請專利範圍第1至8項中任一項所述的抗Claudin18.2抗體,其包含:SEQ ID NO:44所示的重鏈,和SEQ ID NO:41所示的輕鏈;或SEQ ID NO:49所示的重鏈,和SEQ ID NO:47所示的輕鏈。
- 一種分離的抗Claudin18.2抗體,該抗體與申請專利範圍第1至9項中任一項所述的抗Claudin18.2抗體競爭性結合人Claudin18.2。
- 一種核酸分子,其編碼申請專利範圍第1至10項中任一項所述的抗Claudin18.2抗體。
- 一種宿主細胞,其包含如申請專利範圍第11項所述的核酸分子。
- 一種抗體藥物偶聯物,其為由如申請專利範圍第1至10項中任一項所述的抗Claudin18.2抗體與細胞毒性藥物偶聯形成的抗體藥物偶聯物。
- 一種醫藥組成物,其含有治療有效量的如申請專利範圍第1至10項中任一項所述的抗Claudin18.2抗體,或如申請專利範圍第11項所述的核酸分子,或申請專利範圍13項所述的抗體藥物偶聯物,以及一種或更多種藥學上可接受的載體、稀釋劑、緩衝劑或賦形劑。
- 一種用於免疫檢測或測定Claudin18.2的方法,該方法包括:使申請專利範圍第1至10項中任一項所述的抗Claudin18.2抗體接觸待測樣本的步驟。
- 一種試劑盒,其包含如申請專利範圍第1至10項中任一項所述的抗Claudin18.2抗體。
- 一種治療與Claudin18.2相關的疾病的方法,所述方法包括向受試者施用治療有效量的申請專利範圍1至10項中任一項所述的抗Claudin18.2抗體,或申請專利範圍11項所述的核酸分子,或申請專利範圍13項所述的抗體藥物偶聯物或申請專利範圍14項所述的醫藥組成物,較佳地,該疾病為腫瘤;更佳地,該疾病選自:頭和頸鱗狀細胞癌、頭和頸癌、腦癌、神經膠質瘤、多形性成膠質細胞瘤、神經母細胞瘤、中樞神經系統癌、神經內分泌腫瘤、咽喉癌、鼻咽癌、食管癌、甲狀腺癌、惡性胸膜間皮瘤、肺癌、乳腺癌、肝癌、肝細胞瘤、肝細胞癌、肝膽癌、胰腺癌、胃癌、胃腸道癌、腸癌、結腸癌、結腸直腸癌、腎癌、透明細胞腎細胞癌、卵巢癌、子宮內膜癌、子宮頸癌、膀胱癌、前列腺癌、睾丸癌、皮膚癌、黑色素瘤、白血病、淋巴瘤、骨癌、軟骨肉瘤、骨髓瘤、多發性骨髓瘤、骨髓異常增生綜合症、庫肯勃氏瘤、骨髓增生性腫瘤、鱗狀細胞癌、尤因氏肉瘤、全身性輕鏈澱粉樣變性和梅克爾細胞癌;更佳地,該淋巴瘤選自:何傑金淋巴瘤、非何傑金淋巴瘤、彌漫性大B-細胞淋巴瘤、濾泡性淋巴瘤、原發性縱隔大B-細胞淋巴瘤、套細胞淋巴瘤、小淋巴細胞性淋巴瘤、富含T-細胞/組織細胞的大B-細胞淋巴瘤和淋巴漿細胞性淋巴瘤;該肺癌選自:非小細胞肺癌和小細胞肺癌;該白血病選自:慢性髓細胞樣白血病、急性髓細胞樣白血病、淋巴細胞白血病、成淋巴細胞性白血病、急性成淋巴細胞性白血病、慢性淋巴細胞性白血病和髓樣細胞白血病。
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