ENPP3（CD203c）：ENPPs核苷酸代謝胞外酶，能量代謝調(diào)控者、變態(tài)反應(yīng)標(biāo)記物、腎癌RCC治療在研靶點(diǎn)！
日期：2023-09-20 13:54:04
最近，美國(guó)Xencor公司推出臨床藥物AGS-16M8F12（ENPP3 x CD3），一款針對(duì)ENPP3的雙特異性抗體藥物，旨在評(píng)估其在轉(zhuǎn)移性腎細(xì)胞癌（RCC）患者中的安全性、藥代動(dòng)力學(xué)和推薦劑量。膜外核苷酸焦磷酸酯酶/磷酸二酯酶（ENPPs）家族是近年備受研究者關(guān)注的一類胞外酶。ENPP1已有廣泛文獻(xiàn)和臨床研究，相比之下，ENPP3的國(guó)內(nèi)外研究報(bào)道較為有限。然而，陸續(xù)的研究成果逐漸揭示ENPP3在能量代謝和變態(tài)反應(yīng)等生理過(guò)程中具有重要作用。特別是在腫瘤治療領(lǐng)域，靶向ENPP3已展現(xiàn)出巨大潛力。因此，深入研究ENPP3可能揭示新的生理機(jī)制，為相關(guān)疾病的診斷和治療提供創(chuàng)新性方法！
1. 什么是膜外核苷酸焦磷酸酯酶/磷酸二酯酶家族（ENPPs）?
膜外核苷酸焦磷酸酯酶/磷酸二酯酶家族（Ecto-nucleotide pyrophosphatase/phosphodiesterase, E-NPPs/ENPPs）是一組在哺乳動(dòng)物體內(nèi)具有相似結(jié)構(gòu)的膜蛋白。目前共發(fā)現(xiàn)該家族的7個(gè)成員（ENPP1~ENPP7）。該家族名稱的由來(lái)是因?yàn)樽畛醢l(fā)現(xiàn)的ENPP1、ENPP2、ENPP3均具有水解核苷酸及其衍生物的焦磷酸酯鍵/磷酸二酯鍵的活性。而進(jìn)一步的研究表明，ENPPs的一些成員還具有重要的磷脂酶活性。ENPP4、ENPP5、ENPP6則是在大規(guī)模測(cè)序時(shí)發(fā)現(xiàn)的未知功能蛋白，根據(jù)其與ENPPs的結(jié)構(gòu)同源性而將其列入該家族。近幾年來(lái)，有關(guān)ENPPs在多種生理病理過(guò)程中復(fù)雜機(jī)制的研究已取得很大進(jìn)展，它們參與的很多病理過(guò)程與其胞外作用有關(guān)，這使得它們成為治療相關(guān)疾病的潛在靶標(biāo) [1-3]。
2. 什么是ENPP3?
2.1 ENPP3的結(jié)構(gòu)
ENPP3（又名CD203c或NPP3）屬于膜外核苷酸焦磷酸酯酶/磷酸二酯酶家族蛋白成員（ENPPs）。ENPP3最初被命名為Gp130RB13-6，它可以識(shí)別一類中度表達(dá)的酸性神經(jīng)膠質(zhì)纖維蛋白亞類，這類蛋白通常存在于大鼠神經(jīng)膠質(zhì)母細(xì)胞中。ENPP3基因位于人類染色體6q23.2-q23.3區(qū)域。ENPPs的氨基酸序列具有較高的同源性，目前研究較為清楚的NPP1、NPP2、NPP3屬于一個(gè)亞家族，它們是Ⅱ型膜蛋白，這3個(gè)成員均含有一個(gè)短的細(xì)胞內(nèi)N端、單一的穿膜區(qū)和1個(gè)較長(zhǎng)的胞外區(qū)，胞外區(qū)包含有2個(gè)生長(zhǎng)調(diào)節(jié)素B樣結(jié)構(gòu)域、1個(gè)保守的磷酸二酯酶樣催化結(jié)構(gòu)域、1個(gè)核酸酶樣序列和1個(gè)EF-手象的Ca2+結(jié)合模體 （圖1）[5-6]。
2.2 ENPP3的表達(dá)和功能
ENPP3在人體的前列腺、子宮、結(jié)腸、嗜堿性粒細(xì)胞、肥大細(xì)胞、祖細(xì)胞，以及某些腫瘤中表達(dá)。雖然在人的肝臟、胰腺和腸道中未檢測(cè)到ENPP3的表達(dá)，但在大鼠的這些組織中均已發(fā)現(xiàn)。ENPPs這些酶的核苷酸底物可以觸發(fā)P2X離子通道受體/P2X嘌呤受體（如P2RX1、P2RX2、P2RX3、P2RX4、P2RX5、P2RX6、P2RX7）和某些G蛋白偶聯(lián)受體/P2Y嘌呤受體（如P2RY1、P2RY2、P2RY3、P2RY4、P2RY5、P2RY6、P2RY7、P2RY8, etc.）。這些P2X和P2Y受體家族在許多生理和病理過(guò)程中發(fā)揮關(guān)鍵作用 [7-10]。
ENPP3作為調(diào)節(jié)嘌呤代謝的胞外酶，其關(guān)鍵功能之一是抑制肥大細(xì)胞和嗜堿性粒細(xì)胞在慢性炎癥和過(guò)敏反應(yīng)中的活性。值得注意的是，也有研究認(rèn)為ENPP3與人類多種癌癥的發(fā)病可能存在關(guān)聯(lián)，尤其是腎細(xì)胞癌。盡管在國(guó)內(nèi)報(bào)道非常少，但國(guó)外的研究陸續(xù)證明ENPP3與過(guò)敏反應(yīng)和腫瘤的發(fā)生發(fā)展密切相關(guān)。因此，ENPP3有望成為多種過(guò)敏反應(yīng)的診斷標(biāo)志物或腫瘤治療的重要靶點(diǎn) [7-10]！
圖1. ENPP3的結(jié)構(gòu) [6]
3. ENPP3相關(guān)的信號(hào)機(jī)制
3.1 ENPP3在能量代謝中的機(jī)制
ENPPs作為一種能夠水解細(xì)胞外核苷酸的酶，在能量代謝和細(xì)胞外信號(hào)傳導(dǎo)方面扮演著重要的角色。一項(xiàng)研究通過(guò)動(dòng)力學(xué)分析揭示了ENPP3抑制GnT-IX（GnT-Vb）的機(jī)制。GnT-IX是一種糖基轉(zhuǎn)移酶，在糖基化（glycosylation）過(guò)程中發(fā)揮重要作用。GnT-IX（GnT-Vb）酶在進(jìn)行糖基化反應(yīng)時(shí)需要使用UDP-GlcNAc這個(gè)底物。UDP-GlcNAc提供了所需的糖分子GlcNAc，這些分子將被GnT-IX（GnT-Vb）酶轉(zhuǎn)移到其他分子上，形成復(fù)雜的糖鏈結(jié)構(gòu)，從而影響蛋白質(zhì)穩(wěn)定性、細(xì)胞識(shí)別、信號(hào)傳導(dǎo)和細(xì)胞黏附等多個(gè)生物學(xué)過(guò)程 [12]。
然而，在研究中發(fā)現(xiàn)，ENPP3酶可將UDP-GlcNAc分解為UMP（尿苷酸單磷酸）。當(dāng)UMP與UDP-GlcNAc競(jìng)爭(zhēng)性結(jié)合GnT-IX（GnT-Vb）時(shí)，UMP會(huì)占據(jù)GnT-IX（GnT-Vb）酶需要使用的底物位置。這意味著，GnT-IX（GnT-Vb）不再能夠有效地與UDP-GlcNAc結(jié)合。因此，ENPP3通過(guò)分解UDP-GlcNAc，使得GnT-IX（GnT-Vb）酶的活性降低 （圖2） [12]。
圖2. ENPP3介導(dǎo)的UDP-GlcNAc水解 [12]
3.2 ENPP3在變態(tài)反應(yīng)中的機(jī)制
FcεRI（IgE Fc受體，F(xiàn)c epsilon receptor I）是一種免疫受體，主要功能是介導(dǎo)變態(tài)反應(yīng)。FcεRI與免疫球蛋白E（IgE）分子相互作用，并在特定類型的免疫細(xì)胞上表達(dá)，主要包括嗜堿性粒細(xì)胞（basophils）和肥大細(xì)胞（mast cells） [13]。當(dāng)FcεRI交聯(lián)可引發(fā)即時(shí)或慢性過(guò)敏性炎癥，然而其具體機(jī)制仍然不清楚。
有關(guān)研究發(fā)現(xiàn)，F(xiàn)cεRI交聯(lián)引發(fā)的ENPP3表達(dá)在慢性過(guò)敏性炎癥中起關(guān)鍵作用。在ENPP3基因缺陷小鼠中，嗜堿性粒細(xì)胞和肥大細(xì)胞增多，血液中的三磷酸腺苷（ATP，Adenosine Triphosphate）濃度增高，使得它們更容易患慢性過(guò)敏性疾病。此外，F(xiàn)cεRI交聯(lián)會(huì)導(dǎo)致這些細(xì)胞釋放ATP，但在ENPP3−/−的細(xì)胞中，ATP清除能力減弱，導(dǎo)致ATP在細(xì)胞內(nèi)積聚，觸發(fā)過(guò)敏性炎癥。因此，ENPP3可以減少ATP濃度并降低嗜堿性粒細(xì)胞和肥大細(xì)胞的活性，以抑制過(guò)敏性炎癥（圖3） [14]。
圖3. ENPP3抑制依賴于ATP的過(guò)敏性炎癥 [14]
4. ENPP3在各種過(guò)敏和腫瘤等疾病中的作用
4.1 ENPP3與過(guò)敏
4.1.1 嗜堿粒細(xì)胞ENPP3與過(guò)敏
嗜堿粒細(xì)胞和肥大細(xì)胞是參與變態(tài)反應(yīng)的重要細(xì)胞。由于肥大細(xì)胞存在于組織中，而嗜堿粒細(xì)胞存在于血液循環(huán)中，因此，嗜堿粒細(xì)胞成為近年體外研究變態(tài)反應(yīng)的突破點(diǎn)。CD63和ENPP3（CD203c）是目前發(fā)現(xiàn)嗜堿性粒細(xì)胞靈敏度和特異性最高的表面活化標(biāo)記物 [15-16]。
研究發(fā)現(xiàn)，激活狀態(tài)下，嗜堿粒細(xì)胞的ENPP3（CD203c）表達(dá)明顯上升，其診斷特異度和靈敏度高于CD63。過(guò)敏性哮喘患者在粉塵螨刺激后，嗜堿粒細(xì)胞的CD203c和CD63熒光強(qiáng)度顯著增加 [17]；在乳膠和昆蟲(chóng)毒液過(guò)敏的診斷中，檢測(cè)CD203c與CD63同樣可靠，但對(duì)于蜜蜂和黃蜂過(guò)敏患者，CD203c的靈敏度更高 [18-20]；堅(jiān)果過(guò)敏患者接受奧馬珠單抗（Omalizumab）治療后，嗜堿粒細(xì)胞的CD203c表達(dá)水平降低，表明奧馬珠通過(guò)阻斷IgE與嗜堿性粒細(xì)胞表面受體（FcεRI）結(jié)合來(lái)抑制嗜堿性粒細(xì)胞的活化 [21]。
另有研究發(fā)現(xiàn)，通過(guò)使用CRTH2-FlTC、CD203c-PE和CD3-Per-CP這三種抗體，可以檢測(cè)嗜堿粒細(xì)胞表面的ENPP3（CD203c）表達(dá)水平，從而判斷蕁麻疹患者的血清是否能激活嗜堿粒細(xì)胞 [22]。蕁麻疹患者的血液中存在自身抗體，導(dǎo)致組胺釋放活性增加，其中大多數(shù)抗體是針對(duì)高親和力IgE受體（FceRl）的自身抗體，也有少數(shù)是針對(duì)IgE或其他抗體的。這些研究有助于我們了解慢性蕁麻疹的發(fā)病機(jī)制。總的來(lái)說(shuō)，ENPP3（CD203c）在不同過(guò)敏性疾病的診斷和治療中具有重要的潛力。
4.1.2 肥大細(xì)胞ENPP3與過(guò)敏
肥大細(xì)胞表達(dá)ENPP3（CD203c）分子，這一發(fā)現(xiàn)較晚引起關(guān)注。相關(guān)研究揭示，人臍帶血來(lái)源的CD34+造血干細(xì)胞培養(yǎng)的肥大細(xì)胞和人胃腸道中的肥大細(xì)胞都有ENPP3（CD203c） [23-24]。此外，肥大細(xì)胞增多癥患者的肥大細(xì)胞，CD203c表達(dá)上調(diào) [23-24]。因此，ENPP3（CD203c）可能是診斷肥大細(xì)胞相關(guān)疾病的標(biāo)志物。
相關(guān)研究還發(fā)現(xiàn)，抗腫瘤藥物米哚妥林（Midostaurin）能夠抑制人臍帶血來(lái)源的肥大細(xì)胞和人血液中嗜堿性粒細(xì)胞釋放介質(zhì)，但不能抑制嗜堿性粒細(xì)胞上IgE依賴的ENPP3（CD203c）上調(diào)。此外，IgE交聯(lián)會(huì)使肥大細(xì)胞增多癥患者的肥大細(xì)胞CD203e上調(diào)，但不影響干細(xì)胞因子（SCF）水平 [25-27]。此外，一氧化碳釋放分子CORM-3有強(qiáng)大的抗炎作用，但也會(huì)促進(jìn)肥大細(xì)胞組胺釋放和ENPP3（CD203c）表達(dá) [28-29]。
4.2 ENPP3與腫瘤
ENPP3被認(rèn)為是一種腫瘤標(biāo)志物，尤其在腎細(xì)胞癌（RCC）領(lǐng)域得到較多關(guān)注。在RCC中，ENPP3的表達(dá)明顯升高，使其成為新型抗體藥物偶聯(lián)物（ADC）的潛在治療靶標(biāo)。這些ADC藥物研究包括AGS-16M8F和AGS-16C3F，它們結(jié)合了抗ENPP3抗體和毒性有效成分MMAF，能夠特異性地識(shí)別和摧毀RCC細(xì)胞，同時(shí)表現(xiàn)出持久的抗腫瘤活性和可控的不良反應(yīng)。因此，探索新一代抗ENPP3抗體ADC藥物，可能為治療轉(zhuǎn)移性腎細(xì)胞癌提供新的治療途徑 [30]。
在卵巢癌中，有研究提示，卵巢子宮內(nèi)膜異位瘤中胞外酶ADA、ALP、ENPP1和ENPP3可作為子宮內(nèi)膜異位癥的候選生物標(biāo)志物 [31]。在結(jié)腸癌細(xì)胞中，ENPP3高表達(dá)，且與腫瘤細(xì)胞的發(fā)生和轉(zhuǎn)移有關(guān) [32-33]。雖然ENPP3在多種癌癥中起著重要作用，但關(guān)于抑制ENPP3的藥物研究很有限。現(xiàn)有的抑制劑大多是核苷酸衍生物，但它們?cè)谌梭w內(nèi)的表現(xiàn)不符合藥物應(yīng)有的性質(zhì)（如吸收、分布和排泄），因?yàn)樗鼈兛梢栽隗w內(nèi)分解并產(chǎn)生一些可能對(duì)嘌呤受體產(chǎn)生影響的代謝產(chǎn)物，而不是如預(yù)期般有效地抑制ENPP3酶的活性。因此，需要進(jìn)一步研究ENPP3在腫瘤中的機(jī)制，以尋找更有效的抑制劑 [34-35]。
4.3 ENPP3與其它疾病
ENPPs異常表達(dá)可能導(dǎo)致骨質(zhì)礦化異常以及其他代謝性疾病的發(fā)生。例如，增加1,25（OH）2D水平可能通過(guò)維生素D受體（Vitamin D Receptor，VDR）在成熟成骨細(xì)胞和/或骨細(xì)胞上的作用，提高局部骨質(zhì)礦化抑制因子（如Enpp1、Enpp3和Ank）的水平 [36]；ENPP3和GRIA2之間存在直接的物理相互作用，可能影響血管平滑肌細(xì)胞（Vascular Smooth Muscle Cells，VSMCs）的鈣信號(hào)和MAPK信號(hào)傳遞 [37]。
此外，在皮球囊擴(kuò)張血管成形術(shù)（Percutaneous Transluminal Angioplasty，PTA）術(shù)后的動(dòng)脈中，ENPP3和GRIA2的表達(dá)水平顯著上升，與再狹窄的嚴(yán)重程度相關(guān) [37]。ENPP3還參與調(diào)節(jié)呼吸道上皮的液體平衡，可能在肝臟中調(diào)節(jié)膽汁的形成和腦脊液的分泌。膽汁在肝臟中的形成和排泄對(duì)脂質(zhì)代謝和胰島素敏感性等方面都具有重要影響。因此，針對(duì)ENPP3抑制劑的研發(fā)可能有助于預(yù)防糖尿病 [38]。
5. ENPP3的臨床研究前景
ENPP3是一種廣泛參與核苷酸循環(huán)、磷脂信號(hào)調(diào)控、細(xì)胞運(yùn)動(dòng)和細(xì)胞增殖等多種生理過(guò)程的分子，其在變態(tài)反應(yīng)疾病和腫瘤中的作用和價(jià)值正受到越來(lái)越多的關(guān)注。目前，已有一種靶向ENPP3的ADC抗體藥物AGS-16M8F正在進(jìn)行I期臨床試驗(yàn)，用于治療轉(zhuǎn)移性腎細(xì)胞癌（RCC），目前尚未公布臨床結(jié)果。此外，ENPP3（CD203c）標(biāo)記的嗜堿性粒細(xì)胞激發(fā)試驗(yàn)處于廣泛的臨床驗(yàn)證階段。與CD63一樣，CD203c標(biāo)記的嗜堿性粒細(xì)胞激發(fā)試驗(yàn)或可用于診斷慢性蕁麻疹以及食物過(guò)敏等變態(tài)反應(yīng)疾病。因此，ENPP3在變態(tài)反應(yīng)疾病領(lǐng)域以及腎癌等腫瘤中的研究頗具前景，可能為相關(guān)患者帶來(lái)新的治療選擇和機(jī)會(huì)。
為鼎力協(xié)助科研和藥企人員針對(duì)ENPP3在能量代謝、變態(tài)反應(yīng)、腫瘤相關(guān)疾病中的臨床應(yīng)用研究，CUSABIO推出ENPP3活性蛋白（CSB-MP4278MOV； CSB-MP007681HU），助力您在ENPP3機(jī)制方面的研究或其潛在臨床價(jià)值的探索。
華美CUSABIO ENPP3 蛋白
● Recombinant Macaca fascicularis ENPP3, partial (Active)
The high purity is greater than 95% as determined by SDS-PAGE.
Immobilized Macaca fascicularis ENPP3 at 2 μg/ml can bind Anti-ENPP3 recombinant antibody (CSB-RA007681MA1HU), the EC50 is 3.313-4.724 ng/mL.
● Recombinant Human ENPP3, partial (Active)
The high purity is greater than 95% as determined by SDS-PAGE.
Immobilized Human ENPP3 at 2 μg/ml can bind anti-ENPP3 recombinant antibody (CSB-RA007681MA1HU), the EC50 is 2.151-2.492 ng/mL.
華美CUSABIO ENPP3 抗體
ENPP3 Recombinant Monoclonal Antibody
Untransfected and transfected HEK293T cells were stained with anti-ENPP3 antibody and analyzed using flow cytometry with FITC-labeled anti-Human IgG Fc antibody.
華美CUSABIO ENPP3 穩(wěn)定細(xì)胞系
HEK293T/Human ENPP3 Stable Cell Line
Untransfected and transfected HEK293T cells were stained with anti-ENPP3 antibody and analyzed using flow cytometry with FITC-labeled anti-Human IgG Fc antibody.
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