超200款药物进入临床，一体化生物评价助力创新免疫疗法开发

编者按：在过去十年中，T细胞衔接器（TCEs）已逐步成为癌症免疫治疗领域的一种变革性治疗模式。自2014年首款TCE获批以来，全球已有10款TCE获得监管批准，其中8款是在近三年内获批，凸显出该领域蓬勃的发展势头。目前全球已有超过200种TCEs进入临床开发阶段，为满足合作伙伴不断增长的TCE研发需求，药明康德旗下生物学业务平台（WuXi Biology）构建了全面的TCE评价平台，以加速TCE在临床前阶段的开发。该平台结合体外与体内模型——包括评估T细胞激活的体外检测、小鼠模型和功能性免疫检测——为合作伙伴提供一体化、高效且科学严谨的评估服务，助力充分发挥TCE的治疗潜力。

TCE是一类双特异性抗体，旨在同时结合肿瘤细胞与T细胞，通过促进免疫突触的形成，激活T细胞介导的杀伤作用。这类分子在结构和作用机制上具有高度创新性，但其开发过程也面临诸多挑战。特别是在调控TCE对CD3的结合亲和力方面，需要精确优化，以避免引发非特异性T细胞激活或导致T细胞耗竭。同时，传统药理模型在预测TCE引发的复杂免疫反应方面存在局限，难以全面评估其在靶点结合、细胞因子释放以及体内疗效等方面的表现。

▲TCE作用机理（图片来源：参考资料[4]）

上述挑战，尤其是在TCE管线从血液恶性肿瘤不断扩展至实体瘤的背景下，凸显了建立具备临床相关性的检测系统的迫切需求。对于专注于开发潜在“first-in-class”或“best-in-class”TCE的生物技术企业而言，常常缺乏可扩展且经过验证的模型，来全面评估TCE的功能、安全性和转化潜力。

针对这些痛点，WuXi Biology通过一体化解决方案应对挑战，结合细胞功能检测、生物标志物分析与动物模型，系统解析TCE的药效特征。例如，WuXi Biology开发了基于NFAT信号通路的Jurkat-NFAT-Luc体外模型，能够灵敏检测CD3激活信号。在与表达CD19的肿瘤细胞共培养并加入CD19/CD3双抗后，该系统可展现剂量依赖性的信号响应，验证TCE分子对CD3和肿瘤抗原的特异性结合。同时，该模型也可用于检测在无靶细胞条件下的非特异性CD3激活，有助于优化候选TCE的治疗指数。

▲Jurkat-NFAT-Luc的作用原理和实验表现

为更深入评估TCE的功能，WuXi Biology建立了一套高效检测体系，可覆盖T细胞介导的细胞毒性反应、细胞因子分泌、T细胞增殖与激活等关键指标。这些综合工具能够细致描绘TCE所诱导的免疫级联反应，为机制研究与差异化分子开发提供强有力的支持。

在体内研究方面，WuXi Biology搭建了一套全面的小鼠模型组合，用于评估双特异性抗体在血液肿瘤和实体瘤中的抗肿瘤活性。这些模型通过模拟真实的人类肿瘤免疫微环境，提供具备高度转化价值的关键数据。

例如，模拟人类外周血单个核细胞（PBMC）免疫反应的皮下肿瘤模型常用于在可控的体内环境中评估双抗的抗肿瘤效果。在一项研究中，CD19/CD3双抗显著抑制了肿瘤生长，且未引起小鼠体重明显变化，显示出良好的疗效与耐受性。

▲使用PBMC皮下肿瘤模型评估CD19/CD3双抗的实验结果

原位肿瘤模型则因更贴近肿瘤自然生长环境，在评估TCE分布与疗效方面具有更高的临床相关性。例如，WuXi Biology建立了小细胞肺癌原位肿瘤动物模型，用以评估DLL3/CD3双抗在原发病灶中的治疗效果，更精确地反映治疗反应。

此外，WuXi Biology还构建了更完整、更具生理代表性的免疫系统模型，包括单核细胞与淋巴细胞等关键免疫群体，超越了仅含T细胞的模型。这类模型支持对双抗诱导的免疫反应进行深入分析，同时捕捉肿瘤局部和系统性免疫调节效应，提供双重维度的重要数据。

这些模型协同支持TCE及其他双特异性抗体药物的设计与优化，为候选分子的筛选、验证及转化研究提供科学依据。

WuXi Biology平台还可提供靶点表达分析和结合亲和力评估等配套服务。随着TCE疗法向新型肿瘤抗原、多特异性结构和实体瘤等新领域不断拓展，该一体化平台所具备的灵活性与科学深度愈加凸显其价值。

展望未来，药明康德将持续基于其独特的CRDMO模式，赋能全球合作伙伴开发更安全、更高效的TCE疗法。通过加速突破性免疫疗法的开发进程，与合作伙伴一起，早日实现“让天下没有难做的药，难治的病”的愿景。

Accelerating T Cell Engager Development with Integrated Preclinical Platforms at WuXi Biology

T cell engagers (TCEs) have emerged as a transformative modality in cancer immunotherapy. Since the approval of the first TCE in 2014, ten have received regulatory approval worldwide, with eight approved in just the last three years, highlighting the rapid momentum in this field. More than 200 TCEs are in the clinical development stage today. To meet growing demand from global partners, WuXi Biology has built a comprehensive evaluation platform to accelerate preclinical TCE development. Leveraging integrated in vitro and in vivo systems including T cell activation assays, mouse models, and functional immune analyses, WuXi Biology delivers efficient, scientifically rigorous solutions to unlock the full therapeutic potential of TCEs across diverse targets and formats.

TCEs are bispecific antibodies that redirect T cells to tumor cells by simultaneously binding a tumor-associated antigen and CD3 on T cells, triggering cytotoxic immune synapse formation. While structurally and mechanistically innovative, TCEs present unique development challenges. Notably, the affinity for CD3 must be finely tuned to avoid off-tumor T cell activation and exhaustion. Moreover, conventional pharmacology models often lack the physiological relevance needed to predict target engagement, cytokine release, and anti-tumor efficacy, especially for solid tumors.

These limitations underscore the need for predictive, scalable, and translationally relevant models. As TCE pipelines expand beyond hematologic malignancies, biotech innovators require validated systems that comprehensively assess function, safety, and therapeutic potential.

WuXi Biology’s Solution: End-to-End Preclinical Support

WuXi Biology addresses these challenges with a robust suite of functional assays and in vivo models:

T Cell Activation and Functional Assays:

WuXi Biology has developed the Jurkat-NFAT-Luc reporter system, which sensitively detects CD3 engagement through NFAT pathway activation. When co-cultured with CD19-expressing tumor cells and treated with CD19/CD3 bispecific antibodies, this system shows concentration-dependent luciferase signal, confirming antigen specificity. Critically, it also detects CD3 activation in the absence of tumor cells, aiding therapeutic index optimization.

Additional assays include:

• T cell-mediated cytotoxicity assays

• Cytokine secretion profiling via ELISA

• Proliferation and activation marker analysis (e.g., CD69, CD25, CFSE)

These functional assays enable mechanistic characterization, potency assessment, and candidate differentiation.

In Vivo Models for Translational Insight:

WuXi Biology employs a diverse array of mouse models to assess anti-tumor efficacy in both hematologic and solid tumors:

Models that mimic the human PBMC response are widely used to evaluate bispecific antibody efficacy in subcutaneous tumor settings. In one study, CD19/CD3 bispecific treatment led to significant tumor growth inhibition with no adverse body weight changes, indicating strong efficacy and tolerability.

Orthotopic tumor models provide enhanced clinical relevance by replicating the native tumor microenvironment. For example, WuXi Biology established an orthotopic small cell lung cancer model (SHP-77-Luc) in mice to evaluate a DLL3/CD3 bispecific, enabling precise efficacy assessment within the primary tumor site.

WuXi Biology also established mouse models that mimic the comprehensive responses of human immune cell populations—including T cells, monocytes, and B cells. These models allow for a deeper understanding of TCE-induced immune responses and systemic immune modulation, informing both efficacy and safety profiles.

These in vivo platforms provide critical translational data to guide candidate optimization and clinical positioning.

Expanded Capabilities to Enable TCE Innovation

WuXi Biology’s platform also includes target expression profiling and binding affinity characterization, supporting a data-rich approach to TCE discovery and development. As the field rapidly evolves to include novel antigens, multispecific constructs, and solid tumor indications, WuXi Biology offers the flexibility and scientific depth to adapt and scale with partner needs.

Looking ahead, WuXi AppTec will continue to leverage its unique CRDMO model, integrating discovery, development, and manufacturing to empower global partners in bringing safer, more effective TCEs to patients. By accelerating the advancement of next-generation immunotherapies, WuXi AppTec remains steadfast in its mission: “Every drug can be made and every disease can be treated.”

参考资料：

[1] OncoWuXi Express: Evaluation of T Cell Engagers. Retrieved July 8, 2025, from https://wuxibiology.com/resource/oncowuxi-express-evaluation-of-t-cell-engagers/

[2] Evaluation Platform for Bispecific Antibodies. Retrieved July 8, 2025, from https://wuxibiology.com/resource/evaluation-platform-for-bispecific-antibodies/

[3] Goebeler and Bargou. (2020). T cell-engaging therapies — BiTEs and beyond. Nat Rev Clin Oncol, https://doi.org/10.1038/s41571-020-0347-5

[4] Cech et al., (2024). T-Cell Engagers—The Structure and Functional Principle and Application in Hematological Malignancies. Cancers, doi: 10.3390/cancers16081580

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