Nature Cancer :三特异性抗体可提高肿瘤免疫效果

2019-12-03 小飞飞 BioArt

近年来,肿瘤免疫治疗的进步极大拓展了人们对恶性肿瘤的治疗手段。常见的免疫治疗包括免疫检查点阻断治疗或者利用基因工程手段改造T细胞使得T细胞对肿瘤细胞具有更高且持续的杀伤能力。尽管免疫治疗对一些恶性肿瘤治疗有不错的效果,但大多数恶性肿瘤对免疫治疗依旧没有反应,急需开发新的更有效的免疫治疗方法。其中一种提高免疫治疗效率的方法是双特异性抗体,分别可特异性识别靶细胞表面的抗原和T细胞表面的CD3分子,将T

近年来,肿瘤免疫治疗的进步极大拓展了人们对恶性肿瘤的治疗手段。常见的免疫治疗包括免疫检查点阻断治疗或者利用基因工程手段改造T细胞使得T细胞对肿瘤细胞具有更高且持续的杀伤能力。尽管免疫治疗对一些恶性肿瘤治疗有不错的效果,但大多数恶性肿瘤对免疫治疗依旧没有反应,急需开发新的更有效的免疫治疗方法。其中一种提高免疫治疗效率的方法是双特异性抗体,分别可特异性识别靶细胞表面的抗原和T细胞表面的CD3分子,将T细胞引导至特定的恶性肿瘤细胞靶点发挥细胞杀伤作用,已经展现不错的前景。2017年,三特异性抗体,使得一个抗体分子可以特异性识别人HIV病毒包膜蛋白上的三个抗原表位,并在动物模型中有一定的抗病毒能力。研发团队设想将多特异性抗体策略,应用到肿瘤免疫治疗领域,通过靶向淋巴细胞表面更多的分子,传递更多的激活型号,使活化T细胞能更好的特异性消除肿瘤细胞。

近日,Sanofi公司的Gary J. Nabel和Zhi-yong Yang?团队在Nature Cancer上发表题为Trispecific antibodies enhance the therapeutic efficacy of tumor-directed T cells through T cell receptor co-stimulation 的文章(Nature Cancer创刊后的第一篇研究论文),团队研发出同时抗CD38,CD28和CD3的三特异性抗体,增强了对T细胞的活化以及对肿瘤细胞的识别杀伤,在动物模型中有不错的效果。

T细胞的活化发挥效应功能以及持续增殖需要两种信号的激活,TCR-CD3复合物介导的信号通路可以诱导细胞因子的转录和分泌,CD28等共刺激分子介导的第二信号可激活另一信号通路抑制程序性细胞死亡,维持T细胞的持续性增殖,仅CD3的激活可导致T细胞的活化诱导死亡或失能。因此研究团队利用cross-over dual variable (CODV)双特异性抗体形式,将α-CD3ε (signal 1) 和α-CD28 (signal 2) 的可变区片段连接起来,来评估靶向两种信号分子,是否能进一步提高T细胞的增殖和活化。利用体外PBMCs共培养实验,团队发现α-CD3×CD28 CODV-Fab可以激活T细胞分泌细胞因子,同时α-CD3在近端位置有更好的效果。进一步构建α-CD38/CD3×CD28三特异性抗体(图1),发现三种分子的激活都可促进T细胞的活化增殖,其中CD3的作用是必须的,而CD28的激活促进T细胞的增殖。随后研究团队通过对三特异性抗体Fc受体结合位点的修饰改造,降低了抗体的非特异异性结合与毒性。随后通过PBMCs与CD38high和CD38low的多种骨髓瘤细胞共培养,发现和α-CD38和α-CD28都可以促进对肿瘤细胞的细胞毒活性,和抗CD38的单克隆抗体daratumumab相比,三特异性抗体在体外具有更高的3-4倍的活性,骨髓瘤细胞上的CD28分子也增强了T细胞对肿瘤细胞的识别以及细胞毒作用。

肿瘤免疫治疗在人体内的一大毒副作用是引起严重的细胞因子风暴,研究团队便在非人灵长类猴子上检测该三特异性抗体的毒副作用。在猴子体内,单次给药的最大耐受剂量(maximum tolerated dose,MTD)随给药方式不同而不同,静脉给药MTD在30到75μg/kg之间,而皮下给药,则MTD可大于等于100μg/kg。两种给药方式都可引起循环T,B淋巴细胞的瞬时下降,但在96小时之后可以恢复。之后,研究团队还通过人源化小鼠肿瘤模型,在体内验证了三特异性抗体的抗肿瘤效应,且这种效果是依赖于抗CD28作用的。

总之,本研究研发出三特异性抗体分子,通过靶向T细胞表面两种信号分子和恶性骨髓细胞表面的CD38分子,提高了对T细胞的活化持续增殖和对肿瘤细胞的杀伤,将三特异性抗体治疗首次应用于肿瘤免疫治疗领域,在临床前研究中展现了不错的前景。同时,关于三特异性抗体在肿瘤以及HIV治疗的相关临床试验也正在准备过程中。

据悉,这篇上线于2019年11月18日的文章是Nature新子刊Nature Cancer上线的第一篇文章,也是目前为止的唯一一篇文章。Nature Cancer是Nature 在150周年之际推出的又一新子刊。Nature Cancer旨在提供一个出版平台,帮助大家了解在生命科学,医学,应用和社会科学等方面的最新的肿瘤相关进展。Nature Cancer不仅仅会对关于肿瘤发生,增殖,恶化的基础研究感兴趣,将基础研究转化为临床应用开发新型诊断,治疗,预防手段的工作以及肿瘤相关的社会经济研究也将会很受欢迎。杂志的关注主题包括,肿瘤生物学,肿瘤遗传学和基因组学,肿瘤的进化和异质性,肿瘤和宿主相互作用,肿瘤免疫学和免疫治疗,肿瘤转移,治疗,临床工作,肿瘤模型和方法学,系统生物学,社会伦理和政策问题等。创刊主编是来自Nature Cell Biology的前主编Alexia-IleanaZaromytidou博士,Nature Cancer将在2020年1月分正式发行第一期杂志。

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    2019-12-03 CHANGE

    疗效只是效果的众多方面之一,还要看对患者的获益,包括生活质量等因素共同决定效果的

    0

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    2019-12-03 njwbhuang

    免疫治疗是以后肿瘤治疗的好方法。

    0

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