Obinutuzumab induces superior B-cell cytotoxicity to rituximab in rheumatoid arthritis and systemic lupus erythematosus patient samples.
Obinutuzumab induces superior B-cell cytotoxicity to rituximab in rheumatoid arthritis and systemic lupus erythematosus patient samples.
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DOI：
10.1093/rheumatology/kex067
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发表时间：
2017-07-01
期刊：
影响因子：
--
通讯作者：
Leandro MJ
中科院分区：
文献类型：
--
作者：
Reddy V;Klein C;Isenberg DA;Glennie MJ;Cambridge G;Cragg MS;Leandro MJ
Objective.用标准剂量的利妥昔单抗（RTX）治疗的一部分RA和SLE患者显示出低效的B细胞缺失和差的临床应答，其可以通过递送更高剂量来增强，这表明标准剂量的RTX在这些患者中是次优疗法。本研究旨在研究机制不同的抗CD20 mAb是否可以实现更好的应答。 方法.我们比较了RTX与obinutuzumab（OBZ），一种新一代的，糖工程化的II型抗CD20 mAb，在一系列体外试验中测量RA和SLE患者样本中的B细胞毒性。 结果我们发现OBZ在体外全血测定中诱导B细胞细胞毒性的效率比RTX高至少2倍。剖析这种差异，我们发现RTX比OBZ引起更强的补体依赖性细胞毒性。相比之下，OBZ在诱发Fc γ受体介导的效应器机制方面更有效，包括NK细胞和中性粒细胞的活化，这可能是由于与Fc γ受体的相互作用更强以及OBZ在CD20接合后保持在细胞表面的能力，而RTX变得内化。OBZ在诱导直接细胞死亡方面也更有效。这对于所有CD 19 + B细胞整体以及幼稚（IgD+ CD 27 −）和转换（IgD− CD 27+）记忆B细胞都是如此，其频率较高与RTX后临床应答较差相关。 结论总之，这些数据提供了对利妥昔单抗诱导的B细胞耗竭的抗性的机制基础，并考虑将obinutuzumab作为RA和SLE中的替代B细胞耗竭剂。
Objective. A proportion of RA and SLE patients treated with standard doses of rituximab (RTX) display inefficient B cell deletion and poor clinical responses that can be augmented by delivering higher doses, indicating that standard-dose RTX is a sub-optimal therapy in these patients. This study aimed to investigate whether better responses could be achieved with mechanistically different anti-CD20 mAbs. Methods. We compared RTX with obinutuzumab (OBZ), a new-generation, glycoengineered type II anti-CD20 mAb, in a series of in vitro assays measuring B cell cytotoxicity in RA and SLE patient samples. Results. We found that OBZ was at least 2-fold more efficient than RTX at inducing B-cell cytotoxicity in in vitro whole blood assays. Dissecting this difference, we found that RTX elicited more potent complement-dependent cellular cytotoxicity than OBZ. In contrast, OBZ was more effective at evoking Fc gamma receptor-mediated effector mechanisms, including activation of NK cells and neutrophils, probably due to stronger interaction with Fc gamma receptors and the ability of OBZ to remain at the cell surface following CD20 engagement, whereas RTX became internalized. OBZ was also more efficient at inducing direct cell death. This was true for all CD19+ B cells as a whole and in naïve (IgD+CD27−) and switched (IgD−CD27+) memory B cells specifically, a higher frequency of which is associated with poor clinical response after RTX. Conclusion. Taken together, these data provide a mechanistic basis for resistance to rituximab-induced B-cell depletion, and for considering obinutuzumab as an alternative B-cell depleting agent in RA and SLE.
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影响因子：
5.5
作者：
Dias, Sofia Sapeta;Rodriguez-Garcia, Veronica;Isenberg, David
通讯作者：
Isenberg, David
影响因子：
3.6
作者：
GREENMAN, J;TUTT, AL;GLENNIE, MJ
通讯作者：
GLENNIE, MJ
影响因子：
158.5
作者：
FRANK, MM;HAMBURGER, MI;PLOTZ, PH
通讯作者：
PLOTZ, PH
影响因子：
3.7
作者：
Fossati-Jimack L;Ling GS;Cortini A;Szajna M;Malik TH;McDonald JU;Pickering MC;Cook HT;Taylor PR;Botto M
通讯作者：
Botto M
影响因子：
4.4
作者：
Herter, Sylvia;Birk, Martina C.;Bacac, Marina
通讯作者：
Bacac, Marina