卵巢癌仍然是肿瘤学领域的一个巨大挑战，需要创新的治疗方法。 Claudin-6 (CLDN6) 是紧密连接分子 CLDN 家族的成员，在健康组织中的表达可以忽略不计，但在包括卵巢癌在内的各种恶性肿瘤中表现出异常上调。尽管目前正在研究几种针对 CLDN6 的治疗方式，但仍然需要更有效的治疗选择。虽然 T 细胞接合剂 (TCE) 作为有效的免疫治疗剂具有巨大的前景，但由于仅刺激 CD3 而没有共刺激，因此它们目前在靶抗原选择和 T 细胞耗竭方面的功效和安全性必须得到改善，特别是针对实体瘤。为了为卵巢癌提供有效的治疗选择，我们生成了 SAIL66，这是一种针对 CLDN6/CD3/CD137 的三特异性抗体。使用我们专有的下一代 TCE 技术（双 Ig），SAIL66 被设计为通过一个 Fab 与 CLDN6 结合CD3/CD137 与另一个结合，从而通过 CD3 激活和 CD137 共刺激来激活 T 细胞。 SAIL66 的临床前表征是在一系列体外和体内研究中进行的，其中包括与靶向 CLDN6 和 CD3 的传统 TCE 进行比较。尽管 CLDN6 与其他 CLDN 家族成员之间具有高度相似性，但 SAIL66 表现出对 CLDN6 的高度特异性，从而降低了脱靶毒性的风险。在与 CLDN6 阳性癌细胞的体外共培养测定中，我们证实 SAIL66 强烈激活 Jurkat 报告系统中的 CD137 信号，并优先诱导从人外周血单核细胞分离的 CD4 和 CD8 T 细胞的激活。传统传统文化表现形式。体内研究表明，与传统的 CLDN6 TCE 相比，SAIL66 通过 CD137 共刺激导致肿瘤内 T 细胞浸润更明显增加，耗尽的 T 细胞减少，从而在荷瘤小鼠模型中产生更好的抗肿瘤功效。我们的数据表明，SAIL66 旨在结合 CLDN6、CD3 和 CD137，具有增强抗肿瘤活性的潜力，并为表达 CLDN6 的卵巢癌和其他实体瘤患者提供有效的治疗选择。目前正在进行临床试验，以评估 SAIL66 的安全性和有效性。© 作者（或其雇主）2024。根据 CC BY-NC 允许重复使用。禁止商业再利用。请参阅权利和权限。英国医学杂志出版。

Ovarian cancer remains a formidable challenge in oncology, necessitating innovative therapeutic approaches. Claudin-6 (CLDN6), a member of the tight junction molecule CLDN family, exhibits negligible expression in healthy tissues but displays aberrant upregulation in various malignancies, including ovarian cancer. Although several therapeutic modalities targeting CLDN6 are currently under investigation, there is still a need for more potent therapeutic options. While T-cell engagers (TCEs) hold substantial promise as potent immunotherapeutic agents, their current efficacy and safety in terms of target antigen selection and T-cell exhaustion due to only CD3 stimulation without co-stimulation must be improved, particularly against solid tumors. To provide an efficacious treatment option for ovarian cancer, we generated SAIL66, a tri-specific antibody against CLDN6/CD3/CD137.Using our proprietary next-generation TCE technology (Dual-Ig), SAIL66 was designed to bind to CLDN6 with one Fab and CD3/CD137 with the other, thereby activating T cells through CD3 activation and CD137 co-stimulation. The preclinical characterization of SAIL66 was performed in a series of in vitro and in vivo studies which included comparisons to a conventional TCE targeting CLDN6 and CD3.Despite the high similarity between CLDN6 and other CLDN family members, SAIL66 demonstrated high specificity for CLDN6, reducing the risk of off-target toxicity. In an in vitro co-culture assay with CLDN6-positive cancer cells, we confirmed that SAIL66 strongly activated the CD137 signal in the Jurkat reporter system, and preferentially induced activation of both CD4+ and CD8+ T cells isolated from human peripheral blood mononuclear cells compared to conventional TCEs. In vivo studies demonstrated that SAIL66 led to a more pronounced increase in intratumor T-cell infiltration and a decrease in exhausted T cells compared with conventional CLDN6 TCE by contribution of CD137 co-stimulation, resulting in better antitumor efficacy in tumor-bearing mouse models.Our data demonstrate that SAIL66, designed to engage CLDN6, CD3, and CD137, has the potential to enhance antitumor activity and provide a potent therapeutic option for patients with ovarian and other solid tumors expressing CLDN6. Clinical trials are currently underway to evaluate the safety and efficacy of SAIL66.© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.