Symphogen A/S, Lyngby, Denmark; Department of Haematology L4042, Rigshospitalet, Copenhagen.
Br J Haematol. 2013 Oct;163(2):182-93. doi: 10.1111/bjh.12503. Epub 2013 Aug 8.
The treatment of chronic lymphocytic leukaemia (CLL) has been improved by introduction of monoclonal antibodies (mAbs) that exert their effect through secondary effector mechanisms. CLL cells are characterized by expression of CD5 and CD23 along with CD19 and CD20, hence anti-CD5 Abs that engage secondary effector functions represent an attractive opportunity for CLL treatment. Here, a repertoire of mAbs against human CD5 was generated and tested for ability to induce complement-dependent cytotoxicity (CDC) and antibody-dependent cell-mediated cytotoxicity (ADCC) both as single mAbs and combinations of two mAbs against non-overlapping epitopes on human CD5. The results demonstrated that combinations of two mAbs significantly increased the level of CDC compared to the single mAbs, while no enhancement of ADCC was seen with anti-CD5 mAb combinations. High levels of CDC and ADCC correlated with low levels of Ab-induced CD5 internalization and degradation. Importantly, an anti-CD5 mAb combination enhanced CDC of CLL cells when combined with the anti-CD20 mAbs rituximab and ofatumumab as well as with the anti-CD52 mAb alemtuzumab. These results suggest that an anti-CD5 mAb combination inducing CDC and ADCC may be effective alone, in combination with mAbs against other targets or combined with chemotherapy for CLL and other CD5-expressing haematological or lymphoid malignancies.
慢性淋巴细胞白血病（CLL）的治疗已经通过引入单克隆抗体（mAbs）得到了改善，这些 mAbs 通过二级效应机制发挥作用。CLL 细胞的特征是表达 CD5 和 CD23，同时还表达 CD19 和 CD20，因此，能够发挥二级效应功能的抗 CD5 Abs 为 CLL 治疗提供了一个有吸引力的机会。在这里，生成了针对人 CD5 的 mAb 库，并测试了它们作为单 mAb 以及针对人 CD5 上非重叠表位的两种 mAb 的组合诱导补体依赖性细胞毒性（CDC）和抗体依赖性细胞介导的细胞毒性（ADCC）的能力。结果表明，与单 mAb 相比，两种 mAb 的组合显著增加了 CDC 水平，而抗 CD5 mAb 组合对 ADCC 没有增强作用。高水平的 CDC 和 ADCC 与低水平的 Ab 诱导的 CD5 内化和降解相关。重要的是，抗 CD5 mAb 组合与抗 CD20 mAbs 利妥昔单抗和奥法妥珠单抗以及抗 CD52 mAb 阿仑单抗联合使用时，可增强 CLL 细胞的 CDC。这些结果表明，诱导 CDC 和 ADCC 的抗 CD5 mAb 组合可能单独使用有效，也可与针对其他靶点的 mAbs 联合使用，或与化疗联合用于 CLL 和其他表达 CD5 的血液学或淋巴样恶性肿瘤。
