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敏感性。Sang-Soo Kim团队通过将p53基因表达质粒封装于TFR1单链可变区抗体(TFR1scfv)修饰的脂质体中，构建好的免疫脂质体SGT-53已被证明可以实现脑内递送，有效降低GBM细胞内MGMT的表达。研究表明，SGT-53可以有效克服GBM对TMZ的抗性，SGT-53与TMZ联合给药可以增加GBM对TMZ的敏感性，显著延长GBM模型小鼠的生存期，甚至使肿瘤消退[38] [39]。目前SGT-53和TMZ联合用于治疗GBM的二期临床试验已经结束，不过临床数据尚未公布。M.J. Ramalho等人使用OX26修饰的聚乳酸–乙醇酸共聚物(PLGA)纳米颗粒(NPs)包封TMZ，构建好的TMZ-loaded mAb-PLGA NPs免疫纳米颗粒显著增强TMZ对GBM的细胞毒性，同时OX26的存在降低了TMZ对BBB完整性的损伤[40]。创新型纳米材料的迅速发展，使针对人体深部组织的远程物理刺激成为可能，比如在纳米肿瘤学领域应用的光热、光动力、磁热和机械能电能转换的纳米材料。这些纳米材料已被广泛用于开发治疗肿瘤的新疗法。压电纳米颗粒是一种可以实现机械能和电能相互转换的纳米材料，Attilio Marino等人用TFR1抗体修饰压电纳米材料钛酸钡纳米颗粒(BTNPs)，产生的AbBTNP实现了血脑屏障和脑胶质瘤的双重靶向。实验证明，在外界超声波的机械能激发下，BTNP转化的电能可以对脑胶质瘤增殖产生抑制作用，促进其凋亡。AbBTNP与TMZ联合给药具有协同作用，可以明显增强脑胶质瘤对TMZ的敏感性，体外实验显示出增强的抗肿瘤能力[41]。不可否认，TFR1抗体的存在使得这些药物的脑部生物利用度得到显著提高，显著增加了药物的治疗潜力。随着TFR1抗体转包吞潜力的进一步开发，TFR1介导的转包吞有希望成为药物脑内递送安全可靠的途径。

6. 在脑外肿瘤诊治中的应用

6.1. 在血液恶性肿瘤诊治中的应用

免疫疗法尤其是抗体介导的抗肿瘤疗法在血液恶性肿瘤治疗中的应用越来越广泛，诸如靶向CD38 和SLAMF7的达雷木单抗和埃罗妥珠单抗，均于2015年被FDA批准用于多发性骨髓瘤的治疗。CCR4靶向的mogamulizumab也于2018年被FDA批准用于皮肤T细胞淋巴瘤的治疗中。这些抗体抗肿瘤作用的发挥主要是依靠抗体Fc段的效应功能。虽然我们已经在战胜血液恶性肿瘤的道路上迈出了一大步，但更具治疗潜力靶标抗体的开发依旧是刻不容缓。研究发现，TFR1在多种血液恶性肿瘤中呈现高表达。Manuel L. Penichet等人将hTFR1抗体(ch128.1)应用于恶性B细胞多发性骨髓瘤治疗中，结果显示ch128.1对恶性B细胞多发性骨髓瘤具有异常高的抗肿瘤活性[42] [43]。除此之外，Tracy R. Daniels-Wells等人在B细胞非霍奇金淋巴瘤(AIDS-NHL)异种移植小鼠中也观察到ch128.1显著的抗肿瘤作用[44]。值得注意的是，靶向TFR1所发挥的抗肿瘤作用可以依赖于两个独立机制，一种即为依靠抗体Fc段的效应功能，另一种是由中和作用引起的细胞内铁耗竭效应。这种协同作用被Shunsuke Shimosaki等人印证。研究结果表明，无论是在免疫缺陷或免疫系统健全小鼠体内，TFR1抗体(JST-TFR09)均展现出强烈的抗肿瘤能力，免疫系统健全下肿瘤基本消退。相比而言，mogamulizumab仅在免疫系统健全时对皮肤T细胞淋巴瘤的生长起到温和的抑制作用[45]。TFR1抗体在红白血病的治疗中也展现出很高潜力[9]。这些研究表明TFR1极有希望成为血液恶性肿瘤广谱生物标志物，显示出TFR1抗体在血液恶性肿瘤诊治方面的巨大潜力。

6.2. 在胰腺癌诊治中的应用

胰腺癌侵袭性强，预后差，患者5年生存率不足10%，是全球与癌症相关死亡的第七大主要原因[46]。目前治疗方法依旧是以手术切除治疗为主，但由于胰腺癌早期缺乏典型的临床表现，无特异症状，使得患者确诊时往往已处于晚期，癌细胞已经发生扩散，适合进行手术切除治疗的患者比例少之又少。研究表明，胰腺癌中80%具有KRAS突变，目前设计针对RAS-RAF-MEK-ERK MAPK信号通路及其下游相关信号转导通路的靶向抑制剂有很多已经走向了临床试验，如ERK抑制剂(SCH772984)、MEK抑制剂

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(trametinib)等。MYC处于RAS-RAF-MEK-ERK MAPK信号通路下游，MYC的激活将导致TFR1的表达上调。TFR1有可能成为MAPK信号通路依赖型胰腺癌生物标志物。Kelly E. Henry等人证明了TFR1在评估MARP通路靶向抑制剂胰腺癌治疗响应方面的能力。作者通过对胰腺癌模型小鼠使用TFR1靶向探针进行正电子发射断层扫描(Positron Emission Computed Tomography, PET)成像，成功反映出BRD4、ERK抑制剂胰腺癌治疗响应程度[47]。这些结果表明TFR1靶向探针可以对MARP通路依赖型胰腺癌药物治疗情况进行即时评估，具有指导临床分层加快胰腺癌治疗药物临床试验进程的潜力。针对TFR1开发的67Ga-citrate-Tf放射性探针已被用于评估TFR1表达，但具有更高特异性和更高亲和力的TFR1抗体更能真实反应TFR1的表达和分布情况，这一点已在Aya Sugyo等人做的对比试验中得到证明[48]。Aya Sugyo等人在胰腺癌异种移植小鼠中证实了TFR1抗体对高表达TFR1的胰腺癌的靶向示踪能力[49]，并且以此靶向探针设计的放射性免疫制剂也在高表达TFR1的胰腺癌治疗中显示出明显的抗肿瘤作用[50]。虽然TFR1抗体的放射性免疫疗法局部杀伤力不如X射线疗法，但若针对晚期癌细胞扩散的胰腺癌将显示出巨大的潜力。此外，以TFR1抗体介导的靶向基因疗法也在胰腺癌的治疗中表现出很大潜力。ER Camp等人以TFR1scfv修饰的脂质体包封p53基因表达质粒，形成的免疫脂质体SGT-53成功实现在转移性胰腺癌中p53基因特异性表达。SGT-53和吉西他滨联合治疗，增加了胰腺癌对吉西他滨的敏感性，明显抑制胰腺癌向肝脏转移。吉西他滨和SGT-53联合治疗转移性胰腺癌的二期临床试验正在进行[51]。

7. 在液体活检方面的应用

液体活检是一种无创、非侵入性血液样品检测技术。微流控芯片技术作为捕获细胞的一种方法，其原理是在芯片的微柱上固定特异性亲和配体，样品流过芯片从而对目的细胞进行捕获。但目前该方法的局限在于只能用特异性亲和力配体筛选特定亚型的肿瘤细胞，这往往需要研究人员和临床医生事先获得待分离肿瘤细胞的亚型特征，这往往是耗时而且高成本的。因此目前仍需要一种精简的肿瘤细胞检测方法，在没有对肿瘤细胞有先验知识的情况下，保留目前肿瘤检测方法的灵敏性和选择性，从血样中筛选出肿瘤细胞。TFR1在多种肿瘤细胞表面高表达，且蛋白表达密度跟肿瘤进展呈现正相关，是一种非常有价值的广谱肿瘤细胞生物标志物[52]。Wenjie Li等研究人员使用TFR1抗体包被的微流控芯片对模拟的急性白血病血样进行淋巴母细胞分离，结果显示其分离能力强于急性成淋巴细胞白血病细胞特异性抗体(CD7, CD10)。在急性成淋巴细胞白血病(ALL)细胞占白细胞总数7%的情况下，分离的急性成淋巴细胞白血病细胞纯度达到80%以上。在急性成淋巴细胞白血病细胞(COG-LL-332, COG-LL-317)占白细胞总数只有1%的情况下，分离纯度依旧分别保持在80%~97%、57%~92% [53]。Veronica J. Lyons和Dimitri Pappas将TFR1抗体应用于急性成骨髓细胞白血病(AML)血样的筛选中，使用TFR1抗体作为AML检测的亲和力配体成功分离出白血病细胞，最高产生92%和62%的捕获效率和纯度[54]。

除此之外，TFR1抗体也可以用于孕妇产前诊断。目前主流的孕妇产前诊断方法主要为羊膜穿刺术取样、绒毛膜绒毛取样。但是这两种侵入性取样方法都有可能造成羊膜内或胚胎感染甚至流产。Huimin Zhang等研究人员开发出针对孕妇血液中循环胚胎有核红细胞的微流控芯片。该芯片以TFR1抗体为亲和力配体对血样中循环有核红细胞的富集可以达到90%。在其应用的三组受试者(18名孕妇、5名未孕女孩和5名产后母亲)中，只有孕妇血样中被检出循环胚胎有核红细胞。通过对筛选出的细胞进行DNA测序分析就可以鉴定胚胎来源、确定胚胎是否存在先天性缺陷[55]。无论是在孕妇产前诊断，还是在急性白血病的诊断检测中，以TFR1抗体构建起的亲和力筛选方法都展现出很大潜力。

8. 总结与展望

不可否认，TFR1抗体介导的脑内药物递送极大增强了药物脑内生物利用度，有助于提高药物治疗指

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数。目前进入临床的以TFR1抗体进行脑内递送的药物JR-141、SGT-53已完成二期临床试验。JR-141治疗MPS II临床效果良好，SGT-53与TMZ联合治疗脑胶质瘤也展现巨大潜力。相信随着对TFR1在BBB管腔膜上介导的转包吞机制的深入了解和更多新型纳米载体的开发，无论是药物跨血脑屏障转包吞效率，还是药物载量上都会得到很大提高，脑部疾病治疗最大的屏障终将被攻克。除此之外，TFR1抗体在脑部之外的疾病诊治中也表现出很大潜力，高代谢的肿瘤细胞无论是对物质和能量的需求都远远高于正常细胞，TFR1作为细胞摄取铁的主要途径，在多种恶性肿瘤中呈现高表达。针对TFR1开发的免疫探针、免疫毒素、重组抗体、免疫脂质体、免疫纳米颗粒等在血液恶性肿瘤、胰腺癌等恶性肿瘤的诊治中表现出巨大潜力。

当然，TFR1在造血干细胞等快速增殖的正常细胞上也呈现高表达，TFR1抗体的使用不可避免的会对这些细胞产生一定影响。以TFR1抗体开发的靶向药物需要在临床前进行充分的安全性评估，这可能是TFR1抗体相关药品走向临床使用的最大考验。但同时也有相应的机遇存在，比如通过将TFR1抗体与基因疗法结合，通过抑制致癌基因，激活抑癌基因等，实现对肿瘤细胞的双重甚至多重靶向。SGT-53就是以TFR1抗体结合p53抑癌基因构建起的靶向基因疗法。临床实验表明，SGT-53在自身抗肿瘤作用的基础上，还可以增加肿瘤细胞对其他抗肿瘤药物的敏感性，逆转耐药性。可以预见，依托TFR1抗体的靶向基因疗法将在多种恶性肿瘤治疗中发挥更大作用。

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