Obinutuzumab: what is there to learn from clinical trials?
Obinutuzumab: what is there to learn from clinical trials?
复制标题
DOI：
10.1182/blood-2017-03-771832
复制
发表时间：
2017-08-03
期刊：
影响因子：
20.3
通讯作者：
Watier, Herve
中科院分区：
文献类型：
--
作者：
Cartron, Guillaume;Watier, Herve
Obinutuzumab（OBZ）是一种重组II型抗CD 20和免疫球蛋白G1 Fc优化的单克隆抗体（mAb），最近批准用于慢性淋巴细胞白血病（CLL; B细胞CLL）和滤泡性淋巴瘤（FL）。利妥昔单抗（RTX）通常被认为是其“祖先”，OBZ临床开发的理由是Fc γ RIIIA介导的机制在RTX临床活性中的重要性。然而，RTX与OBZ的不同之处在于2个关键的独立性质：是I型抗CD 20 mAb，并且不是Fc优化的。此外，RTX和OBZ使用不同的给药方案进一步使临床结果的任何解释复杂化。当靶抗原以低密度表达时，CLL中OBZ获得的结果为Fc γ RIIIA介导的机制提供了新的论据。FL中OBZ的结果证实了对Fc γ RIIIA介导机制的关注，但存在一些局限性，其中一些可能是由于缺乏OBZ诱导的补体激活。弥漫性大B细胞淋巴瘤的情况是欺骗性的，因为OBZ活性的可能增加似乎被补体激活的缺乏所消除。尽管RTX是一种具有平衡药效学特性的抗CD 20 mAb，但以补体激活为代价增强了其中一些特性，在某些B细胞疾病中具有优势，同时限制了OBZ适应症。OBZ的故事很好地证明了裸mAb的未来是设计具有优化和定制特性的试剂，并且必须一步一步地完成，并进行全面的临床验证。
Obinutuzumab (OBZ) is a recombinant type II anti-CD20 and immunoglobulin G1 Fc-optimized monoclonal antibody (mAb), recently approved in chronic lymphocytic leukemia (CLL; B-cell CLL) and follicular lymphoma (FL). Rituximab (RTX) is frequently considered as its "ancestor" and OBZ clinical development was justified by the importance of Fc gamma RIIIA-mediated mechanisms in RTX clinical activity. However, RTX differs from OBZ in 2 critical independent properties: being a type I anti-CD20 mAb and not being Fc-optimized. Moreover, the use of a different dosing regimen for RTX and OBZ further complicates any interpretation of clinical results. The results obtained for OBZ in CLL provide new arguments for Fc gamma RIIIA-mediated mechanisms when the target antigen is expressed at a low density. Results of OBZ in FL confirm the interest for Fc gamma RIIIA-mediated mechanisms, with some limitations, some of them being possibly due to lack of OBZ-induced complement activation. The situation in diffuse large B-cell lymphoma is deceiving, as the possible gains of activity of OBZ appear to be annihilated by the lack of complement activation. Although RTX was by chance an anti-CD20 mAb with equilibrated pharmacodynamic properties, the reinforcement of some of these properties, which has been done at the expense of complement activation, has conferred an advantage in some B-cell disorders while restricting OBZ indications. The OBZ story nicely demonstrates that the future of naked mAbs is to design agents with optimized and tailored properties, and that this must be done step by step, with a full clinical validation.