DLL3靶點新突破：再鼎醫(yī)藥公布ZL-1310早期臨床數(shù)據(jù)！
日期：2024-10-29 14:53:00
DLL3（Delta樣配體-3）作為腫瘤治療中的新興靶點，近年來在小細(xì)胞肺癌（SCLC）和神經(jīng)內(nèi)分泌腫瘤等領(lǐng)域的研究中備受關(guān)注。其在腫瘤細(xì)胞中的過度表達(dá)和選擇性表達(dá)特性，使其成為理想的治療靶點。近期，國內(nèi)外藥企紛紛加速布局DLL3靶點藥物的研發(fā)，尤其是抗體藥物偶聯(lián)物（ADC）領(lǐng)域，多筆重磅交易的達(dá)成更是將DLL3推向了市場的聚光燈下。2025年元旦前后，信達(dá)與羅氏、恒瑞與IDEAYA Biosciences就進(jìn)行了兩筆授權(quán)重磅交易。其中信達(dá)生物與羅氏的潛在交易總金額超過10億美元、恒瑞醫(yī)藥與IDEAYA Biosciences的潛在交易總金額達(dá)10.45億美元。
1、DLL3的結(jié)構(gòu)和功能是什么？
δ樣配體（Delta-Like Ligand 3，DLL3）為一種附著在細(xì)胞表面的單次跨膜蛋白，屬于Notch配體家族中的一員。人DLL3基因定位于染色體19q13，其開放閱讀框長度約為1800 bp [3]。人DLL3蛋白由619個氨基酸組成，完整結(jié)構(gòu)包含1個DSL結(jié)構(gòu)域、1個胞內(nèi)結(jié)構(gòu)域和6個表皮生長因子樣結(jié)構(gòu)域 （圖1）[4, 5]。胞外結(jié)構(gòu)域N端的DSL基因序列在配體家族中高度保守，是與Notch受體結(jié)合所必須的功能結(jié)構(gòu)域。DLL3胞內(nèi)結(jié)構(gòu)域較短，其功能尚不清楚。研究發(fā)現(xiàn)DLL3在SCLC和其他神經(jīng)內(nèi)分泌腫瘤中高表達(dá)，而在正常組織中很少表達(dá)，這為靶向治療提供了潛力 [6]。近年來，越來越多的研究提示，DLL3可與不同的Notch受體結(jié)合，參與到復(fù)雜的腫瘤調(diào)控過程中，既可表現(xiàn)出促癌作用，也可表現(xiàn)出抑癌作用。
圖1. DLL3結(jié)構(gòu)示意圖
*圖片來源于Frontiers in immunology 出版物 [4]
2、配體DLL3的受體有哪些？
配體DLL3通過與Notch受體結(jié)合，直接或間接地發(fā)揮作用生物學(xué)功能。Notch受體有4種（Notch 1-4），為一類保守的單次跨膜蛋白，受體分子量約為300 kDa [7]。Notch受體含胞外區(qū)、跨膜區(qū)和胞內(nèi)區(qū)3部分。如圖2所示，其Notch受體的胞外段（N端）由數(shù)量不等的EGF樣重復(fù)片段和一個近膜區(qū)的負(fù)向調(diào)節(jié)區(qū)域（NRR）構(gòu)成，而NRR是由3個Lin12/Notch重復(fù)片段（LNR）和1個異二聚化區(qū)域（HD）組成；胞內(nèi)段通常包含一段蛋白結(jié)合RPBJ相關(guān)分子（RAM）區(qū)域、7個錨蛋白重復(fù)片段、1個轉(zhuǎn)錄激活區(qū)域（TAD）和1個PEST（富含脯氨酸、谷氨酸、絲氨酸和蘇氨酸）降解決定子區(qū)域 [4]。
圖2. 受體Notch1-4結(jié)構(gòu)
*圖片來源于Frontiers in immunology 出版物 [4]
不同于Notch其它配體，目前的研究表明DLL3是一種抑制性Notch配體。配體DLL3和Notch受體結(jié)合，具有Notch通路的抑制作用 [8]。在SCLC中，促進(jìn)DLL3表達(dá)，DLL3與Notch1受體結(jié)合，將抑制Notch信號活化，Notch信號靶基因HES1、HEY1的表達(dá)下調(diào)，對腫瘤的抑制解除，促進(jìn)SCLC的發(fā)生發(fā)展 [9]；DLL3/Notch2可以增加細(xì)胞周期蛋白CyclinD1和CyclinD3的表達(dá)，提示DLL3/Notch2可能通過上調(diào)CyclinD1和CyclinD3蛋白促進(jìn)SCLC細(xì)胞的增殖 [10]。此外DLL3和Notch受體結(jié)合還與其它腫瘤密切相關(guān)，比如，DLL3/Notch2參與垂體腺瘤的增殖和侵襲的調(diào)節(jié) [11]；DLL3/Notch2/Notch4對黑色素瘤細(xì)胞生存和生長至關(guān)重要 [12]；DLL3/Notch2/Notch3介導(dǎo)了卵巢癌細(xì)胞的增殖和分化，并且與較差的生存期相關(guān) [13]。總體而言，DLL3可與不同的Notch受體結(jié)合，在細(xì)胞增殖、分化及凋亡中發(fā)揮著多種功能，然而其涉及的細(xì)胞分子機(jī)制仍未具體闡明。
3、DLL3相關(guān)的信號通路有哪些？
前文提到，DLL3是一種抑制性Notch配體，大量研究發(fā)現(xiàn)，配體DLL3通過和Notch受體結(jié)合，抑制Notch信號，影響相鄰細(xì)胞之間的通訊，進(jìn)而調(diào)控細(xì)胞發(fā)育，其具體機(jī)制尚不明確。除了Notch信號通路，DLL3也在其他信號通路中發(fā)揮作用，DLL3通過抑制Notch信號通路，激活脂酰肌醇-3-激酶/絲氨酸-蘇氨酸蛋白激B（phosphoinositol-3-kinase/serine-threonine protein kinase B，P13K/Akt）信號傳導(dǎo)通路。DLL3表達(dá)上調(diào)時，配體Wnt-1和Wnt-4以及Wnt通路的下游靶基因Axin-2和Lef-1表達(dá)上調(diào)，提示DLL3參與誘導(dǎo)Wnt信號途徑的激活。此外，還有研究證實DLL3通過調(diào)節(jié)Nrarp的循環(huán)表達(dá)來調(diào)節(jié)Notch/Wnt信號通路 [14]。
由此可見，DLL3參與到多個信號通路中的調(diào)節(jié)過程，涉及一系列基因的激活、表達(dá)以及調(diào)控等作用。在腫瘤的發(fā)生發(fā)展中，DLL3發(fā)揮著促癌或抑癌的雙向調(diào)節(jié)功能。因此，進(jìn)一步研究DLL3在各腫瘤中的表達(dá)和作用機(jī)制，將對腫瘤的發(fā)病機(jī)制、治療和預(yù)防等具有重要的意義。
4、DLL3在腫瘤疾病中的作用
根據(jù)腫瘤類型和細(xì)胞生長環(huán)境的不同，DLL3的激活可以發(fā)揮促癌或抑癌作用。有報道，DLL3在小細(xì)胞肺癌 [15, 16]、乳腺癌 [17]、垂體瘤 [11]、急性髓系白血病 [18]中有促癌作用，但在肝癌 [19]、神經(jīng)膠質(zhì)瘤 [20]和惡性膠質(zhì)瘤 [21]中卻發(fā)揮了抑癌作用。
在小細(xì)胞肺癌中，DLL3在超過80%患者中高表達(dá)，并且在腫瘤的細(xì)胞膜和細(xì)胞質(zhì)中都高表達(dá)；但是，在正常組織中少量表達(dá)或不表達(dá)。臨床研究表明，SCLC中的DLL3高表達(dá)與患者的生存期呈現(xiàn)負(fù)相關(guān)，即DLL3表達(dá)量越高，患者的生存期越低 [22]。
在原發(fā)性肝癌中，有研究提示，DLL3的表達(dá)被乙肝病毒誘導(dǎo)的DNA甲基化和組蛋白乙酰化所抑制。抑制組蛋白去乙酰化酶的抑制劑可以使DLL3在HCC中重新表達(dá)。重表達(dá)的DLL3可以抑制HCC細(xì)胞的生長并誘導(dǎo)細(xì)胞凋亡。因此，在原發(fā)性肝癌中，DLL3可以抑制癌細(xì)胞的生長 [23]。
更多研究顯示DLL3在多種癌癥中異常表達(dá)，發(fā)揮不同作用。比如，DLL3在異檸檬酸脫氫酶IDH突變的神經(jīng)膠質(zhì)瘤細(xì)胞中表達(dá)，特別是在1p/19q缺失的神經(jīng)膠質(zhì)瘤細(xì)胞中高表達(dá) [24, 25]；在胰腺癌中，激活的DLL3可以刺激Notch信號從而促進(jìn)癌細(xì)胞的生長 [26]；在黑色素瘤中，DLL3/MAPK通路可以促進(jìn)黑色素瘤細(xì)胞的增殖和遷移 [27, 28]；在子宮內(nèi)膜瘤中，高表達(dá)的DLL3與較差的生存期和較差的無進(jìn)展生存期相關(guān) [29]。
5、靶向DLL3的研發(fā)藥物及臨床意義
隨著DLL3 ADC臨床研究的不斷推進(jìn)和積極數(shù)據(jù)的不斷涌現(xiàn)，該領(lǐng)域的競爭愈發(fā)激烈。中國藥企在這一賽道上的表現(xiàn)尤為引人注目，再鼎醫(yī)藥的ZL-1310等藥物在臨床試驗中展現(xiàn)出優(yōu)異的療效和安全性，有望在國際市場中占據(jù)重要地位。未來，隨著更多創(chuàng)新藥物的不斷涌現(xiàn)，DLL3靶點有望為腫瘤患者帶來更多的治療選擇和希望。
6、DLL3科研產(chǎn)品服務(wù)
為鼎力協(xié)助各藥企針對DLL3靶點在腫瘤中的研發(fā)工作，尤其是在小細(xì)胞肺癌SCLC中，大量的基礎(chǔ)研究和臨床研究證據(jù)表明DLL3是治療SCLC的一種極具潛力的干預(yù)靶點，CUSABIO已推出DLL3系列產(chǎn)品，種屬多樣、標(biāo)簽多樣，能夠充分滿足不同種屬交叉實驗及各類實驗需求，為科研人員提供優(yōu)質(zhì)的產(chǎn)品，助力生命科學(xué)領(lǐng)域的研究與發(fā)展。
DLL3蛋白
Purity ≥ 95% validated by SDS-PAGE
Activity validated by Functional ELISA: Measured by its binding ability in a functional ELISA. Immobilized Human DLL3 at 2 μg/ml can bind Anti-DLL3 recombinant antibody (CSB-RA882142MA2HU). The EC50 is 1.107-1.282 ng/mL.
● Recombinant Human Delta-like protein 3 (DLL3), partial (Active),Fc-tagged (Code: CSB-MP882142HU2)
Purity ≥ 95% validated by SDS-PAGE
Activity validated by Functional ELISA: Measured by its binding ability in a functional ELISA. Immobilized Human DLL3 at 1 μg/ml can bind Anti-DLL3 recombinant antibody (CSB-RA882142MA2HU). The EC50 is 6.211-7.209 ng/mL.
Purity ≥ 85% validated by SDS-PAGE
Activity validated by Functional ELISA: Measured by its binding ability in a functional ELISA. Immobilized DLL3 at 2 μg/ml can bind Anti-DLL3 Recombinant Antibody (CSB-RA882142A1HU). The EC50 is 1.625-2.702 ng/mL.
參考文獻(xiàn)：
[1] https://xueqiu.com/4797094524/309486542
[2] https://www.163.com/dy/article/JDVKQLMO0552Q7S2.html?spss=dy_author
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