TW202246332A - 抗trpv6單株抗體及其應用 - Google Patents
抗trpv6單株抗體及其應用 Download PDFInfo
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Abstract
本發明關於一系列可以識別人TRPV6蛋白質分子的抗體及可分泌該抗體的融合瘤細胞株,本發明選擇了一段TRPV6蛋白特徵性的多肽抗原免疫小鼠後篩選獲得了融合瘤細胞系12CT 9.5.1、16CT 18.1.1.2和16CT 4.1.1.2,該系列細胞可分泌針對TRPV6的單株抗體,並可特異性識別TRPV6蛋白及腫瘤組織。該系列抗體可通過人工或自動化方式,以免疫組織化學(IHC)、酶聯免疫吸附(ELISA)、免疫螢光(IF)、化學發光(CLIA)、免疫比濁(TIA)或免疫印跡(Western Blot)方式檢測細胞中TRPV6的水平,從而用於對腫瘤組織進行診斷的方法中,屬於生物檢測領域。
Description
本發明關於一系列可以識別人TRPV6蛋白的抗體及可分泌該系列抗體的融合瘤細胞系。具體而言,本發明提供了一系列特異性結合腫瘤細胞膜/漿內TRPV6分子的單株抗體,對該抗體重鏈和輕鏈可變區的胺基酸序列和編碼可變區的DNA序列進行了確定,該抗體或其抗原片段可以用於通過人工或自動化方式,以免疫組織化學(IHC)、酶聯免疫吸附(ELISA)、免疫螢光(IF)、化學發光(CLIA)、免疫比濁(TIA)或免疫印跡(Western Blot)方式檢測細胞中TRPV6的水平,從而用於對這些腫瘤進行診斷的方法中,屬於生物檢測領域。
瞬時受體陽離子通道亞家族V成員6(transient receptor potential cation channel subfamily V member 6),即TRPV6,是一種高選擇性鈣離子跨膜轉運通道,介導鈣離子由細胞外向細胞內的主動轉運。TRPV6在人正常的腎臟、胃腸道、胰腺、乳腺、唾液腺等中有表達,但是主要表達於腸上皮細胞,其參與鈣離子向細胞內的轉運,因此當TRPV6通道的數量或功能發生改變時,可引起鈣離子調節的變化,進一步導致與其相關組織器官的結構或功能異常。
和正常組織相比,TRPV6在乳腺癌、膽管癌、卵巢癌、肺鱗癌、前列腺癌等惡性腫瘤中表達明顯升高,其異常表達可能與腫瘤的形成與進展有關。Prevarskaya團隊發現高表達TRPV6的人前列腺癌LNCap細胞攝取鈣離子是由TRPV6介導的,在經過siRNA處理,調低TRPV6蛋白水平後,其S期細胞數量減少,細胞增殖受到抑制。還有利用利多卡因處理人乳腺癌MDA-MB-231細胞、前列腺癌PC-3細胞和卵巢癌ES-2細胞後,使TRPV6 mRNA和蛋白的水平下調,細胞增殖受到抑制,同時鈣離子進入細胞內的速率降低,表明癌細胞的抑制可能與鈣離子的減少有關,並且可能與TRPV6水平有關。可見TRPV6與人體多種腫瘤均有密切聯繫,並且可能與其調節細胞內外鈣離子濃度變化有關。
TRPV6作為腫瘤細胞標記物,針對其的檢測對於病理診斷和相應靶向藥物使用都有重要意義。目前市面上尚未有可用作診斷用途的抗TRPV6抗體,本專利所涉及抗體可以填補該方面的空白。
本案的一個方面提供了一種特異性結合TRPV6的抗體或其抗原結合片段,其中所述抗體或其抗原結合片段包含如下重鏈可變區所包括的三個重鏈互補決定區HCDR1、HCDR2和HCDR3:SEQ ID NO: 25所示的重鏈可變區;SEQ ID NO: 27所示的重鏈可變區;或SEQ ID NO: 29所示的重鏈可變區。在一些實施方式中,所述抗體或其抗原結合片段包含選自下組的三個重鏈互補決定區HCDR1、HCDR2和HCDR3:SEQ ID NO: 7所示的HCDR1、SEQ ID NO: 8所示的HCDR2、SEQ ID NO: 9所示的HCDR3;SEQ ID NO: 13所示的HCDR1、SEQ ID NO: 14所示的HCDR2、SEQ ID NO: 15所示的HCDR3;或SEQ ID NO: 19所示的HCDR1、SEQ ID NO: 20所示的HCDR2、SEQ ID NO: 21所示的HCDR3。
在一些實施方式中,所述抗體或其抗原結合片段進一步包含如下輕鏈可變區所包括的三個輕鏈互補決定區LCDR1、LCDR2和LCDR3:SEQ ID NO: 26所示的輕鏈可變區;SEQ ID NO: 28所示的輕鏈可變區;或SEQ ID NO: 30所示的輕鏈可變區。在一些實施方式中,所述抗體或其抗原結合片段進一步包含選自下組的三個輕鏈互補決定區LCDR1、LCDR2和LCDR3:SEQ ID NO: 10所示的LCDR1、SEQ ID NO: 11所示的LCDR2以及SEQ ID NO: 12所示的LCDR3;SEQ ID NO: 16所示的LCDR1、SEQ ID NO: 17所示的LCDR2以及SEQ ID NO: 18所示的LCDR3;SEQ ID NO: 22所示的LCDR1、SEQ ID NO: 23所示的LCDR2以及SEQ ID NO: 24所示的LCDR3。
在一些實施方式中,所述抗體或其抗原結合片段包含選自下組的三個重鏈互補決定區HCDR1、HCDR2和HCDR3以及三個輕鏈互補決定區LCDR1、LCDR2和LCDR3:SEQ ID NO: 7所示的HCDR1、SEQ ID NO: 8所示的HCDR2、SEQ ID NO: 9所示的HCDR3、SEQ ID NO: 10所示的LCDR1、SEQ ID NO: 11所示的LCDR2以及SEQ ID NO: 12所示的LCDR3;SEQ ID NO: 13所示的HCDR1、SEQ ID NO: 14所示的HCDR2、SEQ ID NO: 15所示的HCDR3、SEQ ID NO: 16所示的LCDR1、SEQ ID NO: 17所示的LCDR2以及SEQ ID NO: 18所示的LCDR3;SEQ ID NO: 19所示的HCDR1、SEQ ID NO: 20所示的HCDR2、SEQ ID NO: 21所示的HCDR3、SEQ ID NO: 22所示的LCDR1、SEQ ID NO: 23所示的LCDR2以及SEQ ID NO: 24所示的LCDR3。
在一些實施方式中,所述抗體或其抗原結合片段包含SEQ ID NO: 7所示的HCDR1、SEQ ID NO: 8所示的HCDR2、SEQ ID NO: 9所示的HCDR3、SEQ ID NO: 10所示的LCDR1、SEQ ID NO: 11所示的LCDR2以及SEQ ID NO: 12所示的LCDR3。
在一些實施方式中,所述抗體或其抗原結合片段包含SEQ ID NO: 13所示的HCDR1、SEQ ID NO: 14所示的HCDR2、SEQ ID NO: 15所示的HCDR3、SEQ ID NO: 16所示的LCDR1、SEQ ID NO: 17所示的LCDR2以及SEQ ID NO: 18所示的LCDR3。
在一些實施方式中,所述抗體或其抗原結合片段包含SEQ ID NO: 19所示的HCDR1、SEQ ID NO: 20所示的HCDR2、SEQ ID NO: 21所示的HCDR3、SEQ ID NO: 22所示的LCDR1、SEQ ID NO: 23所示的LCDR2以及SEQ ID NO: 24所示的LCDR3。
在一些實施方式中,所述抗體或其抗原結合片段包含選自下組的重鏈可變區V
H和:SEQ ID NO: 25所示的重鏈可變區;SEQ ID NO: 27所示的重鏈可變區;或SEQ ID NO: 29所示的重鏈可變區。
在一些實施方式中,所述抗體或其抗原結合片段進一步包含選自下組的輕鏈可變區V
L:SEQ ID NO: 26所示的輕鏈可變區;SEQ ID NO: 28所示的輕鏈可變區;或SEQ ID NO: 30所示的輕鏈可變區。
在一些實施方式中,所述抗體或其抗原結合片段包含選自下組的重鏈可變區V
H和輕鏈可變區V
L:SEQ ID NO: 25所示的重鏈可變區和SEQ ID NO: 26所示的輕鏈可變區;SEQ ID NO: 27所示的重鏈可變區和SEQ ID NO: 28所示的輕鏈可變區;或SEQ ID NO: 29所示的重鏈可變區和SEQ ID NO: 30所示的輕鏈可變區。
在一些實施方式中,所述抗體或其抗原結合片段包含SEQ ID NO: 25所示的重鏈可變區和SEQ ID NO: 26所示的輕鏈可變區。
在一些實施方式中,所述抗體或其抗原結合片段包含SEQ ID NO: 27所示的重鏈可變區和SEQ ID NO: 28所示的輕鏈可變區。
在一些實施方式中,所述抗體或其抗原結合片段包含SEQ ID NO: 29所示的重鏈可變區和SEQ ID NO: 30所示的輕鏈可變區。
在一些實施方式中,所述抗體或其抗原結合片段特異性識別或結合具有SEQ ID NO: 2所示的胺基酸序列的蛋白。
在一些實施方式中,所述抗體或其抗原結合片段與具有SEQ ID NO: 2所示的胺基酸序列的蛋白的Kd值為10
-7-10
-10M。在一些實施方式中,所述Kd值為10
-7-10
-10M、10
-8-10
-10M或10
-9-10
-10M。在一些實施方式中,所述抗體或其抗原結合片段與具有SEQ ID NO: 2所示的胺基酸序列的蛋白的Kd值小於約10
-7M。在一些實施方式中,所述Kd值小於約10
-7M、小於約10
-8M、小於約10
-9M或小於約10
-10M。在一些實施方式中,Kd值是通過表面等離子共振方法檢測的。
在一些實施方式中,所述抗原結合片段是選自F(ab’)2、Fab’、Fab、Fv、scFv、dsFv或dAb。
在一些實施方式中,所述抗體或其抗原結合片段進一步具有重鏈恆定區和/或輕鏈恆定區。在一些實施方式中,重鏈恆定區源於鼠的IgG1或鼠的IgG2a。在一些實施方式中,重鏈恆定區源於人的IgG1。
在一些實施方式中,所述抗體或其抗原結合片段進一步具有綴合部分。在一些實施方式中,所述綴合部分是治療劑、放射性同位素、可檢測標籤、藥物動力學修飾部分或純化部分。所述綴合部分直接連接或者通過連接子連接,所述綴合部分直接連接或者通過連接子連接。
一個方面,本案還提供了一種分離的核酸,其編碼本案所述的特異性結合TRPV6的抗體或其抗原結合片段。
在一些實施方式中,所述核酸包含SEQ ID NO: 31所示的核酸序列或與SEQ ID NO: 31具有至少90%序列同一性的核酸序列,和SEQ ID NO: 32所示的核酸序列或與SEQ ID NO: 32具有至少90%序列同一性的核酸序列中的一者或兩者。在一些實施方式中,所述核酸包含SEQ ID NO: 33所示的核酸序列或與SEQ ID NO: 33具有至少90%序列同一性的核酸序列,和SEQ ID NO: 34所示的核酸序列或與SEQ ID NO: 34具有至少90%序列同一性的核酸序列中的一者或兩者。在一些實施方式中,所述核酸包含SEQ ID NO: 35所示的核酸序列或與SEQ ID NO: 35具有至少90%序列同一性的核酸序列,和SEQ ID NO: 6所示的核酸序列或與SEQ ID NO: 6具有至少90%序列同一性的核酸序列中的一者或兩者。
一個方面,本案還提供了一種載體,其包含本案所述的核酸序列。
一個方面,本案還提供了一種宿主細胞,其包含本案所述的載體。
一個方面,本案還提供了一種多特異性抗體,其包含本案所述的抗體或其抗原結合片段,和一個或多個與其他抗原特異性結合的抗體或其抗原結合部分。
一個方面,本案還提供了一種抗體偶聯物,其包含本案所述的抗體或其抗原結合片段或本案所述的多特異性抗體。
一個方面,本案還提供了分泌抗TRPV6單株抗體的融合瘤細胞株,所述融合瘤細胞株為12CT9.5.1、16CT4.1.1.2和/或16CT18.1.1.2,寄存於中國典型培養物保藏中心,其中12CT9.5.1的寄存編號為CCTCC NO: C202119,16CT4.1.1.2的寄存編號為CCTCC NO: C202124,16CT18.1.1.2的寄存編號為CCTCC NO: C202125。
一個方面,本案還提供了一種藥物組合物,其包含本案所述的抗體或其抗原結合片段、本案所述的分離的核酸、本案所述的載體、本案所述的宿主細胞、本案所述的多特異性抗體或本案所述的抗體偶聯物,和藥學上可接受的載體。
一個方面,本案還提供了一種用於分析和檢測來自受試者的樣品中的TRPV6的試劑,所述試劑包含一種或多種本案所述的抗體或其抗原結合片段。在一些實施方式中,所述試劑用於分析和檢測來自受試者的樣品中的TRPV6。
一個方面,本案還提供了一種檢測來自受試者的樣品中的TRPV6的方法,所述方法包括:(1) 使所述樣品與本案述的抗體或抗原結合片段接觸;(2) 可選地,移除未結合的抗體或抗體片段;(3) 檢測與所述樣品中的TRPV6結合的抗體或抗體片段。
在一些實施方式中,在檢測來自受試者的樣品中的TRPV6的方法的步驟(1)中,本案所述的抗體或抗原結合片段被固定在基板上。在一些實施方式中,在檢測來自受試者的樣品中的TRPV6的方法的步驟(1)中,所述樣品被固定在基板上。
在一些實施方式中,在檢測來自受試者的樣品中的TRPV6的方法的步驟(3)中,還包括使用第二抗體,可選的,所述第二抗體能夠直接或者間接地結合所述樣品中的TRPV6,可選的,所述第二抗體的表位與本案所述的抗體或抗原結合片段的表位不同,可選的,所述第二抗體的表位與本案所述的抗體或抗原結合片段的表位相同,可選的,所述第二抗體的表位與TRPV6的結合不受本案所述的抗體或抗原結合片段的影響,可選的,所述第二抗體的表位與TRPV6的結合受本案所述的抗體或抗原結合片段的影響。
在一些實施方式中,在檢測來自受試者的樣品中的TRPV6的方法的步驟(3)中,還包括使用第二抗體,可選的,所述第二抗體能夠直接或間接地結合本案所述的抗體或抗原結合片段,可選的,所述第二抗體能夠結合本案所述的抗體或抗原結合片段的恆定區部分。
一些實施方式中,所述第二抗體與檢測分子偶聯,可選的,所述檢測分子包括酶、螢光標記物和生物素。在一些實施方式中,所述檢測分子為酶,可選的,所述酶包括辣根過氧化酶、鹼性磷酸酶或其衍生物。在一些實施方式中,所述檢測分子為螢光素,可選的,所述螢光素包括FITC、羅丹明、德克薩斯紅、藻紅蛋白或Dylight。在一些實施方式中,所述檢測分子為生物素或其衍生物。
在一些實施方式中,檢測來自受試者的樣品中的TRPV6的方法進一步包括對與所述樣品中的TRPV6結合的抗體進行定量。在一些實施方式中,所述方法為免疫組織化學(IHC)、免疫螢光(IF)酶聯免疫吸附(ELISA)化學發光(CLIA,chemiluminescent immunoassay)、免疫比濁(TIA,Turbidimetric inhibition immuno assay)或免疫印跡(Western Blot)。在一些實施方式中,所述方法可以評估所述樣品中在細胞表面上表達TRPV6的細胞的比例。
在一些實施方式中,在檢測來自受試者的樣品中的TRPV6的方法中,所述受試者為人類。
一個方面,本案還提供了一種判斷受試者疾病的形成或形成的風險、評估受試者疾病的進展或預後、或在接受疾病治療的受試者中預測或監測所述受試者對治療的反應的方法,所述方法包括通過本案所述的檢測來自受試者的樣品中TRPV6的方法,以檢測來自所述受試者的樣品中的TRPV6。
在一些實施方式中,判斷受試者疾病的形成或形成的風險、評估受試者疾病的進展或預後、或在接受疾病治療的受試者中預測或監測所述受試者對治療的反應的方法包括評估所述樣品中在細胞表面上表達TRPV6的細胞的比例,若所述比例超過預定的閾值,則認為所述受試者患有所述疾病或者是更可能從治療中獲益,其中所述閾值為10%。在一些實施方式中,所述治療是靶向藥物治療。
在一些實施方式中,本案所述的疾病為癌症。在一些實施方式中,癌症為乳腺癌、卵巢癌、子宮內膜癌、膽管癌、胃癌、食道癌、肺癌、腸癌、胰腺癌。
一個方面,本案還提供了一種試劑盒,所述試劑盒包含本案所述的抗體或其抗原結合片段,可選的,進一步包括用於檢測所述抗體或其抗原結合片段與TRPV6結合情況的試劑。
在一些實施方式中,本案所述的試劑盒用於診斷受試者疾病的形成或形成的風險、評估受試者疾病的進展或預後、或在接受疾病治療的受試者中預測或監測所述受試者對治療的反應。在一些實施方式中,本案所述的試劑盒用於免疫組織化學病理診斷。在一些實施方式中,本案所述的試劑盒用於腫瘤組織免疫組織化學病理診斷。在一些實施方式中,所述疾病為癌症,在一些實施方式中,癌症為乳腺癌、卵巢癌、子宮內膜癌、膽管癌、胃癌、食道癌、肺癌、腸癌、胰腺癌。
一個方面,本案還提供了一種製備特異性結合TRPV6的抗體的方法,所述方法包括:(1) 將SEQ ID NO: 3所示的胺基酸序列與載體蛋白偶聯,以獲得TRPV6抗原肽;(2) 將通過步驟(1)獲得的所述TRPV6抗原肽作為免疫原免疫小鼠;(3) 經細胞融合、免疫肽篩選單株,獲得高效分泌特異性結合TRPV6的抗體的陽性融合瘤細胞系;(4) 獲得特異性結合TRPV6的抗體。
在一些實施方式中,所述載體蛋白為鑰孔蟲戚血藍素(KLH)蛋白。
在一些實施方式中,在SEQ ID NO: 3所示的胺基酸序列的N端增加一個Cys,並通過自由巰基和所述載體蛋白偶聯。
在一些實施方式中,本案所述的融合瘤細胞系為小鼠融合瘤細胞系12CT 9.5.1、16CT 18.1.1.2和16CT 4.1.1.2。
一個方面,本案還提供了本案所述抗體或其抗原結合片段、本案所述的分離的核酸、本案所述的載體、本案所述的宿主細胞、本案所述的多特異性抗體、本案所述的抗體偶聯物以及本案所述的藥物組合物在用於治療和/或預防和/或診斷與TRPV6水平相關的疾病的藥物中的用途。
一個方面,本案還提供了一種治療、預防或診斷疾病的方法,所述方法包括向有需要的受試者施用本案所述抗體或其抗原結合片段、本案所述的多特異性抗體、本案所述的抗體偶聯物以及本案所述的藥物組合物。
以下描述只為說明本案的多種實施方式。因此,此處的具體實施方式不應理解為對申請範圍的限制。本案所屬技術領域中具有通常知識者基於本發明的宗旨和本文的描述,可很容易地得出多種等同方式和修改,應理解這樣的等同實施方式包含在本發明範圍內。在本案中引用的所有文獻,包含公開出版物、專利和專利申請都通過引用的方式全文併入本案。
除非上下文另外明確指出,否則本文所使用的單數形式「一」、「一個」、「一種」和「該」或「所述」包括複數引用。
用於本案的諸如「包括」、「包含」、「含有」、「含有」和「具有」等術語是包括性的或開放式的,並且不排除額外的、未敘述的要素或方法步驟。用於本案的術語「由……組成」是封閉式的。
申請人已將融合瘤細胞株(系)12CT9.5.1、16CT4.1.1.2和16CT18.1.1.2提交至中國典型培養物保藏中心進行寄存。12CT9.5.1的寄存編號為CCTCC NO: C202119,16CT4.1.1.2的寄存編號為CCTCC NO: C202124,16CT18.1.1.2的寄存編號為CCTCC NO: C202125,三融合瘤細胞株的寄存地址為中國武漢大學,寄存時間為2021年1月13日,寄存單位為中國典型培養物保藏中心。
本案的一個方面公開了一種特異性結合TRPV6的抗體或其抗原結合片段,其中所述抗體或其抗原結合片段包含如下重鏈可變區所包括的三個重鏈互補決定區HCDR1、HCDR2和HCDR3:SEQ ID NO: 25所示的重鏈可變區;SEQ ID NO: 27所示的重鏈可變區;或SEQ ID NO: 29所示的重鏈可變區。在一些實施方式中,所述抗體或其抗原結合片段包含選自下組的三個重鏈互補決定區HCDR1、HCDR2和HCDR3:SEQ ID NO: 7所示的HCDR1、SEQ ID NO: 8所示的HCDR2、SEQ ID NO: 9所示的HCDR3;SEQ ID NO: 13所示的HCDR1、SEQ ID NO: 14所示的HCDR2、SEQ ID NO: 15所示的HCDR3;或SEQ ID NO: 19所示的HCDR1、SEQ ID NO: 20所示的HCDR2、SEQ ID NO: 21所示的HCDR3。在一些實施方式中,本案的抗體或其抗原結合片段進一步包含所述抗體或其抗原結合片段進一步包含如下輕鏈可變區所包括的三個輕鏈互補決定區LCDR1、LCDR2和LCDR3:SEQ ID NO: 26所示的輕鏈可變區;SEQ ID NO: 28所示的輕鏈可變區;或SEQ ID NO: 30所示的輕鏈可變區。在一些實施方式中,本案的抗體或其抗原結合片段進一步包含選自下組的三個輕鏈互補決定區LCDR1、LCDR2和LCDR3:SEQ ID NO: 10所示的LCDR1、SEQ ID NO: 11所示的LCDR2以及SEQ ID NO: 12所示的LCDR3;SEQ ID NO: 16所示的LCDR1、SEQ ID NO: 17所示的LCDR2以及SEQ ID NO: 18所示的LCDR3;SEQ ID NO: 22所示的LCDR1、SEQ ID NO: 23所示的LCDR2以及SEQ ID NO: 24所示的LCDR3。
在一些實施方式中,本案的抗體或其抗原結合片段包含SEQ ID NO: 7所示的HCDR1、SEQ ID NO: 8所示的HCDR2、SEQ ID NO: 9所示的HCDR3、SEQ ID NO: 10所示的LCDR1、SEQ ID NO: 11所示的LCDR2以及SEQ ID NO: 12所示的LCDR3。在一些實施方式中,本案的抗體或其抗原結合片段包含SEQ ID NO: 13所示的HCDR1、SEQ ID NO: 14所示的HCDR2、SEQ ID NO: 15所示的HCDR3、SEQ ID NO: 16所示的LCDR1、SEQ ID NO: 17所示的LCDR2以及SEQ ID NO: 18所示的LCDR3。在一些實施方式中,本案的抗體或其抗原結合片段包含SEQ ID NO: 19所示的HCDR1、SEQ ID NO: 20所示的HCDR2、SEQ ID NO: 21所示的HCDR3、SEQ ID NO: 22所示的LCDR1、SEQ ID NO: 23所示的LCDR2以及SEQ ID NO: 24所示的LCDR3。
在一些實施方式中,本案的抗體或其抗原結合片段包含選自下組的重鏈可變區V
H和:SEQ ID NO: 25所示的重鏈可變區;SEQ ID NO: 27所示的重鏈可變區;或SEQ ID NO: 29所示的重鏈可變區。在一些實施方式中,所述抗體或其抗原結合片段進一步包含選自下組的輕鏈可變區V
L:SEQ ID NO: 26所示的輕鏈可變區;SEQ ID NO: 28所示的輕鏈可變區;或SEQ ID NO: 30所示的輕鏈可變區。
在一些實施方式中,本案的抗體或其抗原結合片段包含SEQ ID NO: 25所示的重鏈可變區和SEQ ID NO: 26所示的輕鏈可變區。在一些實施方式中,本案的抗體或其抗原結合片段包含SEQ ID NO: 27所示的重鏈可變區和SEQ ID NO: 28所示的輕鏈可變區。在一些實施方式中,本案的抗體或其抗原結合片段包含SEQ ID NO: 29所示的重鏈可變區和SEQ ID NO: 30所示的輕鏈可變區。
用於本案的術語「抗體」包括任意免疫球蛋白、單株抗體、多價抗體、多特異性抗體或雙特異性(雙價)抗體。一個天然的完整抗體包含通過二硫鏈相互結合的兩條重鏈和兩條輕鏈。抗體的每條重鏈由一個可變區(V
H)以及第一、第二和第三恆定區(分別為C
H1、C
H2、C
H3)組成,而抗體的每條輕鏈由一個可變區(V
L)以及一個恆定區(C
L)組成。輕鏈和重鏈的可變區負責抗原結合。每條鏈中的可變區大致細分為3個高變區,稱為互補決定區(CDR)(其中輕鏈CDR包括LCDR1、LCDR2、LCDR3。重鏈CDR包括HCDR1、HCDR2、HCDR3)。
用於本案的抗體的「抗原結合片段」、抗體的「抗原結合部分」等包括任何天然存在的、可酶促獲得的、合成的或基因改造的多肽,所述多肽特異性結合抗原形成複合物。抗體的抗原結合片段可以,例如,通過使用任何合適的標準技術從完整的抗體分子衍生出,所述合適的標準技術例如蛋白水解消化或涉及操縱和表達編碼抗體可變結構域和任選地恆定結構域的DNA的重組基因工程技術。DNA可以通過化學方法或通過使用分子生物學技術進行定序和操作,從而例如,將一個或多個可變和/或恆定結構域排列成合適的構型,或引入密碼子,產生半胱胺酸殘基,修飾、添加或刪除胺基酸等。抗原結合片段的非限制性實例包括:(i)Fab片段;(ii)F(ab')2片段;(iii)Fd片段;(iv)Fv片段;(v)單鏈Fv(scFv)分子;(vi)dAb片段;和(vii)模擬抗體高變區的胺基酸殘基組成的最小識別單位(例如,分離的互補決定區(CDR)如CDR3肽)或FR3-CDR3-FR4肽。其他改造的分子,如結構域特異性抗體、單域抗體、域缺失抗體、嵌合抗體、CDR嫁接抗體、雙抗體、三抗體、四抗體、微抗體、奈米抗體(例如,單價奈米抗體、二價奈米抗體等)、小模組化免疫藥物(SMIP)和鯊魚變體IgNAR結構域也包括在本文所用的「抗原結合片段」表述內。
本案中公開的抗體和抗原結合片段的CDR邊界可通過Kabat、Chothia或Al-Lazikani命名法命名或識別。(Al-Lazikani, B.,Chothia, C.,Lesk, A. M.,J. Mol. Biol.,273(4), 927 (1997);Chothia, C等,J Mol Biol. Dec 5;186(3):651-63 (1985);Chothia, C.和Lesk, A.M.,J.Mol.Biol.,196, 901 (1987);Chothia, C等,Nature. Dec 21-28;31(6252):877-83 (1989);Kabat E.A.等,National Institutes of Health, Bethesda, Md. (1991))。在一些實施方式中,根據Kabat數據庫確定抗體的CDR邊界。三個CDR由被稱為框架區(FR,其中重鏈FR包括HFR1、HFR2、HFR3和HFR4,輕鏈FR包括LFR1、LFR2、LFR3和LFR4)的側面連續部分間隔開,框架區比CDR更加高度保守並形成一個支架支撐超變環。因此,V
H和V
L各包含按以下順序排布的3個CDR和4個FR(人胺基酸殘基N末端到C末端):FR1、CDR1、FR2、CDR2、FR3、CDR3、FR4。重鏈和輕鏈的恆定區不參與抗原結合,但表現出多種效應功能。哺乳動物重鏈分為α、δ、ε、γ和μ,哺乳動物輕鏈分為λ或κ。抗體根據其重鏈恆定區的胺基酸序列,根據是否分別存在α、δ、ε、γ和μ,可分為5大類:IgA、IgD、IgE、IgG和IgM。幾個主要的抗體分類的亞類如IgG1(γ1重鏈)、IgG2(γ2重鏈)、IgG3(γ3重鏈)、IgG4(γ4重鏈)、IgA1(α1重鏈)或IgA2(α2重鏈)。
在一些實施方式中,本案的抗體或其抗原結合片段特異性識別或結合具有SEQ ID NO: 2所示的胺基酸序列的蛋白。
SEQ ID NO: 2:
MGPLQGDGGPALGGADVAPRLSPVRVWPRPQAPKEPALHPMGLSLPKEKGLILCLWSKFCRWFQRRESWAQSRDEQNLLQQKRIWESPLLLAAKDNDVQALNKLLKYEDCKVHQRGAMGETALHIAALYDNLEAAMVLMEAAPELVFEPMTSELYEGQTALHIAVVNQNMNLVRALLARRASVSARATGTAFRRSPCNLIYFGEHPLSFAACVNSEEIVRLLIEHGADIRAQDSLGNTVLHILILQPNKTFACQMYNLLLSYDRHGDHLQPLDLVPNHQGLTPFKLAGVEGNTVMFQHLMQKRKHTQWTYGPLTSTLYDLTEIDSSGDEQSLLELIITTKKREARQILDQTPVKELVSLKWKRYGRPYFCMLGAIYLLYIICFTMCCIYRPLKPRTNNRTSPRDNTLLQQKLLQEAYMTPKDDIRLVGELVTVIGAIIILLVEVPDIFRMGVTRFFGQTILGGPFHVLIITYAFMVLVTMVMRLISASGEVVPMSFALVLGWCNVMYFARGFQMLGPFTIMIQKMIFGDLMRFCWLMAVVILGFASAFYIIFQTEDPEELGHFYDYPMALFSTFELFLTIIDGPANYNVDLPFMYSITYAAFAIIATLLMLNLLIAMMGDTHWRVAHERDELWRAQIVATTVMLERKLPRCLWPRSGICGREYGLGDRWFLRVEDRQDLNRQRIQRYAQAFHTRGSEDLDKDSVEKLELGCPFSPHLSLPMPSVSRSTSRSSANWERLRQGTLRRDLRGIINRGLEDGESWEYQI
在一些實施方式中,本案的抗體或其抗原結合片段與具有SEQ ID NO: 2所示的胺基酸序列的蛋白的的Kd值為10
-7-10
-10M。在一些實施方式中,所述Kd值為10
-7-10
-10M、10
-8-10
-10M或10
-9-10
-10M。在一些實施方式中,所述抗體或其抗原結合片段與具有SEQ ID NO: 2所示的胺基酸序列的蛋白的Kd值小於約10
-7M。在一些實施方式中,所述Kd值小於約10
-7M、小於約10
-8M、小於約10
-9M或小於約10
-10M。在一些實施方式中,Kd值是通過表面等離子共振方法檢測的。
在一些實施方式中,本案的抗原結合片段是選自F(ab’)2、Fab’、Fab、Fv、scFv、dsFv或dAb。在一些實施方式中,本案的抗體或其抗原結合片段進一步具有重鏈恆定區和/或輕鏈恆定區。在一些實施方式中,重鏈恆定區源於鼠的IgG1或鼠的IgG2a。在一些實施方式中,重鏈恆定區源於人的IgG1。
在一些實施方式中,本案的抗體或其抗原結合片段進一步具有綴合部分。在一些實施方式中,所述綴合部分是治療劑、放射性同位素、可檢測標籤、藥物動力學修飾部分或純化部分。所述綴合部分直接連接或者通過連接子連接。
用於本案的術語「治療劑」可以是用於治療或預防受試者中的疾病的任意藥物化合物,包括分子量小於500小分子、核苷酸(例如,DNA、質體DNA、RNA、siRNA、反義寡核苷酸、適體等)、短肽、蛋白(例如,酶)。
在一些實施方式中,放射性同位素可以選自下組:
3H、
11C、
14C、
18F、
32P、
33P、
35S、
45Ti、
47Sc、
52Fe、
59Fe、
62Cu、
64Cu、
67Cu、
67Ga、
68Ga、
75Sc、
77As、
86Y、
89Sr、
89Zr、
90Y、
90Nb、
94Tc、
99Tc、
99Mo、
105Pd、
105Rh、
111Ag、
111In、
123I、
124I、
125I、
131I、
133Xe、
142Pr、
143Pr、
149Pm、
153Sm、
154Gd、
155Gd、
156Gd、
157Gd、
158Gd、
161Tb、
166Dy、
169Er、
175Lu、
177Lu、
186Re、
188Re、
189Re、
194Ir、
198Au、
199Au、
211At、
211Pb、
212Bi、
212Pb、
213Bi、
223Ra和
225Ac。
用於本案的術語「可檢測標籤」可以是與本發明的抗體直接或間接地偶聯、同時適用於或有助於檢測TRPV6的水平的任何檢測分子。在一些實施方式中,所述檢測分子包括酶、螢光標記物和生物素。所述酶包括過氧化酶(例如,辣根過氧化酶)、鹼性磷酸酶、β-半乳糖苷酶、葡糖澱粉酶、糖氧化酶、尿素酶、雜環氧化酶(例如,黃嘌呤氧化酶)、蘋果酸脫氫酶或它們的衍生物。所述螢光標記物可以是螢光素,可選的,所述螢光素包括異硫氰酸螢光素(FITC)、羅丹明、德克薩斯紅、藻紅蛋白、綠色螢光蛋白(GFP)、Dylight、Cy3或Cy5。
另一個方面,本案還公開了一種分離的核酸,其編碼本案所述的特異性結合TRPV6的抗體或其抗原結合片段。在一些實施方式中,所述核酸包含SEQ ID NO: 31所示的核酸序列或與SEQ ID NO: 31具有至少90%序列同一性的核酸序列,和SEQ ID NO: 32所示的核酸序列或與SEQ ID NO: 32具有至少90%序列同一性的核酸序列中的一者或兩者。在一些實施方式中,所述核酸包含SEQ ID NO: 33所示的核酸序列或與SEQ ID NO: 33具有至少90%序列同一性的核酸序列,和SEQ ID NO: 34所示的核酸序列或與SEQ ID NO: 34具有至少90%序列同一性的核酸序列中的一者或兩者。在一些實施方式中,所述核酸包含SEQ ID NO: 35所示的核酸序列或與SEQ ID NO: 35具有至少90%序列同一性的核酸序列,和SEQ ID NO: 6所示的核酸序列或與SEQ ID NO: 6具有至少90%序列同一性的核酸序列中的一者或兩者。
另一個方面,本案還公開了一種載體,其包含本案所述的核酸序列。
另一個方面,本案還公開了一種宿主細胞,其包含本案所述的載體。
另一個方面,本案還公開了一種多特異性抗體,其包含本案所述的抗體或其抗原結合片段,和一個或多個與其他抗原特異性結合的抗體或其抗原結合部分。
另一個方面,本案還公開了一種抗體偶聯物,其包含本案所述的抗體或其抗原結合片段或本案所述的多特異性抗體。
另一個方面,本案還公開了分泌抗TRPV6單株抗體的融合瘤細胞株,所述融合瘤細胞株為12CT9.5.1、16CT4.1.1.2和/或16CT18.1.1.2,寄存於中國典型培養物保藏中心,其中12CT9.5.1的寄存編號為CCTCC NO: C202119,16CT4.1.1.2的寄存編號為CCTCC NO: C202124,16CT18.1.1.2的寄存編號為CCTCC NO: C202125。
另一個方面,本案還公開了一種藥物組合物,其包含本案所述的抗體或其抗原結合片段、本案所述的分離的核酸、本案所述的載體、本案所述的宿主細胞、本案所述的多特異性抗體或本案所述的抗體偶聯物,和藥學上可接受的載體。
用於本案的術語「藥學上可接受的」指的是在合理的醫學判斷範圍內,其適用於與人和其他動物的細胞接觸而沒有不適當的毒性、刺激性、過敏反應等,並且與合理的效益/風險比是相稱的。
用於本案的術語「藥學上可接受的載體」指的是用於向受試者遞送本案提供的抗體或其抗原結合片段、分離的核酸、載體、宿主細胞、多特異性抗體或抗體偶聯物的藥學上可接受的溶劑、混懸劑或任意其他藥學上惰性的載劑,其不干擾抗體或其抗原結合片段、分離的核酸、載體、宿主細胞、多特異性抗體或抗體偶聯物的結構、形態和性質。某些這樣的載體能夠將抗體或其抗原結合片段、分離的核酸、載體、宿主細胞、多特異性抗體或抗體偶聯物配製成例如片劑、丸劑、膠囊劑、液體、凝膠劑、糖漿劑、漿劑、混懸劑和軟錠劑,供受試者口服攝入。某些這樣的載體能夠將抗體或其抗原結合片段、分離的核酸、載體、宿主細胞、多特異性抗體或抗體偶聯物製成注射、輸注或局部施用的製劑。
用於本案提供的藥物組合物中的藥學上可接受的載體包括但不限於,例如藥學上可接受的液體、凝膠或固體載體、水性載劑(例如,氯化鈉注射液、林格氏注射液、等滲右旋糖注射液、無菌水注射液或者右旋糖和乳酸林格氏注射液)、非水性載劑(例如,植物來源的固定油、棉籽油、玉米油、芝麻油或花生油)、抗微生物劑、等滲劑(例如,氯化鈉或右旋糖)、緩衝劑(例如,磷酸或檸檬酸緩衝劑)、抗氧劑(例如,硫酸氫鈉)、麻醉劑(例如,鹽酸普魯卡因)、混懸劑/分散劑(例如,羧甲基纖維素鈉、羥丙基甲基纖維素或聚乙烯吡咯烷酮)、螯合劑(例如,EDTA(乙二胺四乙酸)或EGTA(乙二醇四乙酸))、乳化劑(例如,聚山梨醇酯80(吐溫-80))、稀釋劑、佐劑、賦形劑、或無毒性輔助物質、本領域公知的其他成分或其各種組合。適宜的成分可以包括例如填充劑、黏合劑、緩衝劑、防腐劑、潤滑劑、調味劑、增稠劑、著色劑或乳化劑。
在一些實施方式中,藥物組合物是注射製劑。注射製劑包括無菌水溶液或分散劑、混懸劑或乳劑。在所有情況下,注射製劑應該是無菌的並且應該是流體以便於注射。注射製劑應在生產和儲存條件下保持穩定,並且必須防止細菌和真菌等微生物的污染。載體可以是含有例如水、乙醇、多元醇(例如,甘油、丙二醇和液體聚乙二醇等)及其適宜的混合物和/或植物油的溶劑或分散介質。注射製劑應保持適當的流動性。例如,可以通過使用諸如卵磷脂的包衣、通過使用表面活性劑等保持適當的流動性。可以通過各種抗細菌劑和抗真菌劑實現阻止微生物的作用,例如對羥基苯甲酸酯、氯丁醇、苯酚、山梨酸、硫柳汞等。
在一些實施方式中,藥物組合物是口服製劑。口服製劑包括但不限於膠囊、扁膠囊、丸劑、片劑、錠劑(使用調味基質,通常為蔗糖和阿拉伯膠或黃蓍膠)、粉劑、顆粒劑、或在水性或非水性液體中的溶液劑或混懸劑、或者作為水包油或油包水液體乳劑、或者作為酏劑或糖漿、或者作為軟錠劑(使用惰性基質,如明膠和甘油,或者蔗糖和阿拉伯膠)和/或作為漱口劑等。
在用於口服施用的固體劑型(例如,膠囊、片劑、丸劑、糖衣丸、散劑、顆粒劑等)中,將抗體或其抗原結合片段、分離的核酸、載體、宿主細胞、多特異性抗體或抗體偶聯物的與一種或多種藥學上可接受的載體混合,如檸檬酸鈉或磷酸氫二鈣,和/或下述中的任意一種:(1)填充劑或增量劑,例如,澱粉、乳糖、蔗糖、葡萄糖、甘露醇和/或矽酸;(2)黏合劑,例如,羧甲基纖維素、藻酸鹽、明膠、聚乙烯吡咯烷酮、蔗糖和/或阿拉伯膠;(3)保濕劑,例如,甘油;(4)崩解劑,例如,瓊脂、碳酸鈣、馬鈴薯或木薯澱粉、海藻酸、某些矽酸鹽和碳酸鈉;(5)溶液阻滯劑,例如,石蠟;(6)吸收促進劑,例如,季銨化合物;(7)潤濕劑,例如,乙醯基醇和單硬脂酸甘油酯;(8)吸收劑,例如,高嶺土和膨潤土;(9)潤滑劑,例如,滑石、硬脂酸鈣、硬脂酸鎂、固體聚乙二醇、月桂基硫酸鈉及其混合物;以及(10)著色劑。
在用於口服施用的液體劑型中,將抗體或其抗原結合片段、分離的核酸、載體、宿主細胞、多特異性抗體或抗體偶聯物與下述中的任意一種混合:藥學上可接受的乳劑、微乳、溶液、混懸劑、糖漿劑和酏劑。除了抗體或其抗原結合片段、分離的核酸、載體、宿主細胞、多特異性抗體或抗體偶聯物以外,液體劑型可以含有本領域常用的惰性稀釋劑,例如,水或其他溶劑、增溶劑和乳化劑,例如,乙醇、異丙醇、碳酸乙酯、乙酸乙酯、苯甲醇、苯甲酸苄酯、異丙醇、1,3-丁二醇、油(特別是,棉籽油、花生油、玉米油、橄欖油、蓖麻油和芝麻油)、甘油、四氫糠醇、聚乙二醇和脫水山梨醇脂肪酸酯及其混合物。除了惰性稀釋劑以外,口服組合物還可以包含佐劑,例如,潤濕劑、乳化劑和混懸劑、甜味劑、調味劑、著色劑、增香劑和防腐劑。
在一些實施方式中,藥物組合物是口腔噴霧製劑或鼻噴霧製劑。噴霧製劑包括但不限於水性氣霧劑、非水性混懸劑、脂質體製劑或固體顆粒製劑等。水性氣霧劑通過將藥劑的水溶液或混懸液與常規藥學上可接受的載體和穩定劑混合製備。載體和穩定劑根據具體藥物成分的要求而改變,但是在通常情況下,其包括非離子表面活性劑(吐溫或聚乙二醇)、油酸、卵磷脂、胺基酸,例如,甘胺酸、緩衝溶液、鹽、糖或糖醇。氣霧劑通常由等滲溶液製備,並且能夠通過噴霧遞送。
在一些實施方式中,藥物組合物可以通過與一種或多種其他藥物混合使用。在一些實施方式中,藥物組合物包含至少一種其他藥物。在一些實施方式中,其他藥物是抗腫瘤藥、心血管藥、抗炎藥、抗病毒藥、消化系統藥、神經系統藥、呼吸系統藥、免疫系統藥、皮膚病藥、代謝藥等。
在一些實施方式中,可以通過適宜的途徑向有需要的受試者施用藥物組合物,包括但不限於口服、注射(例如,靜脈內、肌內、皮下、皮內、心內、鞘內、胸膜內、腹膜內注射等)、黏膜(例如,鼻內、口內施用等)、舌下、直腸、經皮、眼內和肺部施用。在一些實施方式中,藥物組合物可以靜脈內、皮下、口服、肌內或心室內施用。
另一個方面,本案還公開了一種用於分析和檢測來自受試者的樣品中的TRPV6的試劑,所述試劑包含一種或多種本案所述的抗體或其抗原結合片段。在一些實施方式中,所述試劑用於分析和檢測來自受試者的樣品中的TRPV6。
另一個方面,本案還公開了一種檢測來自受試者的樣品中的TRPV6的方法,所述方法包括:(1) 使所述樣品與本案述的抗體或抗原結合片段接觸;(2) 可選地,移除未結合的抗體或抗體片段;(3) 檢測與所述樣品中的TRPV6結合的抗體或抗體片段。
用於本案的術語「檢測」可以是通過確定和測定分子(例如,多肽、蛋白或核酸分子)的存在或不存在,或是確定和測定分子之間的相互作用(例如,結合、激動或拮抗等作用),例如蛋白質-蛋白質相互作用(例如,抗體和抗原之間的相互作用)、蛋白-核酸相互作用、或核酸-核酸相互作用。在一些實施方案中,「檢測」和「測定」包括定量檢測和測定。在一些實施方式中,檢測是通過確定和測定與抗體直接或間接偶聯的檢測分子的訊號進行的。可以通過本發明所屬技術領域中具有通常知識者熟悉的方法進行檢測。在一些實施方式中,使用免疫組織化學(IHC)、酶聯免疫吸附(ELISA)、免疫螢光(IF)、化學發光(CLIA)、免疫比濁(TIA)或免疫印跡(Western Blot)進行檢測。
在一些實施方式中,在檢測來自受試者的樣品中的TRPV6的方法的步驟(1)中,本案所述的抗體或抗原結合片段被固定在基板上。在一些實施方式中,在檢測來自受試者的樣品中的TRPV6的方法的步驟(1)中,所述樣品被固定在基板上。在一些實施方式中,樣品是細胞或組織。樣品包括但不限於細胞離心製備物、細胞學塗片、核心活檢、細針穿刺和/或組織切片(例如,低溫恆溫器組織切片、石蠟包埋組織切片)。在一些實施方式中,樣品包含活細胞。在一些實施方式中,樣品包含腫瘤細胞。在一些實施方式中,使用化學固定劑進行所述固定。可以使用交聯固定劑(例如醛類,包括例如甲醛、多聚甲醛和戊二醛)製備組織學樣品。組織樣品可以經甲醛固定並包埋在石蠟中。還可以使用多聚甲醛固定,包埋在溫度敏感的低溫材料中,並使用液態氮速凍。其他類化學固定劑還包括氧化劑和酒精固定劑。還可以通過物理方法進行固定。
在一些實施方式中,在檢測來自受試者的樣品中的TRPV6的方法的步驟(3)中,還包括使用第二抗體,可選的,所述第二抗體能夠直接或者間接地結合所述樣品中的TRPV6,可選的,所述第二抗體的表位與本案所述的抗體或抗原結合片段的表位不同,可選的,所述第二抗體的表位與本案所述的抗體或抗原結合片段的表位相同,可選的,所述第二抗體的表位與TRPV6的結合不受本案所述的抗體或抗原結合片段的影響,可選的,所述第二抗體的表位與TRPV6的結合受本案所述的抗體或抗原結合片段的影響。
用於本案的術語「表位」是指與抗體分子可變區中的特定抗原結合位點(稱為互補位)相互作用的抗原決定簇。單一抗原可以具有超過一個表位。因此,不同抗體可以結合至一個抗原上的不同區域並且可以具有不同的生物作用。表位可以是構象表位或線性表位。構象表位是通過空間並列的來自線性多肽鏈不同區段的胺基酸產生的。線性表位是由多肽鏈中的相鄰胺基酸殘基產生的表位。在某些情況中,表位可以包含抗原上的醣、磷醯基或磺醯基部分。
在一些實施方式中,在檢測來自受試者的樣品中的TRPV6的方法的步驟(3)中,還包括使用第二抗體,可選的,所述第二抗體能夠直接或間接地結合本案所述的抗體或抗原結合片段,可選的,所述第二抗體能夠結合本案所述的抗體或抗原結合片段的恆定區部分。本文所使用的的「第二抗體」旨在於更好地檢測抗TRPV6抗體,第二抗體一般可以通過商購獲得。一些實施方式中,本案所述的第二抗體與檢測分子偶聯,可選的,所述檢測分子包括酶、螢光標記物和生物素。在一些實施方式中,所述檢測分子為酶,可選的,所述酶包括過氧化酶(例如,辣根過氧化酶)、鹼性磷酸酶、β-半乳糖苷酶、葡糖澱粉酶、糖氧化酶、尿素酶、雜環氧化酶(例如,黃嘌呤氧化酶)、蘋果酸脫氫酶或其衍生物。在一些實施方式中,所述檢測分子為螢光素,可選的,所述螢光素包括FITC、羅丹明、德克薩斯紅、藻紅蛋白、GFP、Cy3、Cy5或Dylight。在一些實施方式中,所述檢測分子為生物素或其衍生物。
在一些實施方式中,檢測來自受試者的樣品中的TRPV6的方法進一步包括對與所述樣品中的TRPV6結合的抗體進行定量。在一些實施方式中,所述方法為免疫組織化學(IHC)、酶聯免疫吸附(ELISA)、免疫螢光(IF)、化學發光(CLIA)、免疫比濁(TIA)或免疫印跡(Western Blot)。在一些實施方式中,所述方法可以評估所述樣品中在細胞表面上表達TRPV6的細胞的比例。
在一些實施方式中,在檢測來自受試者的樣品中的TRPV6的方法中,所述受試者為人類。
另一個方面,本案還公開了一種判斷受試者疾病的形成或形成的風險、評估受試者疾病的進展或預後、或在接受疾病治療的受試者中預測或監測所述受試者對治療的反應的方法,所述方法包括通過本案所述的檢測來自受試者的樣品中TRPV6的方法,以檢測來自所述受試者的樣品中的TRPV6。
在一些實施方式中,判斷受試者疾病的形成或形成的風險、評估受試者疾病的進展或預後、或在接受疾病治療的受試者中預測或監測所述受試者對治療的反應的方法包括評估所述樣品中在細胞表面上表達TRPV6的細胞的比例,若所述比例超過預定的閾值,則認為所述受試者患有所述疾病或者是更可能從治療中獲益,其中所述閾值為10%。在一些實施方式中,所述治療是靶向藥物治療。
用於本案的術語「獲益」、「受益」或「有益」指任何期望的效果,包括但不限於:(1)在某種程度上抑制(如減少、減慢或完全停止)疾病的發展,包括減慢速度和完全停滯;(2)減少疾病發作和/或症狀的數量;(3)縮小病變尺寸;(4)抑制疾病細胞浸潤到鄰近的周圍器官和/或組織中;(5)抑制疾病傳播;(6)在一定程度上緩解與該疾病有關的一種或多種症狀;(7)治療後無病表現的時間增加;(8)自身免疫反應降低,可能但不一定導致疾病病變消退或消融,例如無進展生存期;(9)增加總生存率;(10)反應率更高;和/或(11)治療後給定時間點死亡率降低。
在一些實施方式中,預測或監測所述受試者對治療的反應涉及評估受試者的腫瘤是否減輕或加重。在一些實施方式中,預測或監測所述受試者對治療的反應可能涉及評估受試者在接受治療(例如,用特定的藥物進行治療)後是否好轉和/或好轉的可能性。本案的預測或監督的方法可以被用於在臨床上做出治療決定。在施用治療方案(例如,給定的治療方案,包括例如給定的治療藥物或組合的施用、手術干預等)後,本案的預測或監督的方法在評價特定受試者能否長期存活的可能性上是有價值的工具。
在一些實施方式中,本案所述的疾病為癌症。在一些實施方式中,癌症為乳腺癌、卵巢癌、子宮內膜癌、膽管癌、胃癌、食道癌、肺癌、腸癌、胰腺癌。在一些實施方式中,癌症為HER2
+乳腺癌、三陰乳腺癌或結直腸癌。
另一個方面,本案還公開了一種試劑盒,所述試劑盒包含本案所述的抗體或其抗原結合片段,可選的,進一步包括用於檢測所述抗體或其抗原結合片段與TRPV6結合情況的試劑。
在一些實施方式中,本案所述的試劑盒用於診斷受試者疾病的形成或形成的風險、評估受試者疾病的進展或預後、或在接受疾病治療的受試者中預測或監測所述受試者對治療的反應。在一些實施方式中,本案所述的試劑盒用於免疫組織化學病理診斷。在一些實施方式中,本案所述的試劑盒用於腫瘤組織免疫組織化學病理診斷。在一些實施方式中,所述疾病為癌症,在一些實施方式中,癌症為乳腺癌、卵巢癌、子宮內膜癌、膽管癌、胃癌、食道癌、肺癌、腸癌、胰腺癌。在又一些實施方式中,所述癌症是HER2
+乳腺癌、三陰乳腺癌或結直腸癌。
另一個方面,本案還公開了一種製備特異性結合TRPV6的抗體的方法,所述方法包括:(1) 將SEQ ID NO: 3所示的胺基酸序列與載體蛋白偶聯,以獲得TRPV6抗原肽;(2) 將通過步驟(1)獲得的所述TRPV6抗原肽作為免疫原免疫小鼠;(3) 經細胞融合、免疫肽篩選單株,獲得高效分泌特異性結合TRPV6的抗體的陽性融合瘤細胞系;(4) 獲得特異性結合TRPV6的抗體。
在一些實施方式中,所述載體蛋白為鑰孔蟲戚血藍素(KLH)蛋白。
在一些實施方式中,在SEQ ID NO: 3所示的胺基酸序列的N端增加一個Cys,並通過自由巰基和所述載體蛋白偶聯。
SEQ ID NO: 3:PLKPRTNNRTSPRDNTLLQQKLLQEAYMTPK。
在一些實施方式中,本案所述的融合瘤細胞系為小鼠融合瘤細胞系12CT 9.5.1、16CT 18.1.1或16CT 4.1.1.2。其中,細胞系12CT 9.5.1產生的抗體包括CB-Anti-0001抗體,細胞系16CT4.1.1.2產生的抗體包括CB-Anti-0002抗體,細胞系16CT18.1.1產生的抗體包括CB-Anti-0003抗體。
另一個方面,本案還公開了本案所述抗體或其抗原結合片段、本案所述的多特異性抗體、本案所述的抗體偶聯物以及本案所述的藥物組合物在用於治療和/或預防和/或診斷與TRPV6相關的疾病的藥物中的用途。
另一個方面,本案還公開了一種治療、預防或診斷疾病的方法,所述方法包括向有需要的受試者施用本案所述抗體或其抗原結合片段、本案所述的多特異性抗體、本案所述的抗體偶聯物以及本案所述的藥物組合物。
實施例
以下實施例旨在更好地說明本發明,且不應理解為限制本發明的範圍。所有下述的特定組合物、材料和方法,其整體或部分,都在本發明的範圍內。這些特定的組合物、材料和方法不是為了限制本發明,而只是為說明特定的實施方式在本發明的範圍內。本發明所屬技術領域中具有通常知識者可不添加進步性及不偏離本發明範圍而開發出等同的組合物、材料和方法。應理解,在對本發明的方法作出的多種改動可以仍然包含在本發明範圍內。發明人意在將這樣的變動包含在本發明的範圍內。
實施例 1 抗原多肽的合成和重組抗原的製備
1. 抗原多肽選擇
針對Uniprot及Genbank中登錄號為Q9H1D0和GI: 1918017293的蛋白質序列(如SEQ ID NO: 2所示)進行序列和二級結構分析。該TRPV6蛋白全長為765個胺基酸,其分子量約為87kDa左右。通過在線服務器http://www.cbs.dtu.dk/services/NetSurfP/預測該蛋白的二級結構和表面可及性(Surface Accessibility)參數,並通過針對其抗原性指數的分析結果,選擇胺基酸序列IFQTEDPEELGHF(SEQ ID NO: 4)、DGPANYNVDLPF(SEQ ID NO: 5)或PLKPRTNNRTSPRDNTLLQQKLLQEAYMTPK(SEQ ID NO: 3)作為抗原並進行化學合成。為便於偶聯,在該多肽的胺基端添加了一個半胱胺酸,用於提供硫基。
2. 多肽的偶聯及純化
選擇Thermo Scientific的馬來醯胺活化的鑰孔蟲戚血藍素蛋白試劑盒,按照試劑盒提供的流程操作。
對於待偶聯的多肽,首先以Ellman試劑檢測多肽中自由硫基:在96孔板中加入100 µL Ellman試劑儲備液,再加入10 µL多肽溶液,用Nano Drop分光光度計在λ=412 nm下測其紫外吸收值,如果OD值>0.15,則進行下一步;若OD值<0.15且>0.05,則補加多肽,直至達到要求;若OD值<0.05,則返回多肽合成步驟重新質控。
開始偶聯時,在每個mcKLH包裝中加入200 µL去離子水,配製成10 mg/mL的KLH溶液,在500µL的Imject EDC偶聯緩衝液中溶解2mg半抗原,將500 µL多肽溶液加入到200 µL的載體蛋白溶液中。將l mL去離子水加入到一個包裝的EDC(10 mg)中,緩慢搖動至完全溶解,取50µL加入到mcKLH多肽溶液中,反應2小時後,經脫鹽柱處理除去未偶聯的交聯劑和鹽類。
實施例 2 融合瘤 細胞系的建立
1. 免疫
將實施例1中交聯的多肽用弗氏完全佐劑乳化,免疫4~6週齡雌性Balb/c小鼠(購自北京維通利華實驗動物技術有限公司),腹部皮下注射,每隻小鼠6點,劑量為60µg/隻。每14天加強免疫一次,抗原使用弗氏非完全佐劑乳化,劑量為30µg/隻。第3次加強免疫後7天,以間接ELISA(波長450nm)檢測小鼠血清中抗免疫原的多抗效價,效價最高的小鼠以尾靜脈注射衝擊免疫,抗原用生理鹽水混勻,劑量為50µg/隻。
2. 細胞融合
製備免疫達標的小鼠脾細胞懸液,與小鼠骨髓瘤細胞F0以5:1比例混合,離心1500rpm,5分鐘。棄上清後,離心管放入37°C水浴中,在1分鐘內緩慢加入1 mL的PEG1500(Roche公司),並攪動細胞。在溫水中靜置l分鐘後,加入10 mL無血清的IMDM(Sigma公司),混勻,離心1000rpm,5分鐘。棄上清後,加入10 mL血清(PAA公司),小心的將細胞吹打起來,並加入5 mL混合10XHAT(Sigma公司)的胸腺細胞,混勻。再加入25 mL含有2.1%硝基纖維素(Sigma公司)的半固體培養基,充分混勻,然後均勻的倒入20個細胞培養皿中。將細胞培養皿放入到濕盒中,放入37°C、5% CO
2培養箱中培養。
3. 單株化及ELISA篩選陽性融合瘤細胞
融合後7天,細胞團大小密度適中,在解剖鏡下,吸取圓、實、大的細胞團,打入事先準備好培養基的96孔培養板中,放入37°C、5% CO
2培養箱中培養。
3天後,細胞量大約占底面積2/3,取100 µL上清,用免疫原和合成多肽分別進行ELISA篩選。陽性單株完全換液,加入200 µL的含飼養細胞和1% HT(Sigma公司)的完全培養基。兩天後進行第二次ELISA篩選,陽性單株轉入事先準備好培養基(含飼養細胞和HT)的24孔板培養。五天後取100 µL上清,進行第三次ELISA篩選,篩選得到12CT 9.5.1、16CT 18.1.1.2和16CT 4.1.1.2三株效價較高的陽性單株,並逐次轉入6孔板和細胞培養瓶擴大培養並凍存。
實施例 3 腹水誘生法製備單株抗體
1. 腹水製備
對數生長期細胞用無血清培養基洗滌並懸起,計數~5x10
5/mL,l mL懸浮的細胞腹腔注射事先用石蠟油致敏的小鼠。7天後開始收集腹水。取出的腹水於4°C下離心4000rpm,10分鐘。小心吸出中間的腹水收集於離心管中,4°C或-20°C保存。
2. 單株抗體的純化
用Protein G(GE公司)親和層析法按說明書從腹水中純化抗體。SDS-PAGE膠鑑定純度,Bradford法測定濃度。純化的抗體保存於-20°C。
實施例 4 單株抗體特性鑑定
1. 亞型鑑定
用100 mL MPBS(pH 7.4)稀釋包被羊抗鼠IgG至0.5 µg/mL,每孔加100 µL,4°C,過夜。傾空液體,用含0.05% Tween的PBS洗3次,每孔加入200 µL封閉液(含2% BSA和3%蔗糖的PBS),37°C下孵育l小時,傾空液體,用PBST清洗3次。每孔加入0.l mL融合瘤上清,37°C下孵育l小時,傾空液體,用PBST清洗3次。用封閉液1:1000稀釋HRP標記的羊抗鼠(κ,λ)抗體或1:2000稀釋HRP標記的羊抗鼠(IgM、IgG1、IgG2a、IgG2b、IgG3、IgA)抗體,0.l mL每孔分別加入適當的孔中,37°C下孵育l小時,傾空液體,用PBST清洗3次。每孔加50 µL含0.15% ABTS和0.03% H
2O
2的擰檬酸緩衝液(pH 4.0)進行顯色反應,10-20分鐘內測定405 nm波長下的OD值。結果顯示,獲得的CB-Anti-0001和CB-Anti-0002抗體為IgG1型鼠源單株抗體,CB-Anti-0003抗體為IgG2a型鼠源單株抗體。
2. 親和常數測定
首先,在SPR芯片上固定獲得的抗TRPV6抗體,之後用1×PBST作為稀釋液,將免疫肽稀釋至11.52 nM,之後以1.3倍稀釋,最後一個濃度為4.04 nM,共計5個濃度梯度。利用SPR儀器進行親和力檢測,經儀器自動分析,計算出CB-Anti-0001的親和常數為5.19x10
-10。
3. 單抗反應特異性和應用效果
選擇轉染TRPV6蛋白的293T細胞,用免疫細胞化學的方法檢測本發明的單株抗體的識別特異性,免疫細胞化學實驗過程如下:在293T細胞中轉染TRPV6質體,轉染後的細胞鋪在含爬片的24孔板中,在IMDM+10% FBS培養基中培養細胞72小時,去除上清,PBS清洗一遍,加入甲醇固定30秒,PBS清洗兩遍。用抗體稀釋液按照適當稀釋比配製抗TRPV6抗體工作液,去除24孔板中的PBS,加入抗體工作液,4度孵育過夜,PBS清洗三遍,滴加二抗(Elivision
TMplus Polyer HRP (Mouse/Rabbit) IHC Kit,購自福州邁新生物技術開發有限公司,產品編號KIT-9903),室溫孵育15-20分鐘,PBS沖洗3X3分鐘(即,沖洗3次,每次持續3分鐘),甩去PBS,用新鮮配置的DAB顯色液顯色3分鐘。蘇木素複染25秒,PBS返藍30秒。按照75%、95%、100%、100%的酒精梯度依次脫水,最後二甲苯透明3分鐘,中性樹膠封片。
如圖1A-1C所示,CB-Anti-0001抗體、CB-Anti-0002抗體和CB-Anti-0003抗體分別能夠在轉染了TRPV6質體的293T細胞中通過免疫細胞化學特異地檢測出TRPV6蛋白,而同時在未轉染TRPV6質體的293T細胞中未顯示出檢測到TRPV6蛋白。該結果表明獲得的抗TRPV6抗體能特異性地識別TRPV6蛋白,即具有識別特性。
實施例 5 抗體的可變區序列測定
取培養的融合瘤細胞系1x10
6,離心取上清,將細胞沉澱委託蘇州金唯智生物科技有限公司進行抗體重鏈和輕鏈可變區序列測定,如下示出示例性的抗體重鏈可變區序列和抗體輕鏈可變區序列。
表1 抗體CDR胺基酸序列
表2 抗體可變區胺基酸序列
表3 編碼抗體可變區的核酸序列
實施例 6 組織切片染色和鑒定
抗體 | CDR1 | CDR2 | CDR3 | |
CB-Anti-0001 | HCDR | SEQ ID NO: 7 | SEQ ID NO: 8 | SEQ ID NO: 9 |
GYTFTSYW | IDPSDGYT | GWAGDF | ||
LCDR | SEQ ID NO: 10 | SEQ ID NO: 11 | SEQ ID NO: 12 | |
QSLLDSDGKTY | LVS | WQGTHFPQT | ||
CB-Anti-0002 | HCDR | SEQ ID NO: 13 | SEQ ID NO: 14 | SEQ ID NO: 15 |
GFTFSYYW | IRLKSHNYAT | ARLAYDGERYYYALDY | ||
LCDR | SEQ ID NO: 16 | SEQ ID NO: 17 | SEQ ID NO: 18 | |
QSLLYSNNQKNY | WAS | QQYYSYPFT | ||
CB-Anti-0003 | HCDR | SEQ ID NO: 19 | SEQ ID NO: 20 | SEQ ID NO: 21 |
AFTFSHYW | IRLKSYNYAT | TRLGYFGSLYYAMDY | ||
LCDR | SEQ ID NO: 22 | SEQ ID NO: 23 | SEQ ID NO: 24 | |
QSLLYSTNQKNY | WAS | QQYYSYPWT |
抗體(融合瘤細胞株) | 重鏈可變區 | 輕鏈可變區 |
CB-Anti-0001 抗體(12CT9.5.1) | SEQ ID NO: 25 | SEQ ID NO: 26 |
QVQVQQPGAELVKPGTSVKLSCKASGYTFTSYWMHWVKQRPGQGLEWIGEIDPSDGYTNYNQKFRGKATLSVDKSSTTAYMQLSSLTSEDSAVYYCGWAGDFWGQGTTLTVSS | DVVLTQSPLTLSVTIGQPASISCKSSQSLLDSDGKTYLNWLLQRPGQSPKRLIYLVSKLDSAAPDRFAGSGSGTDFTLKISRVEAEDLGIYYCWQGTHFPQTFGGGTKLEIK | |
CB-Anti-0002(16CT4.1.1.2) | SEQ ID NO: 27 | SEQ ID NO: 28 |
EVKLEESGGGLVQPGGSMKLSCVASGFTFSYYWMNWVRQSPEKGLEWVAEIRLKSHNYATHYAESVKGRFTISRDDSKSSVYLQMNNLRSEDTGIYYCARLAYDGERYYYALDYWGQGTSVTVSS | DIVMSQSPSSLAVSVGEKFTMSCKSSQSLLYSNNQKNYLAWYQQKPGQSPKLLIYWASTRESGVPDRFTGSGYGTDFTLTISSVKAEDLAVYYCQQYYSYPFTFGSGTKLEIK | |
CB-Anti-0003(16CT18.1.1) | SEQ ID NO: 29 | SEQ ID NO: 30 |
EVMLEESGGGLVQPGGSMKLSCVASAFTFSHYWMNWVRQSPEKGLEWVAEIRLKSYNYATHYAESVKGRFTISRDDSKSSVYLQMNSLRPEDTGIYYCTRLGYFGSLYYAMDYWGQGTSVTVSS | DIVMSQSPSSLAVSVGEKVTMSCKSSQSLLYSTNQKNYLAWSQQKPGQSPKLLIYWASTESGVPDRFTGSGSGTDFTLTISSVKAEDLAVYYCQQYYSYPWTFGGGTKLEIK |
重鏈可變區 | 輕鏈可變區 | |
CB-Anti-0001 抗體 | SEQ ID NO: 31 | SEQ ID NO: 32 |
CAGGTCCAAGTGCAGCAGCCTGGGGCTGAGCTTGTGAAGCCTGGGACTTCAGTGAAGCTGTCCTGCAAGGCTTCTGGCTACACCTTCACCAGCTACTGGATGCACTGGGTGAAGCAGAGGCCTGGACAAGGCCTTGAGTGGATCGGAGAGATTGATCCTTCTGATGGTTATACTAACTACAATCAAAAGTTCAGGGGCAAGGCCACATTGTCTGTAGACAAATCCTCCACCACAGCCTACATGCAGCTCAGCAGCCTGACATCTGAGGACTCTGCGGTCTATTACTGTGGGTGGGCGGGGGACTTCTGGGGCCAAGGCACCACTCTCACAGTCTCCTCA | GATGTTGTGCTGACCCAGAGTCCACTCACTTTGTCGGTTACCATTGGACAACCAGCCTCCATCTCTTGCAAGTCAAGTCAGAGCCTCTTAGATAGTGATGGAAAGACATATTTGAATTGGTTGTTACAGAGGCCAGGCCAGTCTCCAAAGCGCCTAATCTATCTGGTGTCTAAGCTGGACTCTGCAGCCCCTGACAGGTTCGCTGGCAGTGGATCAGGGACAGATTTCACACTGAAAATCAGCAGAGTGGAGGCTGAAGATTTGGGAATTTACTATTGCTGGCAAGGTACACATTTTCCTCAGACGTTCGGTGGAGGCACCAAGCTGGAAATCAAA | |
CB-Anti-0002 | SEQ ID NO: 33 | SEQ ID NO: 34 |
GAAGTGAAGCTTGAGGAGTCTGGAGGAGGCTTGGTGCAACCTGGAGGATCCATGAAACTCTCCTGTGTTGCCTCTGGATTCACTTTCAGTTACTACTGGATGAACTGGGTCCGCCAGTCTCCAGAGAAGGGGCTTGAGTGGGTTGCTGAAATTAGATTGAAATCTCATAATTATGCAACACATTATGCGGAGTCTGTGAAAGGGAGGTTCACCATCTCAAGAGATGATTCCAAAAGTAGTGTCTACCTGCAAATGAACAACTTAAGATCTGAAGACACTGGCATTTATTACTGTGCCAGGCTTGCTTACGACGGGGAGCGGTATTACTATGCTCTGGACTACTGGGGTCAAGGAACCTCAGTCACCGTCTCCTCA | GACATTGTGATGTCACAGTCTCCATCCTCCCTAGCTGTGTCAGTTGGAGAGAAGTTTACTATGAGCTGCAAGTCCAGTCAGAGCCTTTTATATAGTAACAATCAAAAGAACTACTTGGCCTGGTACCAGCAGAAACCAGGGCAGTCTCCTAAACTGCTGATTTACTGGGCATCCACTAGGGAATCTGGGGTCCCTGATCGCTTCACAGGCAGTGGATATGGGACAGATTTCACTCTCACCATCAGCAGTGTGAAGGCTGAAGACCTGGCAGTTTATTACTGTCAGCAATATTATAGCTATCCATTCACGTTCGGCTCGGGGACAAAGTTGGAAATAAAA | |
CB-Anti-0003 | SEQ ID NO: 35 | SEQ ID NO: 6 |
GAAGTGATGCTTGAGGAGTCTGGAGGAGGCTTAGTGCAACCTGGAGGATCCATGAAGCTCTCCTGTGTTGCCTCTGCATTCACTTTCAGTCACTACTGGATGAACTGGGTCCGCCAGTCTCCAGAGAAGGGGCTTGAGTGGGTTGCTGAAATTAGATTGAAATCTTATAATTATGCAACACATTATGCGGAGTCTGTGAAAGGGAGGTTCACCATCTCCAGAGATGATTCCAAGAGTAGTGTCTACCTGCAAATGAACAGCCTAAGGCCTGAAGACACTGGCATTTATTACTGTACCAGGCTTGGTTACTTCGGTAGCCTCTACTATGCTATGGACTACTGGGGTCAAGGAACCTCAGTCACCGTCTCCTCA | GACATTGTGATGTCACAGTCTCCATCCTCCCTAGCTGTGTCAGTTGGAGAGAAGGTTACTATGAGCTGCAAGTCCAGTCAGAGCCTTTTATATAGTACCAATCAAAAGAACTACTTGGCCTGGTCCCAGCAGAAACCAGGGCAGTCTCCTAAACTGCTGATTTACTGGGCATCCACTAGGGAATCTGGGGTCCCTGATCGCTTCACAGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTGTGAAGGCTGAAGACCTGGCAGTTTATTACTGTCAGCAATATTATAGCTATCCGTGGACGTTCGGTGGAGGCACCAAGCTGGAAATCAAA |
1. 切片製備過程
組織蠟塊在修片後進行連續切片,厚度定為5 µm,將連續切片在45°C的溫水中展開,用正電子防脫載玻片裱貼切片,室溫風乾過夜後,放入-20°C中長期保存。
2. IHC染色及分析
常規二甲苯脫蠟2次,每次15分鐘,100%、100%、95%、75%梯度乙醇中水化,每次3分鐘,最後自來水沖洗。進行抗原修復,然後將切片放入濕盒中,PBS沖洗3X3分鐘。滴加3% H
2O
2孵育10分鐘,PBS沖洗3X3分鐘。甩去PBS,滴加封閉液(動物非免疫血清)室溫孵育60分鐘。甩幹切片,滴加適當比例稀釋的一抗,4°C下孵育過夜,PBS沖洗3X3分鐘,滴加二抗(Elivision
TMplus Polyer HRP (Mouse/Rabbit) IHC Kit,購自福州邁新生物技術開發有限公司,產品編號KIT-9903),室溫孵育15-20分鐘,PBS沖洗3X3分鐘,甩去PBS,用新鮮配置的DAB顯色液顯色3分鐘。蘇木素複染25秒,PBS返藍30秒。按照75%、95%、100%、100%的酒精梯度依次脫水,最後二甲苯透明3分鐘,中性樹膠封片。
3. 數據統計
如圖2A-2C所示,CB-Anti-0001抗體、CB-Anti-0002抗體和CB-Anti-0003抗體分別能夠通過免疫組織化學檢測組織切片中的TRPV6蛋白。
此外,發明人還通過採用H-score計分方法記錄腫瘤細胞細胞膜染色情況,將H-score為60分以上記錄為強染色,H-score為1-60分記錄為弱染色,強染色以及弱染色合計為陽性;H-score為0記為陰性。分別統計IHC檢測的各腫瘤組織中TRPV6的水平,並於TCGA數據庫中TRPV6 mRNA水平進行對比驗證,以評估抗體特異性,記錄訊息列於表4。結果顯示,使用本發明的抗體檢測TRPV6蛋白水平,陽性率較高(特別是強染色比例較高)的癌種對應地在腫瘤基因組圖譜數據庫(the Cancer Genome Atlas Program,即TCGA數據庫)中統計的TRPV6 mRNA水平也較高(例如,TPM大於1)。由此可見,使用本發明的抗體能夠準確的評估細胞表面表達TRPV6的情況,進而判斷被檢測的樣品是否為表達TRPV6的癌細胞。
表4 IHC檢測的腫瘤組織中TRPV6的水平
實施例 7 IHC 對比實驗
組織類型 | 樣本數 | 強染色 | 弱染色 | 陽性 | 陰性 | TCGA數據庫中TRPV6 mRNA表達水平 (TPM, Transcript per milliom) |
膽管癌 | 20 | 10% | 30% | 40% | 60% | 5 |
食道癌 | 20 | 0% | 0% | 0% | 100% | 0.35 |
胃癌 | 20 | 0% | 10% | 10% | 90% | 0.2 |
Her2 +乳腺癌 | 90 | 32% | 21% | 53% | 47% | 26 |
三陰乳腺癌 | 100 | 48% | 26% | 74% | 26% | 9 |
卵巢癌 | 100 | 36% | 35% | 71% | 29% | 2 |
肺腺癌 | 30 | 6% | 21% | 27% | 73% | 0.1 |
將市售抗體「Anti-Human TRPV6 (extracellular) Antibody」(貨號ACC-028,購於Alomone Labs,RRID:AB_2756545,本文簡稱「ACC-028抗體」)、抗體「Anti-TrpV6 Antibody, clone 4A5.1」(貨號MABN839,購於Sigma-Aldrich公司,本文簡稱「MABN839抗體」)和CB-Anti-0001抗體進行對比實驗。
使用與實施例6第2部分相同的步驟,獲取CDX腫瘤模型RT4(人膀胱移行細胞乳頭瘤細胞)的切片。滴加ACC-028抗體(稀釋比例為1:50)、MABN839抗體(稀釋比例為1:50)和CB-Anti-0001抗體(稀釋比例為1:2000),4°C下孵育過夜,PBS沖洗3X3分鐘,滴加二抗(Elivision
TMplus Polyer HRP (Mouse/Rabbit) IHC Kit,購自福州邁新生物技術開發有限公司,產品編號KIT-9903),室溫孵育15-20分鐘,PBS沖洗3X3分鐘,甩去PBS,用新鮮配置的DAB顯色液顯色3分鐘。蘇木素複染25秒,PBS返藍30秒。按照75%、95%、100%、100%的酒精梯度依次脫水,最後二甲苯透明3分鐘,中性樹膠封片,讀取染色結果。結果表明,ACC-028抗體檢測靈敏度偏低,僅在少量RT4細胞膜上檢測到特異性訊號(參見附圖3A);MABN839抗體特異性較差,在所有組織細胞和間質細胞都檢測到訊號(參見附圖3B);相比之下,CB-Anti-0001抗體檢測訊號定位準確清晰、特異性好、靈敏度高(參見附圖3C),是理想的IHC應用抗體。
實施例 8 穩定性實驗
採用加速破壞方法對CB-Anti-0001抗體進行穩定性驗證,即分別(1)將抗體原液在4℃下保存14天;(2)將抗體原液放置在37℃恆溫孵育箱中孵育14天;以及(3)將抗體工作液(使用中杉金橋ZLI-9028抗體稀釋液以1:2000的比例稀釋抗體原液後獲得該抗體工作液)放置在37℃恆溫孵育箱中孵育14天。在相同實驗條件下,使用前述三類抗體液進行IHC檢測,以評估三種處理方式下抗體的穩定性。
經檢測,在不同條件下保存的抗體的組織染色強度和染色比例均未出現顯著改變(參見附圖4,其中附圖4A為在4℃下保存14天的CB-Anti-0001抗體原液的IHC結果,附圖4B為在37℃下保存14天的CB-Anti-0001抗體原液的IHC結果,附圖4C為在37℃下保存14天的CB-Anti-0001抗體工作液的IHC結果)。可見,CB-Anti-0001抗體工作液在37℃溫度下保存14天後,抗體依舊穩定,且保留好的檢測能力。
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圖式形成本說明書的一部分,以進一步說明本揭露內容的某些方面。通過參考這些圖式中的一個或多個,結合本揭露內容中呈現的具體實施方式的詳細描述,可以更好地理解本揭露內容。
圖1A示出了CB-Anti-0001能夠通過免疫細胞化學特異地檢測出TRPV6質體轉染的293T細胞中的TRPV6蛋白(左圖),而同時在非TRPV6質體轉染的293T細胞中未顯示出檢測到TRPV6蛋白(右圖)。圖1B示出了CB-Anti-0002能夠通過免疫細胞化學特異地檢測出TRPV6質體轉染的293T細胞中的TRPV6蛋白(左圖),而同時在非TRPV6質體轉染的293T細胞中未顯示出檢測到TRPV6蛋白(右圖)。圖1C示出了CB-Anti-0003能夠通過免疫細胞化學特異地檢測出TRPV6質體轉染的293T細胞中的TRPV6蛋白(左圖),而同時在非TRPV6質體轉染的293T細胞中未顯示出檢測到TRPV6蛋白(右圖)。
圖2A示出了CB-Anti-0001抗體的免疫組織化學檢測結果。圖2B示出了CB-Anti-0002抗體的免疫組織化學檢測結果。圖2C示出了CB-Anti-0003抗體的免疫組織化學檢測結果。
圖3顯示了ACC-028抗體、MABN839抗體和CB-Anti-0001抗體針對人膀胱移行細胞乳頭瘤細胞(RT4)的IHC對比結果實驗。其中附圖3A為ACC-028抗體的IHC結果,附圖3B為MABN839抗體的IHC結果,附圖3C為CB-Anti-0001抗體的IHC結果。可以看到,附圖3C中細胞膜有清晰、顯著的染色效果。
圖4顯示了在不同條件下保存的抗體的組織染色強度和染色比例均未出現顯著改變。其中附圖4A為在4℃下保存14天的CB-Anti-0001抗體原液的IHC結果,附圖4B為在37℃下保存14天的CB-Anti-0001抗體原液的IHC結果,附圖4C為在37℃下保存14天的CB-Anti-0001抗體工作液的IHC結果。
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序列表 <![CDATA[<110> 大陸商同宜醫藥(蘇州)有限公司]]> <![CDATA[<120> 抗TRPV6單株抗體及其應用]]> <![CDATA[<140> TW111101701]]> <![CDATA[<141> 2022-01-14]]> <![CDATA[<150> PCT/CN2021/072249]]> <![CDATA[<151> 2021-01-15]]> <![CDATA[<150> CN202210029357.7]]> <![CDATA[<151> 2022-01-11]]> <![CDATA[<160> 35 ]]> <![CDATA[<170> PatentIn version 3.5]]> <![CDATA[<210> 1]]> <![CDATA[<211> 14538]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 智人(Homo sapiens)]]> <![CDATA[<220>]]> <![CDATA[<221> 編碼TRPV6的DNA]]> <![CDATA[<222> (1)..(14538)]]> <![CDATA[<400> 1]]> agagtcctgg ctggctctgc caagtgtaac aaactcacag ccctctccaa actggctggg 60 gctgctggga gactcccaag gaactcgtca ggaaggcagg agacaggaga cgggacctct 120 acagggagac ggtgggccgg cccttggggg ggctgatgtg gccccaaggc tgagtcccgt 180 cagggtctgg cctcggcctc aggcccccaa ggagccggcc ctacacccca tgggtttgtc 240 actgcccaag gagaaagggc taattctctg cctatggagc aagttctgca gatggttcca 300 gagacgggag tcctgggccc agagccgaga tgagcagaac ctgctgcagc agaagaggta 360 aggccccctt ggtctgctcc cttccccacc tccccaggcc tgcacctcta cccctcaccc 420 ctccctcacc tcccgtcttt gtttggcacc tttggctgga cagatggtgc tcccaggccc 480 ggactggctc cttgggagca ttctgtctta agagcctcag cctgtagggc tggtgaaaga 540 ggatggggtt gagatgggca caggtgttca ctatcttaag atctaattcg attctgcaag 600 cctcttgtga gtacttctct aagggccagg cgtcttgctg gggcttgtaa ggatagagca 660 tcacagcccc tccacccaag aggggacggc aggtgaggac aatgccttct gtatctccac 720 tgcttgcctc tagaacagtc tctctggcag gaacacatag tatacatatg ttcgcatgga 780 ggaatgagtg aacgattgaa tgaatgaagc agagagaacc gcggacacca ggaaccagaa 840 aataagacaa aatgtgaaaa aagtgaccat tcctatgtat ctgtctcatc agacactgac 900 caaggcctta ctatttgccc agcactgggg ggatatgaag acctacaacg ctcaaaccca 960 accttgaggt gtatttctct ctcagtgcgg gtggggactg aggggaagcg ggtcaaaata 1020 acagatgttc cgaggacctg tgctcttccg cattcaggtg gtggaaatcg agactctagc 1080 gtttaagccc taaggacatt cactggtggc ttccagcccc tgaaaacttc ctaaacccgt 1140 gtcctgcttt cttcaccatg acagcttgga gtacagagca ggagaggagc agggaatcgg 1200 aactcagggc tatccctgca tgtggtctct tcttcaaggt ctctaataga gttctctacc 1260 cagttggtgg catgctagaa ggaagtcctg cctgttgggg ctttccctgg gtcacgaagg 1320 aggcagatgt ctggtcatag aggaaagcct gaagtctttg tgccttaggg tttttctctg 1380 accccaagag taggagcctg ctttagcctg accggggagg ctgcctggag gcccctgtgt 1440 tttcttttgc tgaaggattc tgggttgggg atggtctctt tctgtgaatt atggcttccc 1500 atctctccag ccgcccacct ctcccccaag gcctgggaga gtggggactg gagcacatgt 1560 ttggctgatg acatcttggg gcaacagaat ggcattgttg ttagagagta ggtcgtcctc 1620 actggcttca ctcatcctct tcccactctt aggaccccag ggccagggga tccaggcaca 1680 gagtgcaaaa aggcctgggg gattggaagg ggtggtggag attccctgtg tgcgatatca 1740 ggggagagca gaggggaggc cctgcgctga gtggctgaga ataggctgct tccgcatgtc 1800 ctgtctgccc tcacttttcc tcagatcata tgggggctgc ctctgcagac tttggctaga 1860 aaggcttgat gtcacccttg ggagggatcc cccctccctg ccctgatctc cttactggcc 1920 tccgcacttt cttggccttc ttcttgctgg atatcaggtg tccagagcaa tgactcttct 1980 ttgggtgggc acttcccaga aggatgctga aattgcctgc aaggggagtt tcctaatctg 2040 tgccgtcaac caaagagaag gcatgggggc attgagataa acatgggatg actaagtaaa 2100 taggaacaat atggacaagt gaggggtgag ctaatggaag aaaggagcac acaatgattg 2160 agaacccagt gctgtactag gtactaccac ctgccttatc tccgtcatcc cggtaacaat 2220 aatggaaggt gggtcctgtt atccccctat gaatggggca ggcccagaac cctagagcaa 2280 gtaaatggtg aagttgaatt tgttccaaag gggactcaca gggagaactg tggggtggga 2340 ttgcgtggga ttccatgcgg tacaggatgg tctagtgaga aaggaaggct ttgagtctct 2400 ccaggatgat cgggaaccca aactcctctt tttacagtgg acgtttcttg gtgcttagca 2460 cgcagcccgc tctgcttaaa tctacattgc tgggatccaa gtcgagctct caactttctc 2520 ccgtgtcctc caggtcatct cccccttggg cttgggtttt ctcacttcct gatatttaat 2580 gcattacaca tttattgaac ataaggcact ccacctttct gcagaaaatg aatatgacac 2640 tgttcctgct ctcagggagt tctcattcct atgaccaaag tttactgaag gcacatacgg 2700 ggctaaagat gggcttagta gacatcacta gaagggtgta aatgagtgtt ctggaagcat 2760 agagggggaa gtgtgagatc tgatttcggc tgctgtgggg tgtcctgggc agcttcatag 2820 aggctgctta acctgaaccc cactccagcc catgtgctgg cactttgtca tctaaggagc 2880 aatttggagg gaaggtgatg cttgttggag ctttttttag ggttaaatac ctgtatgaaa 2940 tgtgtgaatt gagtgtctga aaagtcatcc ctgggtttct ctggtatatt gtgcacgctt 3000 gccttggtaa atacttacac acatgcctac ttgtaaatgc gcaaatagac atgtgcacaa 3060 aaggagctgt ggcacttagg atggcagccg attccaaatc tctaaacaac cactttggct 3120 ttctcatccc cattgccagg aacatgagct ggagggaggt ggcccacaag tgcccaatgt 3180 atgcctccgc cccacacatt accgctcttt ccttcatctg tggtcactgc tcaggcttgc 3240 cccccaacct ccaagaaaaa tcaggaggag ccataaaact agaagaacca cataatttag 3300 tggtcagagc ctggggctgg attcttggcc aagcatcctg cctttaactc cgtgtgatct 3360 tctggcaatg atttggttat gccgcttcag tttccttttc tgaagcatgg gagaactatt 3420 cagctggtgt tagaaggttg taaagagcaa aagtgataat gagtgagatg ctgcgggaat 3480 gagaggggcc atgaacttcc cctgcacagc actgtatcca cccaggaatg caagaagcca 3540 cgcactccga gcaaccctgt tatgtaccag ccccagccct gcccagaggg tacactcact 3600 ggtgggaaag gtatttgtgg agagaccagt gggacccatg cctgtcttct ctaactcctc 3660 ttccagccct gattaaaact gagaatcgtg accaagaaat gaccagtggg gcatgcgtcg 3720 tggctctgtc tctgacttgc ttcctccatc tgtttcatga gcagatttga ctcagtttct 3780 gaggggcttt ctagctctaa aaatcttatt tgaacttttc tcaagagtct tgtgatcctg 3840 ccttgtttct cagcacctaa aaaccaaatt ggacccatgc acacagtgca cacatctaca 3900 aggatggagg agcagatgag ggtgtggggc ggaggagacg gagagaggaa gtcaggaatc 3960 cttccctggt ggcccagagg cagccctgag aaggaggtca ttgatctgtt tgctcaagaa 4020 ataatgtgct agattttgtg ccaggaaccc cttagttggg ttttcaccag gctaatgttg 4080 aactagaccg ttcaatttta ttataattaa ttgcctagta aaagaaaaca ttctagaacc 4140 tgaaaatacc tttcatattg ttacagtttc agatttgctc tataatctct tttgactact 4200 tcatcagtgg gagcttaaaa ggcttcatct gacttttttt tgtttctccc ttagttgagt 4260 atttagtgat ccataagaaa acatttttat gtataggata tttctgattc cttttcgagt 4320 gaagaatcct cattctaaaa cggattatga atcattgtac ctctgaatca ggggttctcc 4380 accttggact attgacattt tggacaggat aattctttgc agtgagggct gtcatgtgca 4440 gggtgcttag ccgtgtccct gcctttgacc cccgtgttgt gatctaaact cctgtgataa 4500 gttgctattg aaaaatctat ttgtccccca agcacaggaa tctttgagta ggtcagctct 4560 gtgcacctcc ttcagggacc caaggagagt caggtgtttt ggggtcagcc ttactcccaa 4620 gcaggtgagc tagggctttc tgtgctgtcc ccttgtgggc atatgaggtt attgcaagta 4680 atggctgggc cggatacctt caaaacccgt ccacaggctg ggcccccctt tttgctggag 4740 tctggagttc acagtcggag gaggctagtt ctctacaaac cttgctgggt tgggtcataa 4800 gctggctctt cacgcagggt gtggtctggc taggttgcca gataaaatgc aggacactca 4860 gttcaattta aatttgagat aacgaatagg ctgctagtat aagtgtatcc ccaatattgc 4920 acgtgacata cttatactaa aaaaaaattg tgcatctgac attcaaatct aactgagcat 4980 cctgtatttt tatttggtaa ctctagcaac tctgggtctg acagtagctt tttgttttcc 5040 ccaggccact agagtgtcag aattcatagg gaatggaggt ttatggggga cactttcagc 5100 ttcagagacg tgtagggacc aaaggggaat ctttgagcct gccactgact ataccaccac 5160 taacatctag gatacagcga gtagaactct ggacttggaa aaggtgctct ctcggaccca 5220 tttctagatt tgccatcaat ctttcacaca tttggtcaaa atgggacaca aacgtggaag 5280 catattggag gagggcaggg aagagttagt ggctggtctc ttccctcgag tacccttagc 5340 atagaggaag ggacacagat acatagcaat tacagcaccc agtgaaagat gctgaaataa 5400 aagtaaggcc acaggagaga gtgaagaact tctgagtgtc tgtgtgtgtg tatgtggtgc 5460 tagcgattgt tttcccctca gtctagggta tctagagagg agggctttgt gcaaatggtt 5520 gatgtggtgg tggtgatgga gggaatgtgg aaaacttgtt ttgaagctgt gtttgcatac 5580 caagtgtact atttttcact tatatgcttg ctgaaagttg gcttagcggg cagctgatga 5640 aaataataat aacagttaat tcaaaccacc ttttggcatt gctgctgatt cattcactct 5700 acagatggtg tcagtgagca tctacaccat cctaggtgta tttctaggca taggcagtgc 5760 agaagacaca atgaacaatt ggcgggctgg gggagttgga ttctagaagg aaagagcttc 5820 atgggcacag acatagggag aatggtgtgc tctgcagtgc tgagacagga tgagaccaaa 5880 atgccaggtc taaggagtgg gtgggacgtg cagagggtgg aaaagtagtt gcacaaagac 5940 cttaaagagc ttctgtgttc cttatcctta gcattttgct aatctgggct agagaatgaa 6000 gacttgaatt aatgagggtt agcaggagca aggaggtagg gactgaatga agagagagct 6060 ttccatgctg aactgacagg acctggtggc agctgctgtg catgggggca aggcagagga 6120 gatgagtgag ctgatgtctc ctctctgatt gccctcccac ctccagctct ggagtcaatt 6180 tcttgccact gccagcgctt tagaatgtga gctcctgtct atgtcttttt gtatgtcaca 6240 taattgtcaa actatggata aatagagtta tttcatttac tcccatagaa agaccaaatg 6300 gctccaggcc aagagaaaat tgaatcaaag ggacccatgt gtcttagttg gggtaagttc 6360 taattttaaa agagattttt agcacacagt aggtataaga ataaagagat gatctgggga 6420 ttcagagaag ataattttgc ctaaaacaag cgagaagtgg ataataagga gagactaatc 6480 tgactcagca aaataaacgg atccatgaat cccaaattgg gtaaatccag gaagggtccg 6540 aagacagaat gggaacattc agatgcacat gaaattcgat gaatgaatcc tctagattgg 6600 attctctttt ttctctgcat ctgtcattgt tggccatagt ttgtgtctta ggggccaata 6660 gccgaaacaa agtagtatct aaagccctct agacagctgg tctgaaaatg atggagaaca 6720 ctgtttcgca aactttaatg tgagctgttt ggaaactgag acccctgagc ttgtctctga 6780 tttatcgcca ccggtttttg catgcaagga ccacttaagc aatgcttctc caactttcat 6840 atgcccagga atcagctgga aatcttctta aactgcagat ttggattcac taggtggaag 6900 ggtccgccag agcatttcca tttcttataa gggctcatgt gctgctgctg atccaggggt 6960 ccactttaag aaggaaggct gttgagatga tgtgagaaga aagacgagag gcagaaagga 7020 agagacagag ataatgaatg aatgaatgaa tgaatgaatg aatgaacacc tatgaggaag 7080 gaaggcctgg agccaggctt gttcttatgg tccactgttc ttttgtgtta agccctgaag 7140 atgctattgt tgggagggaa gcgccaggat caaagggttc tgctgagaag gttgagtagg 7200 cagaggatgg tgcaacagga gaaatcctgc tagcctgtgc atatgactcc ctccacaaat 7260 atgagacagg aattccttgc acccctcggt ccatgcaaaa caaggcttat cctggagggc 7320 aatctcaggg cacctggtga gggtcaaaca ggaccactcc aggggtaaac tggttagcag 7380 gtaagcacat gtctacatag aactcctccc ctccgtacct gaaatgcact gataatacat 7440 tcacacatga tacattctgg tcccaggacc cggtaggggg gaaggaaacc agtcacggac 7500 aatctcaaaa cgcatgctaa atgggcaaaa agttgattgt atttactgac tgtaaagaga 7560 aaagacatca atggccccac ctgccttgat tgaagaccct gaggttcctg ctgctgaggc 7620 acacacatct gtgtataata atggagtcaa gccagggcct ctccctccac aactaggtat 7680 gctcactgtt tccagctttc ctattccatc ccttcatagg atctgggagt ctcctctcct 7740 tctagctgcc aaagataatg atgtccaggc cctgaacaag ttgctcaagt atgaggattg 7800 caaggtgcac cagagaggta agaagcacaa atgcagcatg atctcctagg tgagccccac 7860 acatggggcc tcccaggagt gcccaggacc tcgtgctgtt ggcctctgaa tctatcgtct 7920 ccaatccgct gtcccacaga agccatataa cccacctctc tgtaaatgcc aggagccatg 7980 ggggaaacag cgctacacat agcagccctc tatgacaacc tggaggccgc catggtgctg 8040 atggaggctg ccccggagct ggtctttgag cccatgacat ctgagctcta tgagggtgag 8100 ggcccacggg tctggggtga agagcaggag tgactggttg ggtatttcaa gtcagtctct 8160 gtgatggata atttgggaaa gacacagggg atctgagcct cctactcttt ttttctcttc 8220 tctgtctccc ttccgtgtca gtcctgactg cccatcacta gaacgcctgc cccctgaaat 8280 gccaggggcc tagagaagag gaagagatgg gcagcagctg gatcccctgg gaatcctgaa 8340 cacccgagag ctccctgttc tccatcccag gctacccctg agggaaagag actggggtgc 8400 atatgggagg gaccccctgc aggatcctgg ggacagaccc gtgactgaca gctgtctctg 8460 ggccaggtca gactgcactg cacatcgctg ttgtgaacca gaacatgaac ctggtgcgag 8520 ccctgcttgc ccgcagggcc agtgtctctg ccagagccac aggcactgcc ttccgccgta 8580 gtccctgcaa cctcatctac tttggtgaga gcagggctgg gcttggagga cgggcagttg 8640 gaaaggtggg caaggcaggg cagggccagg cagaggagga tcctgtcttc agccgtatct 8700 gttgggcagc tgggaggagc aatccttcta gggcttaatt agactagagg ccaatttacc 8760 ccacgaccct tcctctggtt ctgcaggaaa agtgtcctca agccctgagc tgagatgtgg 8820 gggaagataa ggctgtcact tgggggagac tgtccacccc atcctgccat cctgcactct 8880 cctaccatag atctctctgt gtccacaggg gagcaccctt tgtcctttgc tgcctgtgtg 8940 aacagtgagg agatcgtgcg gctgctcatt gagcatggag ctgacatccg ggcccaggac 9000 tccctgggta agagctgaga tggggagggg agctgggatg ctgcagggag tgagggacag 9060 ggtgaggaga ggggctggga ccttcaggaa gacctcaggg tggggatggg gacatcaggg 9120 actttaggcc agtggccaca tgataccctg tgtcctcccc aggaaacaca gtgttacaca 9180 tcctcatcct ccagcccaac aaaacctttg cctgccagat gtacaacctg ttgctgtcct 9240 acgacagaca tggggaccac ctgcagcccc tggacctcgt gcccaatcac cagggtctca 9300 cccctttcaa gctggctgga gtggagggta acactgtggt gagagacggt ccccatccct 9360 gaggtgtctt tctaatgacc ctcaacctat cccgctggcc ctgggagaaa cagaggtgaa 9420 cgcgatccct gatgcttaga tcccattctc aactcagaaa tttttcaacc cctcccactg 9480 tggttacctg ttccctttct tgcccactcc ttttcccctg aggcattggg ggttacagag 9540 tctagatccc atgctaggat tgtctgtaat gccccagccc accttccctt tcagccccca 9600 gagcagggcc ctccagcctc tcgtctctcc tttccaaact ctggagggag tcatgggaga 9660 ggatgaggaa cctatgaatg tcactgtgaa tgtgggttct tctgccctct aaaggctgtc 9720 atcaaaatga aagggcagcc accttctcca ggggtgccgt cctcctgcac atgcatccta 9780 tccacactct gtgaccgtcc cctttgctta ctgctcctga gtcatcttca ctttccctta 9840 gatgtttcag cacctgatgc agaagcggaa gcacacccag tggacgtatg gaccactgac 9900 ctcgactctc tatgacctca cagagatcga ctcctcaggg gatgagcagt ccctgctgga 9960 acttatcatc accaccaaga agcgggaggt atggctcatg acagcaggct gtggctgggg 10020 aggggtgtca gggtctctga gccacctgtt ctctttctgt tgcaggctcg ccagatcctg 10080 gaccagacgc cggtgaagga gctggtgagc ctcaagtgga agcggtacgg gcggccgtac 10140 ttctgcatgc tgggtgccat atatctgctg tacatcatct gcttcaccat gtgctgcatc 10200 taccgccccc tcaagcccag gaccaataac cgcacgagcc cccgggacaa caccctctta 10260 cagcagaagc tacttcaggt gacacccttg taggagcaga tcagcagggc aggacttggc 10320 tctctgtcct cagagactgg tgtccctttc ctccctcaca ccatttctcc ccttgctcta 10380 atctcaaata tatgggtaca aactccaaat gcacgcccac aaaaacacac atacgctctt 10440 actctgagag cagagtttga gaagacccaa acctaacaga ttaaaaagaa tctgctaaga 10500 ctggtgaccc tgggcaccat ggaaatgcag ggcagaggcc tgaaagccct gagcattttg 10560 actgttcttc tcccccatta ggaagcctac atgaccccta aggacgatat ccggctggtc 10620 ggggagctgg tgactgtcat tggggctatc atcatcctgc tggtagaggt gaggtgtgga 10680 tggactctgg gtgaggctgt ctgcccgagg aatccagccc aagttccggt atctgagtgc 10740 ctttgtgtct ccctgacctc ttcaggttcc agacatcttc agaatggggg tcactcgctt 10800 ctttggacag accatccttg ggggcccatt ccatgtcctc atgtgagttt ccttcctctc 10860 actcccatcc cttccctcaa cagggctcca gttccactcc ttggattcct gacctctcaa 10920 gaaccttagc tccagagccc cctctctagt gctgtgtgta tgaccctggg cattgagtgt 10980 ggggaggctg aatctgcatg tgtgggtact ttcccagcta cattcttgct gtcaggtccc 11040 caggatcatc ccagccctcc cctcatcacc ctcctccctg ctcccccagc atcacctatg 11100 ccttcatggt gctggtgacc atggtgatgc ggctcatcag tgccagcggg gaggtggtac 11160 ccatgtcctt tgcactcgtg ctgggctggt gcaacgtcat gtacttcgcc cgaggattcc 11220 agatgctagg ccccttcacc atcatgattc agaaggtcag tcctcccccc aagctcccta 11280 gagaaaggcc ccagagccac agtcagcaga cggtcccata aagggcagaa cagtagacat 11340 tgcaggttct gcaagccaca catggcctca ctgcatgttt ttcttctttt ttaacaatcc 11400 ttttaaaaaa tgtagaaacc cttttcagtt caaaggccac accaaagcag gtcaggtaga 11460 tctggtccac aggccataga tagccaatcc ctgtcccaga gggtggagct gtgagacttg 11520 tcggggtgag acctgttaga ggctggatgg ggcaattgct tggggaatgt gtgcagatgt 11580 tctctgcctc ctgctccttc tagatgattt ttggcgacct gatgcgattc tgctggctga 11640 tggctgtggt catcctgggc tttgcttcag gtaatcatct gtccaggacc aggggccatg 11700 gcagggaaga gatgaggaag tctagggggc actggctctg gctaaacttg gggaggagga 11760 gtaatgcaga gatcagagga gacctatggt atcagaggat gggacgtcct ccagaggtga 11820 gaaaaatcgg gagtgttagg gagaggtggc tcttaggatc aagatgaggc tcatacaaaa 11880 ctagggaccg taaaaaccca aagtttggag cactgcagag ctggtgatat tgagatgaag 11940 ggaccaggat ggacatgcac gcagagcccg gggtgggctg gtcgtctgca tggttgccat 12000 ggtaaccctc acccccttgg gtggagcagc cttctatatc atcttccaga cagaggaccc 12060 cgaggagcta ggccacttct acgactaccc catggccctg ttcagcacct tcgagctgtt 12120 ccttaccatc atcgatggcc cagccaacta caacgtggac ctgcccttca tgtacagcat 12180 cacctatgct gcctttgcca tcatcgccac actgctcatg ctcaacctcc tcattgccat 12240 gatgggcgac actcactggc gagtggccca tgagcgggat gagctgtgga gggcccaggt 12300 gagccccctg gtggcaggga gggttagggc aagtcatccc cttcctacca aggaacctgc 12360 caagctgaga gacaggatat ctccacccca cttatgtttg gacagttgtg gcaaagctag 12420 caaaatcatg caaaatgtac agaagcactg attagcaatt caaccaggca atactggaat 12480 cgctgagaag aatgcctcac agttttctca acagttaaaa gctcagtgtt ttctagagga 12540 atcaacaaga aataaatcaa aagaaaatta acgttggcta aaattgcact cagtacattt 12600 tgttcccaaa taaaaactgg agtatcaagt cttcttgata atatttaagt ctgcaaaatt 12660 tgatatggaa agcaggatgt gttaaaaaag taatgccacc aaaacttcct atagtagcag 12720 aagctatctt cagccagatc ttcaagatag ggagagaaga ccatgagatg aatcaaatcc 12780 tcatttaaaa aacacctaga aaataattta tctaaaaaaa tcatttcagc aaaataatgg 12840 aaatttccca aactggaagg catttaacta tgctgtgtag aaaacggagt ggaaaaacta 12900 agctgggaaa taaggttcac tcagaaaaat attttctcca ggaatatata ttgatattct 12960 aagtgggatg tttatattta taagtggcct ttatgtctgt agggtcaaaa tatctgggag 13020 cccttaaaag ccctttctat ttgctttctc tggtgcctgt gctcctggga atggggcttc 13080 tgcttcctgt ctttctcctg cctctggcct ggctgcgtca tggatgttgg gtcattgggt 13140 aaagaattgt tggtctcaag ctctatcaac tctctcccac tgaagaaggt caacaaaggc 13200 tgccctaccc ctacctctgt ctgcgcccag cctcatctct gacttctcct tttgttccca 13260 tacgcagatt gtggccacca cagtgatgct ggagcggaag ctgcctcgct gcctgtggcc 13320 tcgctccggg atctgcggac gggagtatgg cctgggagac cgctggttcc tgcggtgagt 13380 gatatgcggg ggtaggtgtc ccctgagaag cctcatcggc agggtatccc cctgctcaga 13440 cagcttccgg ctcctgggtt ccctgtggag gcctgtgtgc tccctaggct ctatgcttgt 13500 tgattgagct ggtgaggaag gggtcccgtt tggagctcag acttcccaaa gcatccaggg 13560 agtctgtggc agagcctgct gctttctgag gcctagctgc caaggggcca gtgacccagg 13620 catccaccat ggctgcagaa aagggaaaag gccagcaatg gcggggatgg gaggaccagg 13680 ggataacaga caagcatcct tcttggatct gttcttcaag tcctggctgt gtctcaagtc 13740 ctcccgcatt ccacagggtg gaagacaggc aagatctcaa ccggcagcgg atccaacgct 13800 acgcacaggc cttccacacc cggggctctg aggatttgga caaagactca gtggaaaaac 13860 tagagctggg ctgtcccttc agcccccacc tgtcccttcc tatgccctca gtgtctcgaa 13920 gtacctcccg cagcagtgcc aattgggaaa ggcttcggca agggaccctg aggagagacc 13980 tgcgtgggat aatcaacagg ggtctggagg acggggagag ctgggaatat cagatctgac 14040 tgcgtgttct cacttcgctt cctggaactt gctctcattt tcctgggtgc atcaaacaaa 14100 acaaaaacca aacacccaga ggtctcatct cccaggcccc aggggagaaa gaggagtagc 14160 atgaacgcca aggaatgtac gttgagaatc actgctccag gcctgcatta ctccttcagc 14220 tctggggcag aggaagccca gcccaagcac ggggctggca gggcgtgagg aactctcctg 14280 tggcctgctc atcacccttc cgacaggagc actgcatgtc agagcacttt aaaaacaggc 14340 cagcctgctt gggcgctcgg tctccacccc agggtcataa gtggggagag agcccttccc 14400 agggcaccca ggcaggtgca gggaagtgca gagcttgtgg aaagcgtgtg agtgagggag 14460 acaggaacgg ctctgggggt gggaagtggg gctaggtctt gccaactcca tcttcaataa 14520 agtcgttttc ggatccct 14538 <![CDATA[<210> 2]]> <![CDATA[<211> 765]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人(Homo sapiens)]]> <![CDATA[<220>]]> <![CDATA[<221> TRPV6]]> <![CDATA[<222> (1)..(765)]]> <![CDATA[<400> 2]]> Met Gly Pro Leu Gln Gly Asp Gly Gly Pro Ala Leu Gly Gly Ala Asp 1 5 10 15 Val Ala Pro Arg Leu Ser Pro Val Arg Val Trp Pro Arg Pro Gln Ala 20 25 30 Pro Lys Glu Pro Ala Leu His Pro Met Gly Leu Ser Leu Pro Lys Glu 35 40 45 Lys Gly Leu Ile Leu Cys Leu Trp Ser Lys Phe Cys Arg Trp Phe Gln 50 55 60 Arg Arg Glu Ser Trp Ala Gln Ser Arg Asp Glu Gln Asn Leu Leu Gln 65 70 75 80 Gln Lys Arg Ile Trp Glu Ser Pro Leu Leu Leu Ala Ala Lys Asp Asn 85 90 95 Asp Val Gln Ala Leu Asn Lys Leu Leu Lys Tyr Glu Asp Cys Lys Val 100 105 110 His Gln Arg Gly Ala Met Gly Glu Thr Ala Leu His Ile Ala Ala Leu 115 120 125 Tyr Asp Asn Leu Glu Ala Ala Met Val Leu Met Glu Ala Ala Pro Glu 130 135 140 Leu Val Phe Glu Pro Met Thr Ser Glu Leu Tyr Glu Gly Gln Thr Ala 145 150 155 160 Leu His Ile Ala Val Val Asn Gln Asn Met Asn Leu Val Arg Ala Leu 165 170 175 Leu Ala Arg Arg Ala Ser Val Ser Ala Arg Ala Thr Gly Thr Ala Phe 180 185 190 Arg Arg Ser Pro Cys Asn Leu Ile Tyr Phe Gly Glu His Pro Leu Ser 195 200 205 Phe Ala Ala Cys Val Asn Ser Glu Glu Ile Val Arg Leu Leu Ile Glu 210 215 220 His Gly Ala Asp Ile Arg Ala Gln Asp Ser Leu Gly Asn Thr Val Leu 225 230 235 240 His Ile Leu Ile Leu Gln Pro Asn Lys Thr Phe Ala Cys Gln Met Tyr 245 250 255 Asn Leu Leu Leu Ser Tyr Asp Arg His Gly Asp His Leu Gln Pro Leu 260 265 270 Asp Leu Val Pro Asn His Gln Gly Leu Thr Pro Phe Lys Leu Ala Gly 275 280 285 Val Glu Gly Asn Thr Val Met Phe Gln His Leu Met Gln Lys Arg Lys 290 295 300 His Thr Gln Trp Thr Tyr Gly Pro Leu Thr Ser Thr Leu Tyr Asp Leu 305 310 315 320 Thr Glu Ile Asp Ser Ser Gly Asp Glu Gln Ser Leu Leu Glu Leu Ile 325 330 335 Ile Thr Thr Lys Lys Arg Glu Ala Arg Gln Ile Leu Asp Gln Thr Pro 340 345 350 Val Lys Glu Leu Val Ser Leu Lys Trp Lys Arg Tyr Gly Arg Pro Tyr 355 360 365 Phe Cys Met Leu Gly Ala Ile Tyr Leu Leu Tyr Ile Ile Cys Phe Thr 370 375 380 Met Cys Cys Ile Tyr Arg Pro Leu Lys Pro Arg Thr Asn Asn Arg Thr 385 390 395 400 Ser Pro Arg Asp Asn Thr Leu Leu Gln Gln Lys Leu Leu Gln Glu Ala 405 410 415 Tyr Met Thr Pro Lys Asp Asp Ile Arg Leu Val Gly Glu Leu Val Thr 420 425 430 Val Ile Gly Ala Ile Ile Ile Leu Leu Val Glu Val Pro Asp Ile Phe 435 440 445 Arg Met Gly Val Thr Arg Phe Phe Gly Gln Thr Ile Leu Gly Gly Pro 450 455 460 Phe His Val Leu Ile Ile Thr Tyr Ala Phe Met Val Leu Val Thr Met 465 470 475 480 Val Met Arg Leu Ile Ser Ala Ser Gly Glu Val Val Pro Met Ser Phe 485 490 495 Ala Leu Val Leu Gly Trp Cys Asn Val Met Tyr Phe Ala Arg Gly Phe 500 505 510 Gln Met Leu Gly Pro Phe Thr Ile Met Ile Gln Lys Met Ile Phe Gly 515 520 525 Asp Leu Met Arg Phe Cys Trp Leu Met Ala Val Val Ile Leu Gly Phe 530 535 540 Ala Ser Ala Phe Tyr Ile Ile Phe Gln Thr Glu Asp Pro Glu Glu Leu 545 550 555 560 Gly His Phe Tyr Asp Tyr Pro Met Ala Leu Phe Ser Thr Phe Glu Leu 565 570 575 Phe Leu Thr Ile Ile Asp Gly Pro Ala Asn Tyr Asn Val Asp Leu Pro 580 585 590 Phe Met Tyr Ser Ile Thr Tyr Ala Ala Phe Ala Ile Ile Ala Thr Leu 595 600 605 Leu Met Leu Asn Leu Leu Ile Ala Met Met Gly Asp Thr His Trp Arg 610 615 620 Val Ala His Glu Arg Asp Glu Leu Trp Arg Ala Gln Ile Val Ala Thr 625 630 635 640 Thr Val Met Leu Glu Arg Lys Leu Pro Arg Cys Leu Trp Pro Arg Ser 645 650 655 Gly Ile Cys Gly Arg Glu Tyr Gly Leu Gly Asp Arg Trp Phe Leu Arg 660 665 670 Val Glu Asp Arg Gln Asp Leu Asn Arg Gln Arg Ile Gln Arg Tyr Ala 675 680 685 Gln Ala Phe His Thr Arg Gly Ser Glu Asp Leu Asp Lys Asp Ser Val 690 695 700 Glu Lys Leu Glu Leu Gly Cys Pro Phe Ser Pro His Leu Ser Leu Pro 705 710 715 720 Met Pro Ser Val Ser Arg Ser Thr Ser Arg Ser Ser Ala Asn Trp Glu 725 730 735 Arg Leu Arg Gln Gly Thr Leu Arg Arg Asp Leu Arg Gly Ile Ile Asn 740 745 750 Arg Gly Leu Glu Asp Gly Glu Ser Trp Glu Tyr Gln Ile 755 760 765 <![CDATA[<210> 3]]> <![CDATA[<211> 31]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人(Homo sapiens)]]> <![CDATA[<400> 3]]> Pro Leu Lys Pro Arg Thr Asn Asn Arg Thr Ser Pro Arg Asp Asn Thr 1 5 10 15 Leu Leu Gln Gln Lys Leu Leu Gln Glu Ala Tyr Met Thr Pro Lys 20 25 30 <![CDATA[<210> 4]]> <![CDATA[<211> 13]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人(Homo sapiens)]]> <![CDATA[<400> 4]]> Ile Phe Gln Thr Glu Asp Pro Glu Glu Leu Gly His Phe 1 5 10 <![CDATA[<210> 5]]> <![CDATA[<211> 12]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人(Homo sapiens)]]> <![CDATA[<400> 5]]> Asp Gly Pro Ala Asn Tyr Asn Val Asp Leu Pro Phe 1 5 10 <![CDATA[<210> 6]]> <![CDATA[<211> 339]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 小鼠(Mus musculus)]]> <![CDATA[<400> 6]]> gacattgtga tgtcacagtc tccatcctcc ctagctgtgt cagttggaga gaaggttact 60 atgagctgca agtccagtca gagcctttta tatagtacca atcaaaagaa ctacttggcc 120 tggtcccagc agaaaccagg gcagtctcct aaactgctga tttactgggc atccactagg 180 gaatctgggg tccctgatcg cttcacaggc agtggatctg ggacagattt cactctcacc 240 atcagcagtg tgaaggctga agacctggca gtttattact gtcagcaata ttatagctat 300 ccgtggacgt tcggtggagg caccaagctg gaaatcaaa 339 <![CDATA[<210> 7]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 小鼠(Mus musculus)]]> <![CDATA[<400> 7]]> Gly Tyr Thr Phe Thr Ser Tyr Trp 1 5 <![CDATA[<210> 8]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 小鼠(Mus musculus)]]> <![CDATA[<400> 8]]> Ile Asp Pro Ser Asp Gly Tyr Thr 1 5 <![CDATA[<210> 9]]> <![CDATA[<211> 6]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 小鼠(Mus musculus)]]> <![CDATA[<400> 9]]> Gly Trp Ala Gly Asp Phe 1 5 <![CDATA[<210> 10]]> <![CDATA[<211> 11]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 小鼠(Mus musculus)]]> <![CDATA[<400> 10]]> Gln Ser Leu Leu Asp Ser Asp Gly Lys Thr Tyr 1 5 10 <![CDATA[<210> 11]]> <![CDATA[<211> 4]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 小鼠(Mus musculus)]]> <![CDATA[<220>]]> <![CDATA[<221> misc_feature]]> <![CDATA[<222> (4)..(4)]]> <![CDATA[<223> Xaa is absent.]]> <![CDATA[<400> 11]]> Leu Val Ser Xaa 1 <![CDATA[<210> 12]]> <![CDATA[<211> 9]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 小鼠(Mus musculus)]]> <![CDATA[<400> 12]]> Trp Gln Gly Thr His Phe Pro Gln Thr 1 5 <![CDATA[<210> 13]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 小鼠(Mus musculus)]]> <![CDATA[<400> 13]]> Gly Phe Thr Phe Ser Tyr Tyr Trp 1 5 <![CDATA[<210> 14]]> <![CDATA[<211> 10]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 小鼠(Mus musculus)]]> <![CDATA[<400> 14]]> Ile Arg Leu Lys Ser His Asn Tyr Ala Thr 1 5 10 <![CDATA[<210> 15]]> <![CDATA[<211> 16]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 小鼠(Mus musculus)]]> <![CDATA[<400> 15]]> Ala Arg Leu Ala Tyr Asp Gly Glu Arg Tyr Tyr Tyr Ala Leu Asp Tyr 1 5 10 15 <![CDATA[<210> 16]]> <![CDATA[<211> 12]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 小鼠(Mus musculus)]]> <![CDATA[<400> 16]]> Gln Ser Leu Leu Tyr Ser Asn Asn Gln Lys Asn Tyr 1 5 10 <![CDATA[<210> 17]]> <![CDATA[<211> 4]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 小鼠(Mus musculus)]]> <![CDATA[<220>]]> <![CDATA[<221> misc_feature]]> <![CDATA[<222> (4)..(4)]]> <![CDATA[<223> 不存在Xaa。]]> <![CDATA[<400> 17]]> Trp Ala Ser Xaa 1 <![CDATA[<210> 18]]> <![CDATA[<211> 9]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 小鼠(Mus musculus)]]> <![CDATA[<400> 18]]> Gln Gln Tyr Tyr Ser Tyr Pro Phe Thr 1 5 <![CDATA[<210> 19]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 小鼠(Mus musculus)]]> <![CDATA[<400> 19]]> Ala Phe Thr Phe Ser His Tyr Trp 1 5 <![CDATA[<210> 20]]> <![CDATA[<211> 10]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 小鼠(Mus musculus)]]> <![CDATA[<400> 20]]> Ile Arg Leu Lys Ser Tyr Asn Tyr Ala Thr 1 5 10 <![CDATA[<210> 21]]> <![CDATA[<211> 15]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 小鼠(Mus musculus)]]> <![CDATA[<400> 21]]> Thr Arg Leu Gly Tyr Phe Gly Ser Leu Tyr Tyr Ala Met Asp Tyr 1 5 10 15 <![CDATA[<210> 22]]> <![CDATA[<211> 12]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 小鼠(Mus musculus)]]> <![CDATA[<400> 22]]> Gln Ser Leu Leu Tyr Ser Thr Asn Gln Lys Asn Tyr 1 5 10 <![CDATA[<210> 23]]> <![CDATA[<211> 4]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 小鼠(Mus musculus)]]> <![CDATA[<220>]]> <![CDATA[<221> misc_feature]]> <![CDATA[<222> (4)..(4)]]> <![CDATA[<223> 不存在Xaa。]]> <![CDATA[<400> 23]]> Trp Ala Ser Xaa 1 <![CDATA[<210> 24]]> <![CDATA[<211> 9]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 小鼠(Mus musculus)]]> <![CDATA[<400> 24]]> Gln Gln Tyr Tyr Ser Tyr Pro Trp Thr 1 5 <![CDATA[<210> 25]]> <![CDATA[<211> 113]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 小鼠(Mus musculus)]]> <![CDATA[<400> 25]]> Gln Val Gln Val Gln Gln Pro Gly Ala Glu Leu Val Lys Pro Gly Thr 1 5 10 15 Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Trp Met His Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Glu Ile Asp Pro Ser Asp Gly Tyr Thr Asn Tyr Asn Gln Lys Phe 50 55 60 Arg Gly Lys Ala Thr Leu Ser Val Asp Lys Ser Ser Thr Thr Ala Tyr 65 70 75 80 Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Gly Trp Ala Gly Asp Phe Trp Gly Gln Gly Thr Thr Leu Thr Val Ser 100 105 110 Ser <![CDATA[<210> 26]]> <![CDATA[<211> 112]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 小鼠(Mus musculus)]]> <![CDATA[<400> 26]]> Asp Val Val Leu Thr Gln Ser Pro Leu Thr Leu Ser Val Thr Ile Gly 1 5 10 15 Gln Pro Ala Ser Ile Ser Cys Lys Ser Ser Gln Ser Leu Leu Asp Ser 20 25 30 Asp Gly Lys Thr Tyr Leu Asn Trp Leu Leu Gln Arg Pro Gly Gln Ser 35 40 45 Pro Lys Arg Leu Ile Tyr Leu Val Ser Lys Leu Asp Ser Ala Ala Pro 50 55 60 Asp Arg Phe Ala Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile 65 70 75 80 Ser Arg Val Glu Ala Glu Asp Leu Gly Ile Tyr Tyr Cys Trp Gln Gly 85 90 95 Thr His Phe Pro Gln Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys 100 105 110 <![CDATA[<210> 27]]> <![CDATA[<211> 125]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 小鼠(Mus musculus)]]> <![CDATA[<400> 27]]> Glu Val Lys Leu Glu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Met Lys Leu Ser Cys Val Ala Ser Gly Phe Thr Phe Ser Tyr Tyr 20 25 30 Trp Met Asn Trp Val Arg Gln Ser Pro Glu Lys Gly Leu Glu Trp Val 35 40 45 Ala Glu Ile Arg Leu Lys Ser His Asn Tyr Ala Thr His Tyr Ala Glu 50 55 60 Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Ser Ser 65 70 75 80 Val Tyr Leu Gln Met Asn Asn Leu Arg Ser Glu Asp Thr Gly Ile Tyr 85 90 95 Tyr Cys Ala Arg Leu Ala Tyr Asp Gly Glu Arg Tyr Tyr Tyr Ala Leu 100 105 110 Asp Tyr Trp Gly Gln Gly Thr Ser Val Thr Val Ser Ser 115 120 125 <![CDATA[<210> 28]]> <![CDATA[<211> 113]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 小鼠(Mus musculus)]]> <![CDATA[<400> 28]]> Asp Ile Val Met Ser Gln Ser Pro Ser Ser Leu Ala Val Ser Val Gly 1 5 10 15 Glu Lys Phe Thr Met Ser Cys Lys Ser Ser Gln Ser Leu Leu Tyr Ser 20 25 30 Asn Asn Gln Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln 35 40 45 Ser Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val 50 55 60 Pro Asp Arg Phe Thr Gly Ser Gly Tyr Gly Thr Asp Phe Thr Leu Thr 65 70 75 80 Ile Ser Ser Val Lys Ala Glu Asp Leu Ala Val Tyr Tyr Cys Gln Gln 85 90 95 Tyr Tyr Ser Tyr Pro Phe Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile 100 105 110 Lys <![CDATA[<210> 29]]> <![CDATA[<211> 124]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 小鼠(Mus musculus)]]> <![CDATA[<400> 29]]> Glu Val Met Leu Glu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Met Lys Leu Ser Cys Val Ala Ser Ala Phe Thr Phe Ser His Tyr 20 25 30 Trp Met Asn Trp Val Arg Gln Ser Pro Glu Lys Gly Leu Glu Trp Val 35 40 45 Ala Glu Ile Arg Leu Lys Ser Tyr Asn Tyr Ala Thr His Tyr Ala Glu 50 55 60 Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Ser Ser 65 70 75 80 Val Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Gly Ile Tyr 85 90 95 Tyr Cys Thr Arg Leu Gly Tyr Phe Gly Ser Leu Tyr Tyr Ala Met Asp 100 105 110 Tyr Trp Gly Gln Gly Thr Ser Val Thr Val Ser Ser 115 120 <![CDATA[<210> 30]]> <![CDATA[<211> 112]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 小鼠(Mus musculus)]]> <![CDATA[<400> 30]]> Asp Ile Val Met Ser Gln Ser Pro Ser Ser Leu Ala Val Ser Val Gly 1 5 10 15 Glu Lys Val Thr Met Ser Cys Lys Ser Ser Gln Ser Leu Leu Tyr Ser 20 25 30 Thr Asn Gln Lys Asn Tyr Leu Ala Trp Ser Gln Gln Lys Pro Gly Gln 35 40 45 Ser Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Glu Ser Gly Val Pro 50 55 60 Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile 65 70 75 80 Ser Ser Val Lys Ala Glu Asp Leu Ala Val Tyr Tyr Cys Gln Gln Tyr 85 90 95 Tyr Ser Tyr Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys 100 105 110 <![CDATA[<210> 31]]> <![CDATA[<211> 339]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 小鼠(Mus musculus)]]> <![CDATA[<400> 31]]> caggtccaag tgcagcagcc tggggctgag cttgtgaagc ctgggacttc agtgaagctg 60 tcctgcaagg cttctggcta caccttcacc agctactgga tgcactgggt gaagcagagg 120 cctggacaag gccttgagtg gatcggagag attgatcctt ctgatggtta tactaactac 180 aatcaaaagt tcaggggcaa ggccacattg tctgtagaca aatcctccac cacagcctac 240 atgcagctca gcagcctgac atctgaggac tctgcggtct attactgtgg gtgggcgggg 300 gacttctggg gccaaggcac cactctcaca gtctcctca 339 <![CDATA[<210> 32]]> <![CDATA[<211> 336]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 小鼠(Mus musculus)]]> <![CDATA[<400> 32]]> gatgttgtgc tgacccagag tccactcact ttgtcggtta ccattggaca accagcctcc 60 atctcttgca agtcaagtca gagcctctta gatagtgatg gaaagacata tttgaattgg 120 ttgttacaga ggccaggcca gtctccaaag cgcctaatct atctggtgtc taagctggac 180 tctgcagccc ctgacaggtt cgctggcagt ggatcaggga cagatttcac actgaaaatc 240 agcagagtgg aggctgaaga tttgggaatt tactattgct ggcaaggtac acattttcct 300 cagacgttcg gtggaggcac caagctggaa atcaaa 336 <![CDATA[<210> 33]]> <![CDATA[<211> 375]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 小鼠(Mus musculus)]]> <![CDATA[<400> 33]]> gaagtgaagc ttgaggagtc tggaggaggc ttggtgcaac ctggaggatc catgaaactc 60 tcctgtgttg cctctggatt cactttcagt tactactgga tgaactgggt ccgccagtct 120 ccagagaagg ggcttgagtg ggttgctgaa attagattga aatctcataa ttatgcaaca 180 cattatgcgg agtctgtgaa agggaggttc accatctcaa gagatgattc caaaagtagt 240 gtctacctgc aaatgaacaa cttaagatct gaagacactg gcatttatta ctgtgccagg 300 cttgcttacg acggggagcg gtattactat gctctggact actggggtca aggaacctca 360 gtcaccgtct cctca 375 <![CDATA[<210> 34]]> <![CDATA[<211> 339]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 小鼠(Mus musculus)]]> <![CDATA[<400> 34]]> gacattgtga tgtcacagtc tccatcctcc ctagctgtgt cagttggaga gaagtttact 60 atgagctgca agtccagtca gagcctttta tatagtaaca atcaaaagaa ctacttggcc 120 tggtaccagc agaaaccagg gcagtctcct aaactgctga tttactgggc atccactagg 180 gaatctgggg tccctgatcg cttcacaggc agtggatatg ggacagattt cactctcacc 240 atcagcagtg tgaaggctga agacctggca gtttattact gtcagcaata ttatagctat 300 ccattcacgt tcggctcggg gacaaagttg gaaataaaa 339 <![CDATA[<210> 35]]> <![CDATA[<211> 372]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 小鼠(Mus musculus)]]> <![CDATA[<400> 35]]> gaagtgatgc ttgaggagtc tggaggaggc ttagtgcaac ctggaggatc catgaagctc 60 tcctgtgttg cctctgcatt cactttcagt cactactgga tgaactgggt ccgccagtct 120 ccagagaagg ggcttgagtg ggttgctgaa attagattga aatcttataa ttatgcaaca 180 cattatgcgg agtctgtgaa agggaggttc accatctcca gagatgattc caagagtagt 240 gtctacctgc aaatgaacag cctaaggcct gaagacactg gcatttatta ctgtaccagg 300 cttggttact tcggtagcct ctactatgct atggactact ggggtcaagg aacctcagtc 360 accgtctcct ca 372
Claims (57)
- 一種特異性結合TRPV6的抗體或其抗原結合片段,其中所述抗體或其抗原結合片段包含如下重鏈可變區所包括的三個重鏈互補決定區HCDR1、HCDR2和HCDR3: (a) SEQ ID NO: 25所示的重鏈可變區; (b) SEQ ID NO: 27所示的重鏈可變區;或 (c) SEQ ID NO: 29所示的重鏈可變區。
- 如請求項1所述的抗體或其抗原結合片段,其中所述抗體或其抗原結合片段包含選自下組的三個重鏈互補決定區HCDR1、HCDR2和HCDR3: (a) SEQ ID NO: 7所示的HCDR1、SEQ ID NO: 8所示的HCDR2、SEQ ID NO: 9所示的HCDR3; (b) SEQ ID NO: 13所示的HCDR1、SEQ ID NO: 14所示的HCDR2、SEQ ID NO: 15所示的HCDR3;或 (c) SEQ ID NO: 19所示的HCDR1、SEQ ID NO: 20所示的HCDR2、SEQ ID NO: 21所示的HCDR3。
- 如請求項1所述的抗體或其抗原結合片段,其中所述抗體或其抗原結合片段進一步包含如下輕鏈可變區所包括的三個輕鏈互補決定區LCDR1、LCDR2和LCDR3: (a) SEQ ID NO: 26所示的輕鏈可變區; (b) SEQ ID NO: 28所示的輕鏈可變區;或 (c) SEQ ID NO: 30所示的輕鏈可變區。
- 如請求項3所述的抗體或其抗原結合片段,其中所述抗體或其抗原結合片段進一步包含選自下組的三個輕鏈互補決定區LCDR1、LCDR2和LCDR3: (a) SEQ ID NO: 10所示的LCDR1、SEQ ID NO: 11所示的LCDR2以及SEQ ID NO: 12所示的LCDR3; (b) SEQ ID NO: 16所示的LCDR1、SEQ ID NO: 17所示的LCDR2以及SEQ ID NO: 18所示的LCDR3;或 (c) SEQ ID NO: 22所示的LCDR1、SEQ ID NO: 23所示的LCDR2以及SEQ ID NO: 24所示的LCDR3。
- 如請求項1所述的抗體或其抗原結合片段,其中所述抗體或其抗原結合片段包含選自下組的三個重鏈互補決定區HCDR1、HCDR2和HCDR3以及三個輕鏈互補決定區LCDR1、LCDR2和LCDR3: (a) SEQ ID NO: 7所示的HCDR1、SEQ ID NO: 8所示的HCDR2、SEQ ID NO: 9所示的HCDR3、SEQ ID NO: 10所示的LCDR1、SEQ ID NO: 11所示的LCDR2以及SEQ ID NO: 12所示的LCDR3; (b) SEQ ID NO: 13所示的HCDR1、SEQ ID NO: 14所示的HCDR2、SEQ ID NO: 15所示的HCDR3、SEQ ID NO: 16所示的LCDR1、SEQ ID NO: 17所示的LCDR2以及SEQ ID NO: 18所示的LCDR3;或 (c) SEQ ID NO: 19所示的HCDR1、SEQ ID NO: 20所示的HCDR2、SEQ ID NO: 21所示的HCDR3、SEQ ID NO: 22所示的LCDR1、SEQ ID NO: 23所示的LCDR2以及SEQ ID NO: 24所示的LCDR3。
- 如請求項1所述的抗體或其抗原結合片段,其中所述抗體或其抗原結合片段包含選自下組的重鏈可變區V H: (a) SEQ ID NO: 25所示的重鏈可變區; (b) SEQ ID NO: 27所示的重鏈可變區;或 (c) SEQ ID NO: 29所示的重鏈可變區。
- 如請求項6所述的抗體或其抗原結合片段,其中所述抗體或其抗原結合片段進一步包含選自下組的輕鏈可變區V L: (a) SEQ ID NO: 26所示的輕鏈可變區; (b) SEQ ID NO: 28所示的輕鏈可變區;或 (c) SEQ ID NO: 30所示的輕鏈可變區。
- 如請求項1所述的抗體或其抗原結合片段,其中所述抗體或其抗原結合片段包含選自下組的重鏈可變區V H和輕鏈可變區V L: (a) SEQ ID NO: 25所示的重鏈可變區和SEQ ID NO: 26所示的輕鏈可變區; (b) SEQ ID NO: 27所示的重鏈可變區和SEQ ID NO: 28所示的輕鏈可變區;或 (c) SEQ ID NO: 29所示的重鏈可變區和SEQ ID NO: 30所示的輕鏈可變區。
- 如請求項1至8任一項所述的抗體或其抗原結合片段,其中所述抗體或其抗原結合片段特異性識別或結合具有SEQ ID NO: 2所示的胺基酸序列的蛋白。
- 如請求項9所述的抗體或其抗原結合片段,其中所述抗體或其抗原結合片段與具有SEQ ID NO: 2所示的胺基酸序列的蛋白的Kd值小於10 -7M。
- 如請求項10所述的抗體或其抗原結合片段,其中所述Kd值是通過表面等離子共振方法檢測的。
- 如請求項1至11中任一項所述的抗體或其抗原結合片段,其中所述抗原結合片段是選自F(ab’)2、Fab’、Fab、Fv、scFv、dsFv或dAb。
- 如請求項1至12中任一項所述的抗體或其抗原結合片段,其中所述抗體或其抗原結合片段進一步具有重鏈恆定區和/或輕鏈恆定區。
- 如請求項13所述的抗體或其抗原結合片段,其中所述重鏈恆定區源於鼠的IgG1或鼠的IgG2a。
- 如請求項13所述的抗體或其抗原結合片段,其中所述重鏈恆定區源於人的IgG1。
- 如請求項1至15中任一項所述的抗體或其抗原結合片段,其中所述抗體或其抗原結合片段進一步具有綴合部分。
- 如請求項16所述的抗體或其抗原結合片段,其中所述綴合部分是治療劑、放射性同位素、可檢測標籤、藥物動力學修飾部分或純化部分。
- 如請求項15或16所述的抗體或其抗原結合片段,其中所述綴合部分直接連接或者通過連接子連接。
- 一種分離的核酸,其編碼請求項1至18中任一項所述的抗體或其抗原結合片段。
- 如請求項19所述的核酸,其包含: (a) SEQ ID NO: 31所示的核酸序列或與SEQ ID NO: 31具有至少90%序列同一性的核酸序列,和SEQ ID NO: 32所示的核酸序列或與SEQ ID NO: 32具有至少90%序列同一性的核酸序列中的一者或兩者; (b) SEQ ID NO: 33所示的核酸序列或與SEQ ID NO: 33具有至少90%序列同一性的核酸序列,和SEQ ID NO: 34所示的核酸序列或與SEQ ID NO: 34具有至少90%序列同一性的核酸序列中的一者或兩者;或 (c) SEQ ID NO: 35所示的核酸序列或與SEQ ID NO: 35具有至少90%序列同一性的核酸序列,和SEQ ID NO: 6所示的核酸序列或與SEQ ID NO: 6具有至少90%序列同一性的核酸序列中的一者或兩者。
- 一種載體,其包含如請求項19或20所述的核酸序列。
- 一種宿主細胞,其包含如請求項21所述的載體。
- 一種多特異性抗體,其包含請求項1至18任一項所述的抗體或其抗原結合片段,和一個或多個與其他抗原特異性結合的抗體或其抗原結合部分。
- 一種抗體偶聯物,其包含請求項1至18任一項所述的抗體或其抗原結合片段或請求項23所述的多特異性抗體。
- 一種分泌抗TRPV6單株抗體的融合瘤細胞株,所述融合瘤細胞株為12CT9.5.1、16CT4.1.1.2或16CT18.1.1.2,寄存於中國典型培養物保藏中心,其中所述12CT9.5.1寄存編號為CCTCC NO: C202119,所述16CT4.1.1.2寄存編號為CCTCC NO: C202124,所述16CT18.1.1.2寄存編號為CCTCC NO: C202125。
- 一種藥物組合物,其包含請求項1至18中任一項所述的抗體或其抗原結合片段、請求項19-20任一項所述的分離的核酸、請求項21所述的載體、請求項22所述的宿主細胞、請求項23所述的多特異性抗體或請求項24所述的抗體偶聯物,和藥學上可接受的載體。
- 一種用於分析和檢測來自受試者的樣品中的TRPV6的試劑,所述試劑包含一種或多種如請求項1至18所述的抗體或其抗原結合片段。
- 如請求項27所述的試劑,所述試劑用於分析和檢測來自受試者的樣品中的TRPV6。
- 一種檢測來自受試者的樣品中的TRPV6的方法,所述方法包括: (1) 使所述樣品與如請求項1至18中任一項所述的抗體或抗原結合片段接觸; (2) 可選地,移除未結合的抗體或抗體片段; (3) 檢測與所述樣品中的TRPV6結合的抗體或抗體片段。
- 如請求項29所述的方法,其中所述步驟(1)中的所述如請求項1至18中任一項所述的抗體或抗原結合片段被固定在基板上。
- 如請求項29所述的方法,其中所述步驟(1)中的所述樣品被固定在基板上。
- 如請求項29至31中任一項所述的方法,其中所述步驟(3)包括使用第二抗體,可選的,所述第二抗體能夠直接或者間接地結合所述樣品中的TRPV6,可選的,所述第二抗體的表位與如請求項1至18中任一項所述的抗體或抗原結合片段的表位不同,可選的,所述第二抗體的表位與如請求項1至18中任一項所述的抗體或抗原結合片段的表位相同,可選的,所述第二抗體的表位與TRPV6的結合不受如請求項1至18中任一項所述的抗體或抗原結合片段的影響,可選的,所述第二抗體的表位與TRPV6的結合受如請求項1至18中任一項所述的抗體或抗原結合片段的影響。
- 如請求項29至31中任一項所述的方法,其中所述步驟(3)包括使用第二抗體,可選的,所述第二抗體能夠直接或間接地結合如請求項1至18中任一項所述的抗體或抗原結合片段,可選的,所述第二抗體能夠結合如請求項1至18中任一項所述的抗體或抗原結合片段的恆定區部分。
- 如請求項32或33所述的方法,其中所述第二抗體與檢測分子偶聯,可選的,所述檢測分子包括酶、螢光標記物和生物素。
- 如請求項34所述的方法,其中所述檢測分子為酶,可選的,所述酶包括辣根過氧化酶、鹼性磷酸酶或其衍生物。
- 如請求項34所述的方法,其中所述檢測分子為螢光素,可選的,所述螢光素包括FITC、羅丹明、德克薩斯紅、藻紅蛋白或Dylight。
- 如請求項34所述的方法,其中所述檢測分子為生物素或其衍生物。
- 如請求項29至37中任一項所述的方法,其進一步包括對與所述樣品中的TRPV6結合的抗體進行定量。
- 如請求項38所述的方法,其中所述方法為免疫組織化學(IHC)、酶聯免疫吸附(ELISA)、免疫螢光(IF)、化學發光(CLIA)、免疫比濁(TIA)或免疫印跡(Western Blot)。
- 如請求項29至39中任一項所述的方法,其中所述受試者為人類。
- 如請求項29至40中任一項所述的方法,其用於評估所述樣品中在細胞表面上表達TRPV6的細胞的比例。
- 一種判斷受試者疾病的形成或形成的風險、評估受試者疾病的進展或預後、或在接受疾病治療的受試者中預測或監測所述受試者對治療的反應的方法,所述方法包括使用如請求項29至41中任一項所述的方法檢測來自所述受試者的樣品中的TRPV6。
- 如請求項41所述的方法,所述方法包括評估所述樣品中在細胞表面上表達TRPV6的細胞的比例,若所述比例超過預定的閾值,則認為所述受試者患有所述疾病或者更可能從治療中獲益,其中所述閾值為10%,優選的,所述治療為靶向藥物治療。
- 如請求項42或43所述的方法,其中所述疾病為癌症。
- 如請求項44所述的方法,其中所述癌症為乳腺癌、卵巢癌、子宮內膜癌、膽管癌、胃癌、食道癌、肺癌、腸癌、胰腺癌;優選的,所述癌症為HER2 +乳腺癌、三陰乳腺癌或結直腸癌。
- 一種試劑盒,所述試劑盒包含請求項1至18中任一項所述的抗體或其抗原結合片段,可選的,進一步包括用於檢測所述抗體或其抗原結合片段與TRPV6結合情況的試劑。
- 如請求項46所述的試劑盒,其用於診斷受試者疾病的形成或形成的風險、評估受試者疾病的進展或預後、或在接受疾病治療的受試者中預測或監測所述受試者對治療的反應。
- 如請求項46所述的試劑盒,其用於免疫組織化學病理診斷。
- 如請求項48所述的試劑盒,其用於腫瘤組織免疫組織化學病理診斷。
- 如請求項中47所述的試劑盒,其中所述疾病為癌症。
- 如請求項48所述的試劑盒,其中所述疾病為乳腺癌、卵巢癌、子宮內膜癌、膽管癌、胃癌、食道癌、肺癌、腸癌、胰腺癌;優選的,所述疾病為HER2 +乳腺癌、三陰乳腺癌或結直腸癌。
- 一種製備特異性結合TRPV6的抗體的方法,所述方法包括: (1) 將SEQ ID NO: 3所示的胺基酸序列與載體蛋白偶聯,以獲得TRPV6抗原肽; (2) 將通過步驟(1)獲得的所述TRPV6抗原肽作為免疫原免疫小鼠; (3) 經細胞融合、免疫肽篩選單株,獲得高效分泌特異性結合TRPV6的抗體的陽性融合瘤細胞系;和 (4) 獲得特異性結合TRPV6的抗體。
- 如請求項52所述的方法,其中所述載體蛋白為鑰孔蟲戚血藍素(KLH)蛋白。
- 如請求項52或53所述的方法,其中通過在SEQ ID NO: 3所示的胺基酸序列的N端增加一個Cys,並通過自由巰基和所述載體蛋白偶聯。
- 如請求項52至54中任一項所述的方法,其中所述融合瘤細胞系為小鼠融合瘤細胞系12CT 9.5.1、16CT 18.1.1.2或16CT 4.1.1.2。
- 如請求項1-18中任一項所述的抗體或其抗原結合片段、請求項19-20任一項所述的分離的核酸、如請求項21所述的載體、請求項22所述的宿主細胞、請求項23所述的多特異性抗體、請求項24所述的抗體偶聯物以及請求項25所述的藥物組合物在用於治療和/或預防和/或診斷與TRPV6相關的疾病的藥物中的用途。
- 一種治療、預防或診斷疾病的方法,所述方法包括向有需要的受試者施用如請求項1-18中任一項所述的抗體或其抗原結合片段、請求項19-20任一項所述的分離的核酸、請求項21所述的載體、請求項22所述的宿主細胞、請求項23所述的多特異性抗體、請求項24所述的抗體偶聯物以及請求項25所述的藥物組合物。
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