文章：

BR109：一种新型全人源化T细胞接合双特异性抗体，具有GPRC5D结合能力，在多发性骨髓瘤中展现出强效抗肿瘤活性

BR109, a Novel Fully Humanized T-Cell-Engaging Bispecific Antibody with GPRC5D Binding, Has Potent Antitumor Activities in Multiple Myeloma

原文发布日期：9 December 2023

DOI: 10.3390/cancers15245774

类型: Article

开放获取: 是

英文摘要：

At present, multiple myeloma (MM) is still an essentially incurable hematologic malignancy. Although BCMA-targeted therapies have achieved remarkable results, BCMA levels were found to be downregulated in patients with MM who relapsed after these treatments. Therefore, the search for other antigens specific to MM has become a priority. Independently of BCMA expression, G-protein-coupled receptor family C group 5 member D (GPRC5D) is mainly expressed in the plasma cells of MM patients, while it is expressed in a limited number of normal tissues. Combining MM-specific antigen GPRC5D and T-cell-mediated therapies would be a promising therapeutic strategy for MM. Recently, we constructed a new anti-GPRC5D × anti-CD3 T-cell-engaging bispecific antibody (TCB), BR109, which was capable of binding to human GPRC5D and human CD3ε. Moreover, BR109 was proven to have relatively good stability and antitumor activity. BR109 could specifically trigger T-cell-mediated cytotoxicity against many GPRC5D-positive MM cells in vitro. Meanwhile, antitumor activity was demonstrated in MM cell line xenograft mouse models with human immune cell reconstitution. These preclinical studies have formed a solid foundation for the evaluation of MM treatment efficacy in clinical trials.

摘要翻译： 

目前，多发性骨髓瘤（MM）仍是一种基本无法治愈的血液系统恶性肿瘤。尽管靶向BCMA的疗法已取得显著成效，但研究发现接受此类治疗后复发的MM患者体内BCMA水平会出现下调。因此，寻找其他MM特异性抗原已成为当务之急。G蛋白偶联受体C家族5组成员D（GPRC5D）的表达独立于BCMA，主要存在于MM患者的浆细胞中，而在正常组织中表达有限。将MM特异性抗原GPRC5D与T细胞介导疗法相结合，有望成为MM治疗的新策略。近期，我们构建了一种新型抗GPRC5D×抗CD3 T细胞衔接双特异性抗体（TCB）BR109，该抗体能够同时结合人源GPRC5D与人源CD3ε。研究证实BR109具有较好的稳定性与抗肿瘤活性，在体外能特异性激活T细胞介导的细胞毒性作用，有效杀伤多种GPRC5D阳性MM细胞。同时，在重建人源免疫细胞的MM细胞系异种移植小鼠模型中，BR109也展现出显著的抗肿瘤效果。这些临床前研究为后续临床试验评估MM治疗效果奠定了坚实基础。

原文链接：

BR109, a Novel Fully Humanized T-Cell-Engaging Bispecific Antibody with GPRC5D Binding, Has Potent Antitumor Activities in Multiple Myeloma