Département d'Hématologie Clinique, Centre Hospitalier Universitaire (CHU), Montpellier, France.
Unité Mixte de Recherche (UMR) 5235, Centre National de la Recherche Scientifique (CNRS), Université de Montpellier, Montpellier, France.
Blood. 2017 Aug 3;130(5):581-589. doi: 10.1182/blood-2017-03-771832. Epub 2017 Jun 5.
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 FcγRIIIA-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 FcγRIIIA-mediated mechanisms when the target antigen is expressed at a low density. Results of OBZ in FL confirm the interest for FcγRIIIA-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.
奥滨尤妥珠单抗（OBZ）是一种重组型 II 抗 CD20 免疫球蛋白 G1 Fc 优化单克隆抗体（mAb），最近在慢性淋巴细胞白血病（CLL；B 细胞 CLL）和滤泡性淋巴瘤（FL）中获得批准。利妥昔单抗（RTX）常被视为其“前身”，而 OBZ 的临床开发依据是 FcγRIIIA 介导的机制在 RTX 临床活性中的重要性。然而，RTX 在 2 个关键的独立特性上与 OBZ 不同：RTX 是一种 I 型抗 CD20 mAb，且 Fc 未被优化。此外，RTX 和 OBZ 采用不同的剂量方案进一步使临床结果的解释复杂化。OBZ 在 CLL 中获得的结果为靶抗原低表达时 FcγRIIIA 介导的机制提供了新的论据。OBZ 在 FL 中的结果证实了 FcγRIIIA 介导的机制的意义，尽管存在一些局限性，其中一些可能是由于缺乏 OBZ 诱导的补体激活。弥漫性大 B 细胞淋巴瘤的情况具有欺骗性，因为 OBZ 活性的潜在获益似乎因缺乏补体激活而被消除。尽管 RTX 偶然是一种具有平衡药效学特性的抗 CD20 mAb，但强化某些特性（以牺牲补体激活为代价）在某些 B 细胞疾病中赋予了优势，同时限制了 OBZ 的适应证。OBZ 的故事很好地证明了裸 mAb 的未来在于设计具有优化和定制特性的药物，这必须一步一步地进行，同时进行全面的临床验证。
