作者：汪梓昱
美工：何国红 罗真真
排版：马超
01 引言
继PD-1抑制剂引发肿瘤免疫治疗革命之后，T细胞衔接器（T Cell Engager，TCE）正成为免疫疗法领域的新焦点。TCE是一类双特异性分子，可同时结合肿瘤细胞表面抗原和T细胞受体，从而将T细胞精准引导至靶细胞，实现高效、定向的免疫杀伤。相比传统免疫检查点抑制剂，TCE具备更直接的激活机制与更广泛的适应潜力。除了在血液瘤和实体瘤治疗中展现出显著疗效外，研究者也在探索其在自身免疫疾病、感染及免疫调控领域的应用。TCE的出现，不仅代表了一种全新的免疫治疗模式，也为精准医学开辟了更广阔的前景。
02 从OKT3到TCE：推动免疫治疗革新的历史跃进
OKT3（muromonab-CD3）是全球首个获批用于临床治疗的单克隆抗体药物，于1986年问世，标志着抗体疗法时代的正式开启。它能特异性结合T细胞表面的CD3分子，从而抑制T细胞活化，被广泛用于器官移植后的急性排斥反应治疗。尽管OKT3以其创新机制奠定了免疫治疗的基础，但由于为鼠源抗体，易引发细胞因子风暴和免疫排斥等不良反应，限制了长期应用。随着抗体工程和免疫机制研究的进步，人源化与双特异性抗体应运而生。T细胞连接剂（TCE）正是在OKT3概念的延伸与优化中发展而来，实现了更精准、更安全的T细胞激活与肿瘤清除，代表着免疫治疗的新一代方向。以双特异性T细胞衔接疗法市场规模为例，2024年价值约为70亿美元，到2035年，有望突破210亿美元。TCE正成为这场增长浪潮的核心驱动力。本文将系统梳理TCE的作用机制、结构设计、临床布局与技术趋势，深入探讨其如何凭借这些独特优势，在未来重塑多个治疗领域的巨大潜能。
▲ 图1. 全球双特异性T细胞衔接疗法市场规模（十亿美元）
03 TCE是如何“牵线搭桥”的？
TCE是一类创新的双特异性抗体，旨在通过桥接T细胞与肿瘤细胞来重塑肿瘤免疫治疗。其核心机制在于分子的一端结合肿瘤细胞表面的特异性抗原（如CD19、BCMA），另一端则结合T细胞表面的CD3分子。这种连接能形成一个“免疫突触”，不依赖传统的T细胞受体（TCR）识别过程，直接激活T细胞释放穿孔素和颗粒酶等细胞毒性因子，从而高效杀伤肿瘤细胞。
▲ 图2. TCE基本原理（图示来源：Encelta AG）
04 TCE版图全景
01
TCE上市药物介绍
目前，FDA已批准多种TCE用于血液系统恶性肿瘤和部分实体瘤（表 1），这些药物的成功，标志着TCE正从“血液系统肿瘤”走向“实体瘤时代”。
▼ 表1. 批准治疗癌症的TCE药物
02
常见TCE分子形式介绍
T细胞连接剂（TCE）技术的发展是一部在“疗效”与“安全性”之间不断寻求平衡的创新史。最早问世的Catumaxomab是第一代TCE代表性药物，它以EpCAM/CD3双特异性为设计原型，于2009年在欧洲获批用于恶性腹水治疗。catumaxomab成功验证了双特异性抗体能够桥接T细胞与肿瘤细胞，从而实现免疫介导的杀伤，但同时也暴露出其免疫毒性强、副作用重等问题，如细胞因子释放综合征（CRS）和肝毒性，导致最终被撤市。
随后，第二代代表药物Blinatumomab (CD19/CD3 BiTE) 证明了TCE在血液瘤中的强大疗效，但其分子量小、半衰期短，需要持续输注，也限制了临床便利性。为了实现更理想的药效-毒性平衡，研究者在后续设计中引入了IgG Fc骨架以延长半衰期，并通过精细调控亲和力来降低脱靶激活和CRS风险。这种“结构换取稳定”的策略成为TCE设计的关键逻辑。在这一基础上，TCE进一步进化为多种新格式 (表 2) 。
▼ 表2. 常见TCE分子形式
03
从血液瘤到实体瘤
TCE的扩张版图TCE已在血液肿瘤领域取得重大突破，并通过靶点选择，确立了其核心适应症。在血液恶性肿瘤中，TCE主要针对B细胞上稳定高表达的表面抗原。例如，靶向CD19和CD20的TCE药物，已成为治疗B细胞白血病与淋巴瘤的关键疗法。同样，靶向BCMA的TCE在复发或难治性多发性骨髓瘤的治疗中展现出卓越疗效，彻底改变了治疗格局。
基于此成功，TCE正快速向更复杂的实体瘤领域拓展。目前研发热点包括针对前列腺癌的PSMA、肝癌的GPC3，以及结直肠癌等多种上皮源肿瘤的CEA等靶点。然而，实体瘤的治疗挑战远大于血液瘤，主要障碍包括：
1）肿瘤抗原表达不均一的异质性；
2）免疫抑制性的肿瘤微环境（TME）会削弱T细胞功能；
3）致密的组织结构会阻碍T细胞浸润。因此，未来攻克实体瘤的方向不仅是寻找新靶点，更需克服这些生物学障碍。
▲ 图3. 用于癌症治疗的TCE靶点开发概况（G. Albayrak et al. 2025）
04
不止抗癌：TCE的“跨界潜力”
TCE的故事不止于肿瘤。它的核心逻辑——“精准调控免疫系统”，让科学家开始探索更多疾病的可能性。在自身免疫性疾病中，研究者尝试用TCE来“清除过度活跃的免疫细胞”，以恢复免疫平衡。
目前较受关注的方向是B细胞深度耗竭。这一策略的里程碑式突破源于CD19 CAR-T疗法在难治性系统性红斑狼疮（SLE）中取得的卓越疗效，成功诱导了患者的长期缓解。这一成功极大地鼓舞了使用“即用型”TCE来达成类似目标的探索。例如，作为首款获批的CD19 TCE，Blinatumomab正被探索用于治疗难治性类风湿关节炎（RA）；而已在淋巴瘤中验证其高效B细胞清除能力的Mosunetuzumab（靶向CD20），也为治疗SLE等B细胞介导的疾病提供了明确的潜在治疗思路。
除了B细胞，致病性浆细胞是另一个关键靶点。由于CD38在这些细胞上高表达，开发靶向CD38的TCE成为清除此类细胞、治疗相关自身免疫疾病的一个重要尝试方向。这些尝试正在把TCE从“杀肿瘤的刀”变成“免疫调节的钥匙”。
▼ 表3. 非癌症类TCE药物
05 中国力量：TCE赛道的本土化崛起与创新
在全球TCE（T细胞接合抗体）疗法的浪潮中，中国本土创新力量正迅速崛起，凭借技术迭代与差异化设计，从“跟跑者”加速迈向与国际巨头“并跑”的阶段，逐步在高壁垒的免疫治疗领域建立竞争优势。伴随平台技术的成熟与国际合作的深化，一批具有全球潜力的原创TCE分子正加速推进临床。其中，和铂医药（Harbour BioMed）自主研发的HBM7020基于HBICE®平台构建，是靶向BCMA×CD3的双特异性抗体，用于多发性骨髓瘤治疗。其“2+1”结构设计可平衡T细胞活化与安全性，有效降低细胞因子释放综合征（CRS）风险。2023年，HBM7020获NMPA批准进入临床，并与日本大冢制药达成高达6.7亿美元的全球授权合作，体现出中国企业在分子设计、临床策略与国际化布局上的全面升级。
与此同时，信达生物开发的IBI389则代表了中国TCE在实体瘤领域的创新突破。IBI389是一款首创的CLDN18.2×CD3双特异性抗体，主要针对CLDN18.2阳性的胃癌、胃食管结合部癌及胰腺癌患者。在2024年ASCO大会公布的I期临床研究中，IBI389在胃癌/胃食管结合部癌患者中实现ORR 30.8%、DCR 73.1%，在胰腺癌患者中ORR 29.6%、DCR 70.4%，且未观察到剂量限制毒性，仅少数病例出现3级CRS。其优异的疗效与安全性表明，IBI389有望成为CLDN18.2靶向免疫治疗的新标杆。HBM7020与IBI389的相继推进，标志着中国TCE创新从实验室走向全球临床舞台，中国企业正以原创力与全球视野重塑TCE竞争格局。
06 小结
TCE抗体药物正从血液系统肿瘤的“黄金赛道”，逐步驶向实体瘤与自身免疫疾病的“深水领域”。双特异性抗体的成熟化与三特异性分子的崛起，预示着免疫治疗技术的迭代进入加速期。然而，实体瘤治疗中的安全性平衡与血液瘤领域的产品同质化竞争依旧构成主要挑战。
未来5年，随着靶点更精准、结构更优化、疗法更智能，TCE有望成为继PD-1之后的下一代免疫疗法引擎。它不仅可能改变癌症的治疗方式，也可能让自身免疫病迎来真正的“免疫耐受”时代。
Sanyou 10th Anniversary: TCE Therapy: A New Force Reshaping the Landscape of Immunotherapy
01 Introduction
Following the revolutionary success of PD-1 inhibitors in cancer immunotherapy, T-cell engagers (TCEs) have emerged as the next major focus in immune-based treatment. These bispecific molecules simultaneously bind to tumor cell antigens and T-cell receptors, guiding T cells precisely to target cells and enabling potent, targeted immune-mediated cytotoxicity. Compared with traditional immune checkpoint inhibitors, TCEs offer a more direct activation mechanism and broader therapeutic potential.Beyond their remarkable efficacy in hematologic and solid tumors, researchers are exploring their applications in autoimmune diseases, infectious diseases, and immune regulation. The rise of TCEs marks not only a new mode of immunotherapy but also opens vast new opportunities for precision medicine.
02 From OKT3 to TCE: A Historical Leap in Immunotherapy
The journey began in 1986 with OKT3 (muromonab-CD3), the world’s first approved monoclonal antibody drug, which targeted the CD3 molecule on T cells to control immune activation-a breakthrough in the era of antibody therapies. While OKT3 pioneered immune modulation, its murine origin led to cytokine storms and immune rejection, limiting its clinical use. With advancements in antibody engineering, humanized and bispecific antibodies emerged. T-cell engagers evolved as optimized successors to OKT3, achieving safer and more precise T-cell activation for tumor clearance-representing a new generation of immunotherapy. The TCE market reflects this rapid ascent: valued at $7 billion in 2024, it is projected to surpass $21 billion by 2035, positioning TCEs as a driving force in the next wave of immunotherapy innovation. This article provides a comprehensive overview of TCEs-from their mechanisms of action and structural design to clinical development and emerging technologies-and explores how their unique advantages could redefine multiple areas of therapy in the years to come.
▲ Figure 1. Global Market Size of Bispecific T-Cell Engager Therapies
03 How Do TCEs Work?
TCEs are designed to bridge T cells and tumor cells. One end of the molecule binds to a tumor-associated antigen (such as CD19 or BCMA), while the other binds to CD3 on T cells. This connection forms an “immune synapse” that bypasses traditional T-cell receptor recognition, directly triggering T cells to release perforin and granzymes- cytotoxic molecules that destroy tumor cells efficiently and selectively.
▲ Figure 2. Basic Principles of TCE (Illustration Source: Encelta AG)
04 The Expanding TCE Landscape
01
Approved TCE Drugs
The FDA has approved several TCE-based therapies for hematologic malignancies and some solid tumors. Their success demonstrates that TCEs are transitioning from blood cancers to the era of solid tumor treatment.
▼ Table 1. Approved TCE drugs for cancer treatment
02
Introduction to Common TCE Molecular Formats
The development of T-cell engagers (TCEs) has been an ongoing effort to balance "efficacy" and "safety." The first-generation TCE, Catumaxomab (EpCAM/CD3), approved in 2009 for malignant ascites, demonstrated the potential of bispecific antibodies in bridging T cells and tumor cells for immune-mediated killing. However, its strong immune toxicity and side effects, such as cytokine release syndrome (CRS) and hepatotoxicity, led to its market withdrawal.
The second-generation TCE, Blinatumomab (CD19/CD3 BiTE), showed strong efficacy in hematologic malignancies but was limited by its short half-life and need for continuous infusion. Later designs introduced an IgG Fc backbone to extend the half-life and optimized binding affinity to reduce off-target activation and CRS risk, marking a key strategy in TCE development. This led to the evolution of several new TCE formats (Table 2).
▼ Table 2. Common TCE Molecular Formats
03
From Hematological Malignancies to Solid Tumors: The Expanding Landscape of TCEs
T-Cell Engagers (TCEs) have achieved major success in hematological malignancies by targeting highly expressed surface antigens. Key examples include TCEs against CD19 and CD20 for B-cell leukemia/lymphoma, and BCMA for relapsed/refractory multiple myeloma, which has revolutionized treatment in these areas.
Building on this success, TCEs are rapidly expanding into the more complex field of solid tumors. Current research hotspots include targets such as PSMA for prostate cancer, GPC3 for liver cancer, and CEA for various epithelial-derived tumors like colorectal cancer. However, treating solid tumors presents challenges far greater than those in hematological cancers. The main obstacles include:
1) the heterogeneity of tumor antigen expression (lack of uniformity);
2) the immunosuppressive Tumor Microenvironment (TME), which impairs T-cell function;
3) the dense tissue structure, which hinders T-cell infiltration. Therefore, the future direction for conquering solid tumors is not merely about finding new targets but also about overcoming these biological barriers.
▲ Figure 3. TCE target profiles for cancer treatment (G. Albayrak et al. 2025)
04
From Oncology to Cross-Boundary Expansions
The potential of T-Cell Engagers (TCEs) extends beyond oncology, utilizing their core logic of "precise immune system modulation" to address other diseases. In autoimmune disorders, researchers are exploring TCEs as a way to "clear hyperactive immune cells" and restore immune balance.
A key focus is profound and sustained B-cell exhaustion, inspired by the success of CD19 CAR-T in refractory Systemic Lupus Erythematosus (SLE). This has spurred the development of "off-the-shelf" TCEs for similar results. For example, the CD19 TCE Blinatumomab is being investigated for refractory Rheumatoid Arthritis (RA), while the robust B-cell elimination efficacy of the CD20 TCE Mosunetuzumab offers a clear therapeutic path for B-cell-mediated conditions like SLE.
Beyond B cells, pathogenic plasma cells represent another critical target. Given the high expression of CD38 on these cells, developing CD38-targeted TCEs is an important research direction for clearing these cells and treating related autoimmune disorders. These efforts are transforming the TCE from a "tumor-killing knife" into a "key for immune regulation."
▼ Table 3. Non-Cancer TCE Drugs
05 The Rise of Chinese Innovation in the TCE Field
Amid the global wave of TCE therapies, China’s domestic innovation is rapidly rising. With technological iterations and differentiated designs, Chinese companies are moving from "followers" to global competitors, gradually establishing competitive advantages in the high-barrier field of immunotherapy. As platform technologies mature and international collaborations deepen, a batch of globally promising original TCE molecules is advancing into clinical trials. For instance, Harbour BioMed’s HBM7020, a BCMA×CD3 bispecific antibody developed on the HBICE® platform, balances T-cell activation with safety, reducing cytokine release syndrome (CRS) risks. In 2023, it received NMPA approval for clinical trials and secured a $670 million global licensing agreement with Otsuka Pharmaceutical.
Meanwhile, IBI389 by Innovent Biologics marks China's TCE breakthrough in solid tumors. As a first-in-class CLDN18.2×CD3 bispecific antibody, it targets CLDN18.2-positive patients with gastric cancer, gastroesophageal junction cancer, or pancreatic cancer. In phase I data presented at the 2024 ASCO Annual Meeting, IBI389 achieved 30.8% ORR and 73.1% DCR in gastric/gastroesophageal junction cancer patients, and 29.6% ORR and 70.4% DCR in pancreatic cancer patients. No dose-limiting toxicity (DLT) was observed, with only few cases of grade 3 cytokine release syndrome (CRS). Its excellent efficacy and safety suggest IBI389 may become a new benchmark for CLDN18.2-targeted immunotherapy. The successive progress of HBM7020 and IBI389 signifies China's TCE innovation moving from lab to global clinical stage, as Chinese companies reshape the TCE landscape with original capabilities and global vision.
06 Conclusion
TCE antibody drugs are gradually shifting from the 'hot spot' of hematologic malignancies to the 'challenging territory' of solid tumors and autoimmune diseases. The maturation of bispecific antibodies and the rise of trispecific molecules signal that the iteration of immunotherapy technologies is entering an acceleration phase. However, balancing safety in solid tumor treatments and the homogenization competition in the hematologic malignancy field remain major challenges.
In the next 5 years, with more precise targets, optimized structures, and smarter therapies, TCEs are poised to become the next-generation immunotherapy engine following PD-1. It not only has the potential to transform cancer treatment methods but also to usher in a true era of 'immune tolerance' for autoimmune diseases.
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公司总部位于中国上海，在亚洲、北美洲、欧洲等多地建立了业务中心，形成了全球化的业务网络，现有投产及布局的研发及GMP场地20000多平方米。
公司已与全球2000多家药企、生技公司等建立了良好的合作关系，已赋能1200多个新药研发项目；已完成50多个合作研发项目，其中10多个协同研发项目已推至IND及临床研发阶段。
公司已申请130多项发明专利，其中30多项发明专利已获得授权，并获得了国家级高新技术企业、上海市专精特新、ISO9001、ISO27001等10余项资质及体系认证。
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