科学篇之九(第1节): T细胞连接器(T Cell Engager, TCE)

目前,已经获批用于临床治疗的十几款双抗中,大部分是T细胞连接器(T Cell Engager, TCE)。 作为效应细胞连接器,TCE将免疫靶点和肿瘤相关靶点进行关联,借助免疫细胞实现对表达目标靶点肿瘤细胞的杀伤。涉及到的免疫细胞包括T细胞、NK细胞和其他先天免疫细胞。

首个上市的TCE是EpCAM/CD3双抗catumaxomab,2009年在欧洲上市,后因为商业原因退市。这个产品还有其他问题,包括严重输注反应、高ADA(因Fc区为鼠源)、不依赖抗原的Fc受体激活(因保留Fc受体结合)。后续开发的下一代TCE则去掉了Fc部分,代表药物是CD19/CD3双抗blinatumomab,2014年上市,用于B-ALL的治疗。但是,完全去除Fc的代价就是半衰期太短,需要连续长时间输注。因此,主流的TCE开发又回到了IgG样结构,通过糖型或点突变降低,甚至去除Fcγ受体的结合。也有通过连接HSA延长半衰期的策略。

TCR可特异性识别MHC递呈的抗原肽,借助TCR这一特点构建TCE也是选择之一。Tebentafusp就是这么一款产品,由识别gp100多肽的TCR和CD3抗体组合而成,2022年在欧洲获批上市,用于治疗葡萄膜黑色素瘤。另外还有识别WT1、KRAS、p53的双抗产品进入临床阶段。

Trade Name

Active Ingredient

Targets

Year Approved

Indication

Removab

Catumaxomab

EpCAMxCD3

2009 (EU)

Malignant ascites (MA) in adults with EpCAM-positive carcinomas

Blincyto

Blinatumomab

CD19xCD3

2014

To treat Philadelphia chromosome-negative relapsed or refractory B cell precursor acute lymphoblastic leukemia

Kimmtrak*

Tebentafusp-tebn

(MHC:gp100p)xCD3

2022

To treat a form of unresectable or metastatic uveal melanoma

Tecvayli

Teclistamab-cqyv

BCMAxCD3

2022

To treat relapsed or refractory multiple myeloma (RRMM)

Lunsumio

Mosunetuzumab-axgb

CD20xCD3

2022

To treat relapsed or refractory follicular lymphoma

Epkinly

Epcoritamab-bysp

CD20xCD3

2023

To treat relapsed or refractory diffuse large B-cell lymphoma

Columvi

Glofitamab-gxbm

CD20xCD3

2023

To treat relapsed or refractory diffuse large B-cell lymphoma or large B-cell lymphoma

Elrexfio

Elranatamab

BCMAxCD3

2023

To treat RRMM

Talvey

Talquetamab

GPRC5DxCD3

2023

To treat RRMM

Imdelltra*

Tarlatamab

DLL3xCD3

2024

Extensive-stage small-cell lung cancer (SCLC)

* 适应症为实体瘤 

TCE类产品目前获批的实体瘤就是Tebentafusp治疗葡萄膜黑色素瘤和Tarlatamab治疗小细胞肺癌(SCLC),其它适应症均为血液肿瘤。出现这一局面的原因是,TCE类产品会激活T细胞,细胞因子风暴是一个很大的挑战。另外,TCE属于高活性产品,比较容易出现on-target-off-tumor毒性。TCE对靶点的要求非常高,要求靶点特异性在肿瘤高表达。像HER2、EGFR、TROP2、MUC1、CEACAM5等靶点在正常组织也有表达,开发TCE就会有一定挑战。还有一点,实体瘤内部的肿瘤微环境呈免疫抑制状态,TCE发挥作用也受影响。所以,TCE在实体瘤的突破是比较缓慢的。不过,理想双抗靶点虽然少,也不是没有,比如新生抗原p95-HER2、EGFRvIII、MUC16、claudin18.2、DLL3、STEAP1等。

还有一种降低TCE毒性的策略是双抗的T细胞连接端不采用CD3,毕竟CD3激活的是传统T细胞,总量大,毒性强,而是选择采用γδT细胞作为效应细胞。LAVA-1207就是这么一款PSMA-γδTCE,目前处于临床研究阶段。

目前TCE在整个效应细胞连接器领域占据着主导地位,但基于先天免疫细胞连接器的研发也在如火如荼的进行,包括基于NK细胞的连接器(NKCE)、髓系细胞如中性粒细胞和巨噬细胞/单核细胞的连接器。这类产品的逻辑其实也比较好理解,像已经上市的rituximab、cetuximab、trastuzumab,均需要通过ADCC发挥作用。Obinutuzumab、mogamulizumab、tafasitamab、margetuximab、amivantamab这类ADCC增强型的产品也已经上市。而ADCC发挥作用主要依赖Fc受体与先天免疫细胞表面的Fcγ受体的结合。因此,不依赖Fc直接将肿瘤相关抗原TAA与NK或其它细胞连接的双抗或多抗方案顺势而生。NK细胞表面常用的分子包括CD16、NKG2D、NKp46、NKp30等。一款名为AFM13的CD30/CD16A的NKCE在临床霍奇金淋巴瘤的治疗中显示出不错的治疗潜力。AFM24则是一款EGFR/CD16A的NKCE,在与PD-L1抗体Tecentriq联用临床试验中,在胃癌和胰腺癌患者中观察到药效。

Klein et al., 2024. Nat Rev Drug Discov 23:301–319
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