15.3億美元BD引爆賽道，CDH17成為消化道腫瘤下一代明星靶點
日期：2023-03-27 14:58:09
近期，CDH17作為消化道腫瘤潛力靶點熱度快速攀升，2025年連續(xù)兩筆重磅BD交易引發(fā)關(guān)注：10月翰森制藥將其CDH17 ADC（HS-20110）大中華區(qū)外權(quán)益授權(quán)給羅氏，首付款8000萬美元，潛在總額達15.3億美元；1月樂普生物亦將CDH17 ADC（MRG007）海外權(quán)益授予ArriVent，交易總額超12億美元。國際方面，Multitude Therapeutics的CDH17 ADC（AMT-676）已進入臨床I期并在2025年ASCO公布試驗設(shè)計，而國內(nèi)宜聯(lián)生物的YL217也步入臨床階段。這些進展顯示CDH17靶點正從基礎(chǔ)研究向臨床轉(zhuǎn)化加速邁進。
1. 什么是CDH17？
1.1 CDH17的結(jié)構(gòu)
肝腸鈣黏蛋白（liver- intestine cadherin, Cadherin-17，又名CDH17；HPT-1；LI-Cadherin）是近年來新發(fā)現(xiàn)的一種鈣黏蛋白，其最早于1994年由Dietmar等通過分子克隆技術(shù)從鼠肝細胞cDNA文庫中分析得到的，由于在小鼠僅表達于肝臟和小腸，故命名為肝腸鈣黏蛋白 [11]。人CDH17基因定位于染色體8q22. 1，其結(jié)構(gòu)與鈣黏蛋白家族成員具有同源性，但CDH17又有以下獨特的結(jié)構(gòu)：①CDH17的胞外部分含有7個鈣黏蛋白重復(fù)區(qū)域，而經(jīng)典鈣黏蛋白和橋粒鈣黏蛋白為5個；②在CDH17氨基末端的細胞黏附識別區(qū)內(nèi)，決定細胞黏附特性的HAV序列由AAL序列代替；③CDH17細胞質(zhì)尾僅含有20個氨基酸殘基，經(jīng)典鈣黏蛋白有150-160個。因此，CDH17被劃分為經(jīng)典鈣黏蛋白的變異體 （圖1） [12-14]。
圖1. CDH17的結(jié)構(gòu) [14]
1.2 CDH17的表達及功能
CDH17主要表達于胚胎、成人腸上皮細胞和部分胰腺導(dǎo)管上皮細胞，在健康人群肝細胞、食管上皮細胞及胃黏膜中幾乎不表達 [15-18]。CDH17在細胞黏附過程中充當(dāng)了與鈣黏蛋白同樣重要的角色，CDH17可直接與細胞支架連接，發(fā)揮其細胞黏附作用，而經(jīng)典的鈣黏蛋白必須與鏈蛋白結(jié)合形成復(fù)合體才能發(fā)揮其黏附功能 [19-20]。在一些病理情況下，CDH17可表達于其它組織。目前研究發(fā)現(xiàn)，CDH17在胃癌、結(jié)直腸癌、肝癌、胰腺癌和膽管癌等多種腫瘤組織中均有不同程度的表達，CDH17的高水平表達與患者預(yù)后和風(fēng)險評估密切相關(guān) [21-23]。
2. CDH17在腫瘤中的作用機制
CDH17作為鈣黏蛋白超家族中的獨特一員，在多種疾病中均發(fā)現(xiàn)CDH17的異常表達。研究揭示CDH17的功能紊亂與腫瘤細胞的外周浸潤及轉(zhuǎn)移關(guān)系密切，對腫瘤的復(fù)發(fā)及患者的生存率均有影響。然而，目前對于CDH17與腫瘤相關(guān)作用機制尚未闡明。
在胃癌中，CDH17高表達可使E-cadherin/catenin復(fù)合物失去穩(wěn)定而解離 [23]。研究已證實β-catenin和E-cadherin/catenin復(fù)合物通過Wnt信號傳導(dǎo)途徑參與胃癌的發(fā)生發(fā)展 [24-25]。此外，CDH17表達上調(diào)可影響GSK3的活性，抑制β-catenin-AXIN-APC-GSK3復(fù)合物的形成，穩(wěn)定β-catenin表達水平，可使其與轉(zhuǎn)錄因子LEF/TCF結(jié)合，誘導(dǎo)Cyclin D1的產(chǎn)生，從而促進細胞增殖，抑制細胞凋亡（圖2） [26]。有研究認為β-半乳糖苷結(jié)合蛋白Galectin-3在胃癌侵襲過程中的異常表達對CDH17起調(diào)控作用，但具體調(diào)控機制有待進一步研究 [27-28]。
圖1. CDH17誘導(dǎo)Cyclin D1的產(chǎn)生 [26]
此外，利用慢病毒介導(dǎo)的microRNA干擾技術(shù)發(fā)現(xiàn)，抑制CDH17表達后，MMP-2和MMP-9的活性明顯降低，說明CDH17表達上調(diào)可增強MMP-2和MMP-9的活性，導(dǎo)致細胞外基質(zhì)的降解和重塑，利于腫瘤細胞的轉(zhuǎn)移 [17]。另有報道，CDH17通過整合Ras/Raf/MEK/ERK信號通路，在胃癌細胞的增殖和腫瘤的生長中發(fā)揮重要作用（圖3） [29]。在肝癌中，敲低CDH17表達，導(dǎo)致Wnt/β-catenin信號通路失活，腫瘤生長受到抑制，因此推測靶向CDH17可滅活Wnt信號通路并激活抑癌基因，促進腫瘤細胞的凋亡 [30]。
圖3. CDH17介導(dǎo)Ras/Raf/MEK/ERK信號通路 [29]
3. CDH17在癌癥治療中的作用
CDH17作為新型鈣黏蛋白，在細胞粘附、細胞識別、組織器官的發(fā)育和形態(tài)的維持等方面發(fā)揮重要作用。細胞間的粘附及運動能力的失調(diào)是腫瘤發(fā)生發(fā)展的重要機制之一。近年來有關(guān)于CDH17與腫瘤關(guān)系的靶向研究越來越多，主要見于胃癌、肝癌、結(jié)腸癌及胰腺癌等胃腸道惡性腫瘤。
3.1 CDH17和胃癌
CDH17最早被發(fā)現(xiàn)在胃癌中過度表達。臨床研究中，對71例胃癌患者的癌組織和正常胃組織進行半定量PCR、免疫組化及Western blot分析發(fā)現(xiàn)CDH17的表達水平與胃癌的組織學(xué)類型、腫瘤侵襲和淋巴結(jié)轉(zhuǎn)移均呈正相關(guān)。在CDH17過表達的BGC-823細胞株中，胃腺癌的增殖、侵襲及遷移能力增強。RNA干擾CDH17表達，發(fā)現(xiàn)下調(diào)CDH17能夠抑制MKN-45胃癌細胞的增殖、粘附和侵襲能力，同時NF-κB信號轉(zhuǎn)導(dǎo)通路被抑制、其下游蛋白（VEGF-C和MMP-9）減少 [31-33]。
3.2 CDH17和肝癌
研究表明CDH17與肝癌發(fā)生也有一定的關(guān)系。采用RT-PCR方法對57例肝癌組織及正常肝組織進行分析，結(jié)果顯示CDH17在肝癌組織中的陽性表達率顯著高于正常肝組織，說明CDH17與肝癌的發(fā)生有關(guān)，提示CDH17可能作為早期診斷肝癌的腫瘤標志物 [34]。對34例肝內(nèi)膽管癌研究發(fā)現(xiàn)CDH17表達與腫瘤的分化程度和血管侵犯有關(guān)，敲除CDH17，發(fā)現(xiàn)CDH17表達下調(diào)，促進血管生成有關(guān)的MTF-1和胎盤生長因子PLGF的表達，進而誘導(dǎo)腫瘤血管生成 [11, 35]。另有研究發(fā)現(xiàn)CDH17的剪接異構(gòu)體和基因多態(tài)性增加正常人群肝癌的發(fā)生風(fēng)險 [26]。
3.3 CDH17和結(jié)腸癌
一項對45例結(jié)腸癌標本的研究發(fā)現(xiàn)，CDH17的表達下調(diào)與結(jié)腸癌的進展及淋巴結(jié)轉(zhuǎn)移有顯著關(guān)系。下調(diào)結(jié)腸癌細胞中CDH17基因的表達水平，可以抑制結(jié)腸癌細胞的侵襲和轉(zhuǎn)移過程。對原發(fā)部位的結(jié)腸癌組織和其轉(zhuǎn)移部位的癌組織中CDH17表達進行比較，發(fā)現(xiàn)二者之間的表達一致。因此，CDH17有望成為結(jié)腸癌轉(zhuǎn)移檢測的標志物 [22, 36]。
3.4 CDH17和食管癌
有研究分析食管癌組織中CDH17的表達情況與食管癌患者臨床特征的關(guān)系，發(fā)現(xiàn)在分化良好的食管癌組織中有較高的CDH17免疫反應(yīng)，而低分化的食管腺癌組織中CDH17的表達水平較低或表達不明顯，證明食管腺癌的CDH17免疫反應(yīng)與患者的臨床特征具有一定的關(guān)系 [37]。在食管鱗狀細胞癌ESCC中，CDH17 CpG 島甲基化狀態(tài)增強，CDH17表達水平降低，CDH17 CpG 島的甲基化狀態(tài)與CDH17的表達呈負相關(guān) [38-39]。因此，CDH17可成為食管癌治療的新靶點。
3.5 CDH17和胰腺癌
一項對胰腺導(dǎo)管癌患者CDH17表達情況的研究發(fā)現(xiàn)，高分化癌中CDH17表達高于低分化癌者，Kaplan-Meier曲線分析表明CDH17高表達與患者預(yù)后生存有關(guān) [40]。低CDH17表達與腫瘤去分化相關(guān)，由于相關(guān)研究甚少，因而CDH17與胰腺癌臨床病理特征及預(yù)后之間的關(guān)系還有待進一步探討。
3.6 CDH17和其它癌癥
對CDH17與卵巢上皮癌關(guān)系的研究發(fā)現(xiàn)，CDH17在低分化、高分期的腫瘤中高表達 [41]。單變量分析表明，CDH17高表達與預(yù)后不良有關(guān)。在導(dǎo)管內(nèi)乳頭狀粘液性腫瘤（IPMN）中，CDH17誘導(dǎo)IPMN的腸型分化及癌變，隨著IPMN級別的增高，CDH17與之呈正相關(guān) [42]。總而言之，陸續(xù)的研究提示CDH17可能成為胃癌、肝癌和結(jié)直腸癌等惡性腫瘤診斷和預(yù)后的標志物，監(jiān)測腫瘤的進展及復(fù)發(fā)。
4. CDH17的臨床研究前景
目前已有多款基于CDH17的臨床藥物在研（表1），主要用于胃腸道腫瘤治療。其中，3款為雙特異性抗體：ARB-202（CDH17 x CD3），ARB-001.T（CDH17 x CD3），BI-905711（CDH17 x DR5/TRAIL-R2）；1款CAR-T藥物CHM-2101；2款單抗。晚期消化道惡性腫瘤的治療，往往是以化療為基礎(chǔ)的單藥或聯(lián)合治療方案，雖然化療藥物及聯(lián)合治療策略迭代更新，但療效始終未能獲得突破性進展。腫瘤靶向免疫治療提供了全新高效、安全、低毒的治療策略，有望改變目前困境。現(xiàn)有研究成果已表明，靶向干擾CDH17可以抑制腫瘤生長。因此，CDH17作為新發(fā)現(xiàn)的肝腸鈣黏蛋白，正成為胃腸道腫瘤靶向治療的熱門靶點！
| 藥物 | 靶點 | 作用機制 | 藥物類型 | 在研適應(yīng)癥 | 在研機構(gòu) | 最高研發(fā)狀態(tài) |
|---|---|---|---|---|---|---|
| ARB-202 | CDH17；CD3 | 免疫調(diào)節(jié)劑； CDH17調(diào)節(jié)劑；CD3調(diào)節(jié)劑 |
雙特異性抗體 | 膽管癌； 結(jié)直腸癌； 胃腸道腫瘤；胃癌；膽道腫瘤；胰腺癌；肝癌；胰腺腺泡癌 |
Arbele | 臨床1期 |
| BI-905711 | DR5；CDH17 | DR5激動劑； CDH17調(diào)節(jié)劑 |
雙特異性抗體 | 彌漫性大B細胞淋巴瘤； 胃癌； 膽管癌；胃腸道腫瘤；胰腺癌；食管癌；膽管癌 |
C.H. Boehringer Sohn AG & Co. KG；勃林格殷格翰（中國）投資有限公司 Boehringer Ingelheim (China) Investment Co., Ltd.；勃林格殷格翰 Boehringer Ingelheim GmbH |
臨床1期 |
| Anti-CDH17 mAbs (ProAlt) | CDH17 | CDH17調(diào)節(jié)劑 | 單克隆抗體 | 轉(zhuǎn)移性結(jié)直腸癌；轉(zhuǎn)移性黑色素瘤 | 普羅克拉拉生物科學(xué)股份有限公司 Proclara Biosciences, Inc. |
臨床前 |
| ARB-001.M | CDH17 | CDH17拮抗劑 | 雙特異性抗體 | 胃腸道腫瘤 | Arbele | 臨床前 |
| ARB-001.T | CD3；CDH17 | CDH17調(diào)節(jié)劑 | 雙特異性抗體 | 結(jié)直腸癌；肝癌； 胃癌 |
Arbele | 臨床前 |
| ARB-201 | CDH17 | CDH17拮抗劑；CD3抑制劑 | 雙特異性抗體 | 結(jié)直腸癌 | Arbele | 臨床前 |
| CHM-2101 | CDH17 | CDH17調(diào)節(jié)劑；基因轉(zhuǎn)移 | CAR-T | 結(jié)直腸癌； 胃腸道腫瘤； 神經(jīng)內(nèi)分泌腫瘤 |
/ | 臨床前 |
| CHM-2301 | CDH17 | CDH17調(diào)節(jié)劑 | CAR-NK | 實體瘤 | / | 臨床前 |
| Anti-CDH17-based antibody drug conjugates(ProAlt) | CDH17 | CDH17調(diào)節(jié)劑 | ADC；單克隆抗體 | 結(jié)直腸癌 | Protein Alternatives SL | 藥物發(fā)現(xiàn) |
表1：CDH17的臨床藥物在研
為鼎力協(xié)助各藥企針對CDH17在胃腸道腫瘤等其它腫瘤在臨床中的研究，CUSABIO推出CDH17活性蛋白產(chǎn)品，（Code：CSB-MP613267HU），助力您在CDH17機制方面的研究或其潛在臨床價值的探索。
● CDH17重組蛋白
Recombinant Human Cadherin-17 (CDH17), partial (Active); CSB-MP613267HU
Recombinant Human Cadherin-1(CDH1),partial (Active); CSB-MP005034HU1
Recombinant Macaca fascicularis Cadherin 17 (CDH17), partial (Active); CSB-MP4664MOV
Recombinant Rat Cadherin-17 (Cdh17), partial (Active); CSB-MP005042RA
● CDH17抗體
CDH17 Recombinant Monoclonal Antibody; CSB-RA613267MA3HU
CDH17 Recombinant Monoclonal Antibody; CSB-RA613267MA1HU
● CDH17 穩(wěn)轉(zhuǎn)細胞株
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