Nature: 癌症治疗的概念性突破:三特异性抗体靶向治疗方法

2020-04-30 Nature自然科研 Nature自然科研

疫治疗的核心是增强免疫系统对肿瘤细胞的响应。最新开发的抗体经过改造,能够同时识别三个靶点。动物实验表明,这种抗体有望增强T细胞的抗肿瘤能力。

疫治疗的核心是增强免疫系统对肿瘤细胞的响应。最新开发的抗体经过改造,能够同时识别三个靶点。动物实验表明,这种抗体有望增强T细胞的抗肿瘤能力。
单克隆抗体,即特异性针对单一靶点的抗体,是首个被广泛用于临床的癌症免疫疗法。对抗体加以改造,使其能够识别两个分子靶标(即抗原),就能增强其治疗效力。这些双特异性抗体可以同时与肿瘤细胞和名为T细胞的免疫细胞结合,让T细胞杀灭肿瘤细胞。

Lan Wu等人1在《自然-癌症》上报道了一种三特异性抗体,其靶点包括肿瘤细胞、激活T细胞的受体和维持T细胞持续激活、攻击肿瘤细胞的T细胞蛋白(图1)。

图1|一种能让免疫细胞锚定癌细胞的抗体。Wu等人1报道了一种经过工程改造的抗体,可以让名为T细胞的免疫细胞靠近骨髓瘤细胞这类癌细胞,并增强T细胞的抗癌作用。这种三特异性抗体有三个靶点:骨髓瘤细胞上的CD38蛋白、T细胞上的CD28蛋白,以及T细胞上的CD3蛋白复合物(抗体的靶标结合域分别用红色、蓝色和黄色标注)。CD3是T细胞受体(TCR)的一部分,TCR通过结合抗原分子识别异常细胞。抗体与CD3结合可促使T细胞活化(不需要TCR识别抗原),杀死骨髓瘤细胞,同时产生并释放有毒的细胞因子。抗体与CD28结合可以促进Bcl-xL蛋白的表达,而Bcl-xL能够阻止T细胞死亡——如果抗体不激活CD28,TCR长期活化可能会导致T细胞死亡。
哺乳动物的免疫系统会产生大量的抗体;如若加以改造,就能让抗体识别特定的治疗靶点。通常情况下,抗体只能识别单个抗原,这个抗原可以是某个致病成分,也可以是某种异常的蛋白质或糖类分子。针对癌细胞上某个靶点的单克隆抗体会募集中性粒细胞细胞、天然杀伤细胞、巨噬细胞等免疫细胞,杀死或吞噬癌细胞。

经过改造的抗体还能阻断或刺激与其结合的蛋白的功能。例如,有些调节受体会抑制T细胞功能,经过改造的抗体可以阻断这些受体,这种增强T细胞功能的临床治疗策略即所谓的“检查点阻断”疗法。这些抑制性受体控制着“T细胞衰竭”——一种T细胞无功能的状态,可以避免自身免疫反应的发生;肿瘤微环境中也存在“T细胞衰竭”,让肿瘤细胞逃脱T细胞介导的抗肿瘤作用。检查点阻断治疗可以唤醒衰竭的抗肿瘤T细胞,带来极大的临床获益,但也会导致自身免疫毒性。Wu等人开发的抗体采用类似方法增强T细胞对癌细胞的活性,但主要通过刺激能够强化T细胞功能的受体,而非阻断抑制性受体。

Wu等人开发的人源抗体基于双特异性抗体技术,这种技术将两种不同抗体的抗原识别域重新整合为一个双特异性分子。双特异性抗体的靶点通常是肿瘤细胞表面的某种抗原和T细胞上的CD3蛋白复合物。CD3是T细胞受体(TCR)复合物的一部分。当与一个抗原结合后,TCR也会包含抗原识别结构域,并向T细胞传递激活信号,而抗体与CD3结合也能产生激活信号。

因此,这种双特异性抗体可以激活T细胞,使其与肿瘤细胞贴得很近,不论T细胞的天然抗原特异性如何,都能将其杀伤能力重新导向癌症细胞。

这一方法的临床有效性已在双特异性抗体博纳吐(blinatumomab)上得到了证实,这种抗体靶向CD3和癌细胞上的CD19蛋白,能让B细胞急性淋巴细胞白血病(B-ALL)晚期患者的缓解率和生存率翻倍2。目前,该药物正在进行一线治疗评估测试,并已取得较好的初步结果3。

Wu和同事采用了极为巧妙的方法,可在促进T细胞活化的同时强化对多发性骨髓瘤相关癌细胞的特异性攻击——多发性骨髓瘤是血液中浆细胞恶性增殖导致的癌症。

作者开发的三特异性抗体经过工程改造,具有三个而非两个抗原结合位点,包括CD3、(肿瘤细胞上的)CD38蛋白、(T细胞上的)CD28蛋白。以CD38为靶点的抗体达雷木单抗(daratumumab)已被证实对多发性骨髓瘤具有临床疗效4,而CD38可能也是其他癌症的靶点,如急性淋巴白血病和急性髓系白血病。

CD28蛋白属于一类名为共刺激受体的蛋白,这类蛋白可以正向调节T细胞活化。当T细胞通过TCR识别靶抗原时,必须有CD28这种共刺激受体的参与才能保证持续的T细胞增殖,实现有效的免疫应答。仅有TCR而没有共刺激受体,活化会使T细胞进入无反应状态或衰竭状态。在没有共刺激的情况下,长时间激活TCR可能导致T细胞的程序性死亡,即细胞凋亡。

加入CD28这种共刺激信号值得注意,是因为这种信号也被纳入了另一种名为“嵌合抗原受体T细胞”(CAR-T)的免疫疗法5。在CAR-T治疗中,经过改造的受体能够同时识别癌细胞抗原和T细胞活化结构域,如CD3和CD28。在三特异性抗体中加入CD28这个靶点的主要目的是为T细胞提供共刺激。此外,CD28在多发性骨髓瘤细胞中表达水平也较高,可能有助于增加抗体对骨髓瘤细胞的亲和力,特别是那些CD38表达水平较低甚至完全缺失的细胞,或是接受过达雷木单抗治疗的细胞。

为了证实CD28结合域确实能增强三特异性抗体的活性,研究人员制作了不同版本的抗体,让一个或多个靶点结合域发生突变。他们在拥有人类T细胞和人类骨髓瘤细胞的“人源化”模型小鼠中对这些抗体进行了测试,发现相比没有CD28靶点结合域的抗体,该结合域未发生突变的抗体能够更大程度地活化T细胞,促使T细胞增殖并提高T细胞中抗凋亡蛋白Bcl-xL的表达。

这一结果验证了研究人员的假设:共刺激信号可以防止T细胞凋亡。抗体中CD28靶点结合域的存在增强了T细胞在体外和人源化小鼠模型中杀死不同骨髓瘤细胞系的能力——即使使用最低的测试剂量。

这项研究的主要局限在于名为“细胞因子释放综合征”(CRS)的副作用未明。当免疫系统受到高强度刺激时可能会产生这种不良反应。在CRS中,许多T细胞会同时被激活,导致免疫系统的细胞过度释放细胞因子这种信号分子,引发炎症。双特异性抗体和CAR-T治疗都可能引发CRS,其常见症状为发热,严重情况下可发生致命的多器官衰竭6。

作者报告,他们给猴子静脉注射三特异性抗体时曾出现过细胞因子相关毒性,但如果采用皮下给药,抗体释放相对缓慢,这类毒性则小得多。令人放心的是,测试结果显示,加入CD28靶点结合域并未导致严重的CRS。但值得警惕的是,猴子骨髓瘤细胞中的CD38含量远低于人类,而CD38表达水平越高,抗体介导的T细胞活化程度也就越高,可能会提高CRS发生的风险。

关于抗体可能对健康细胞造成的负面影响,令人放心的是,在猴子测试中,表达CD38的正常白细胞(例如淋巴细胞和骨髓细胞)仅出现了暂时性下降。该研究的另一个局限在于,作者并未评估这种三特异性抗体是否会诱发针对抗体的免疫响应,使三特异性抗体被迅速破坏。

使用三特异性抗体靶向治疗癌症是非常重要的概念性突破,这些工作基于团队之前在艾滋病病毒(HIV)三特异性抗体上取得的结果7。多发性骨髓瘤需要新的治疗方法,因为目前最有前景的新兴疗法,包括以BCMA抗原为靶点的CAR-T疗法,也只能给大多数人带来短暂的缓解8-10。而三特异性抗体是一个灵活的载体,可以在肿瘤微环境中特异性地传递免疫调节信号(如共刺激信号和检查点阻断剂)组合,这可能比多个特异性免疫调节单抗的组合更安全有效。这种策略能提高目前免疫疗法的精准性和疗效,进一步扩大免疫疗法的适用范围,包括多种难以靶向治疗的癌症。


原始出处:
Alfred L. Garfall & Carl H. June. Trispecific antibodies offer a third way forward for anticancer immunotherapy. Nature. 18 NOVEMBER 2019

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    2020-08-05 liye789132251
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