PDF(Pubmed)
Abstract：
Complement-dependent cytotoxicity (CDC), which eliminates aberrant target cells through the assembly and complex formation of serum complement molecules, is one of the major effector functions of anticancer therapeutic antibodies. In this study, we discovered that breaking the symmetry of natural immunoglobulin G (IgG) antibodies significantly increased the CDC activity of anti-CD20 antibodies. In addition, the expression of CD55 (a checkpoint inhibitor in the CDC cascade) was significantly increased in a rituximab-resistant cell line generated in-house, suggesting that CD55 overexpression might be a mechanism by which cancer cells acquire rituximab resistance. Based on these findings, we developed an asymmetric bispecific antibody (SBU-CD55 × CD20) that simultaneously targets both CD55 and CD20 to effectively eliminate rituximab-resistant cancer cells. In various cancer cell lines, including rituximab-resistant lymphoma cells, the SBU-CD55 × CD20 antibody showed significantly higher CDC activity than either anti-CD20 IgG antibody alone or a combination of anti-CD20 IgG antibody and anti-CD55 IgG antibody. Furthermore, the asymmetric bispecific antibody (SBU-CD55 × CD20) exhibited significantly higher CDC activity against rituximab-resistant cancer cells compared to other bispecific antibodies with symmetric features. These results demonstrate that enhancing CDC with an asymmetric CD55-binding bispecific antibody could be a new strategy for developing therapeutics to treat patients with relapsed or refractory cancers.
摘要：
补体依赖性细胞毒性（CDC），通过血清补体分子的组装和复合物形成消除异常靶细胞，是抗癌治疗性抗体的主要效应子功能之一。在这项研究中,我们发现,打破天然免疫球蛋白G(IgG)抗体的对称性能显著增加抗CD20抗体的CDC活性.此外,CD55（CDC级联中的检查点抑制剂）的表达在内部产生的利妥昔单抗抗性细胞系中显著增加，提示CD55过表达可能是癌细胞获得利妥昔单抗耐药的一种机制.基于这些发现,我们开发了一种同时靶向CD55和CD20的不对称双特异性抗体(SBU-CD55×CD20),以有效消除利妥昔单抗耐药癌细胞.在各种癌细胞系中，包括利妥昔单抗耐药的淋巴瘤细胞,SBU-CD55×CD20抗体的CDC活性显著高于单独抗CD20IgG抗体或抗CD20IgG抗体和抗CD55IgG抗体的组合.此外，与其他具有对称特征的双特异性抗体相比,不对称双特异性抗体(SBU-CD55×CD20)对利妥昔单抗耐药癌细胞的CDC活性明显更高.这些结果表明,用不对称CD55结合双特异性抗体增强CDC可能是开发治疗复发性或难治性癌症患者的治疗剂的新策略。
