Inhibition of B cell activation following in vivo co-engagement of B cell antigen receptor and Fcγ receptor IIb in non-autoimmune-prone and SLE-prone mice.
Inhibition of B cell activation following in vivo co-engagement of B cell antigen receptor and Fcγ receptor IIb in non-autoimmune-prone and SLE-prone mice.
复制标题
DOI：
10.1016/j.jtauto.2020.100075
复制
发表时间：
2021
影响因子：
3.9
通讯作者：
Stohl W
中科院分区：
文献类型：
--
作者：
Chu SY;Pong E;Bonzon C;Yu N;Jacob CO;Chalmers SA;Putterman C;Szymkowski DE;Stohl W
Fcγ受体II B b（FcγRIIb）的结合抑制B细胞活化，是一种有前景的自身免疫治疗靶点。Obexelimab是一种非消耗性抗人CD 19 mAb，其Fc区经工程改造对人FcγRIIb具有高亲和力，从而共结合BCR和FcγRIIb。为了评估其在体内抑制B细胞活化的能力，我们制备了非自身免疫易感性C57 BL/6（B6）和SLE易感性NZM 2328（NZM）小鼠，其中人FcγRIIb胞外结构域敲入小鼠Fcgr 2 B基因座（分别为B6.hRIIb和NZM.hRIIb小鼠，后者保留了SLE的特征）。XENP 8206是一种mAb，其携带与obexelimab相同的Fcγ RIIb增强人Fc结构域，但识别鼠CD 19而非人CD 19，可抑制B6. hRIIb和NZM.hRIIb小鼠的B细胞的体外BCR触发活化。向B6. hRIIb或NZM.hRIIb小鼠给予XENP 8206后，脾脏和淋巴结中的B细胞数量保持稳定，但对BCR触发的活化反应迟钝至少14天。这些发现证明了BCR和人FcγRIIb的药理学共结合抑制非自身免疫和SLE易感宿主中的B细胞活化，同时保留B细胞数量的原理证明。这些观察结果为使用共结合BCR和FcγRIIb的药物在人类SLE中进行临床试验奠定了坚实的基础。此外，B6.hRIIb和NZM.hRIIb应作为强有力的体内模型，用于阐明BCR/FcγRIIb共结合诱导的变化的细胞和分子基础。我们针对人FcγRIIb细胞外结构域产生了非自身免疫性B6.hRIIb和SLE易感性NZM.hRIIb敲入小鼠。XENP 8206是一种抗鼠CD 19 mAb，经工程改造后对人FcγRIIb具有高亲和力。XENP 8206抑制B6. hRIIb和NZM.hRIIb小鼠的B细胞的体外BCR触发活化。XENP 8206抑制体内BCR触发的B细胞活化，同时保持B细胞数量。这些观察结果为使用共结合BCR和FcγRIIb的药物在人类SLE中进行临床试验奠定了坚实的基础。
Engagement of Fcγ receptor IIb (FcγRIIb) suppresses B cell activation and represents a promising target for therapy in autoimmunity. Obexelimab is a non-depleting anti-human CD19 mAb with an Fc region engineered to have high affinity for human FcγRIIb, thereby co-engaging BCR and FcγRIIb. To assess its ability to suppress B cell activation in vivo, we generated non-autoimmune-prone C57BL/6 (B6) and SLE-prone NZM 2328 (NZM) mice in which the human FcγRIIb extracellular domain was knocked into the mouse Fcgr2b locus (B6.hRIIb and NZM.hRIIb mice, respectively, the latter retaining features of SLE). XENP8206, a mAb which bears the same FcγRIIb-enhanced human Fc domain as does obexelimab but which recognizes murine CD19 rather than human CD19, inhibited in vitro BCR-triggered activation of B cells from both B6.hRIIb and NZM.hRIIb mice. Following administration of XENP8206 to B6.hRIIb or NZM.hRIIb mice, B cell numbers in the spleen and lymph nodes remained stable but became hyporesponsive to BCR-triggered activation for at least 14 days. These findings demonstrate proof-of-principle that pharmacologic co-engagement of BCR and human FcγRIIb inhibits B cell activation in non-autoimmune and SLE-prone hosts while preserving B cell numbers. These observations lay a strong foundation for clinical trials in human SLE with agents that co-engage BCR and FcγRIIb. Moreover, B6.hRIIb and NZM.hRIIb should serve as powerful in vivo models in the elucidation of the cellular and molecular underpinnings of the changes induced by BCR/FcγRIIb co-engagement. We generated non-autoimmune B6.hRIIb and SLE-prone NZM.hRIIb knockin mice for the human FcγRIIb extracellular domain. XENP8206 is an anti-murine CD19 mAb engineered to have high affinity for human FcγRIIb. XENP8206 inhibited in vitro BCR-triggered activation of B cells from both B6.hRIIb and NZM.hRIIb mice. XENP8206 inhibited in vivo BCR-triggered activation of B cells while preserving B cell numbers. These observations lay a strong foundation for clinical trials in human SLE with agents that co-engage BCR and FcγRIIb.
登录
查看更多内容
影响因子：
13.3
作者：
Chu, Seung Y.;Yeter, Karen;Szymkowski, David E.
通讯作者：
Szymkowski, David E.
影响因子：
4.4
作者：
Horton, Holly M.;Chu, Seung Y.;Szymkowski, David E.
通讯作者：
Szymkowski, David E.
影响因子：
4.4
作者：
Agrawal, Hemant;Jacob, Noam;Jacob, Chaim O.
通讯作者：
Jacob, Chaim O.
影响因子：
158.5
作者：
Edwards, JCW;Szczepanski, L;Shaw, T
通讯作者：
Shaw, T
影响因子：
20.3
作者：
Carson, Kenneth R.;Evens, Andrew M.;Bennett, Charles L.
通讯作者：
Bennett, Charles L.