Chu Seung Y, Pong Erik, Bonzon Christine, Yu Ning, Jacob Chaim O, Chalmers Samantha A, Putterman Chaim, Szymkowski David E, Stohl William
Xencor, Inc., Monrovia, CA, 91016, USA.
Division of Rheumatology, Department of Medicine, University of Southern California Keck School of Medicine, Los Angeles, CA, 90033, USA.
J Transl Autoimmun. 2020 Dec 15;4:100075. doi: 10.1016/j.jtauto.2020.100075. eCollection 2021.
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 , 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 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 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 models in the elucidation of the cellular and molecular underpinnings of the changes induced by BCR/FcγRIIb co-engagement.
Fcγ受体IIb（FcγRIIb）的参与可抑制B细胞活化，是自身免疫性疾病治疗的一个有前景的靶点。Obexelimab是一种非耗竭性抗人CD19单克隆抗体，其Fc区域经过工程改造，对人FcγRIIb具有高亲和力，从而共同参与BCR和FcγRIIb。为了评估其抑制B细胞活化的能力，我们构建了不易发生自身免疫的C57BL/6（B6）小鼠和易患系统性红斑狼疮的NZM 2328（NZM）小鼠，其中人FcγRIIb细胞外结构域被敲入小鼠基因座（分别为B6.hRIIb和NZM.hRIIb小鼠，后者保留系统性红斑狼疮的特征）。XENP8206是一种单克隆抗体，其具有与obexelimab相同的FcγRIIb增强型人Fc结构域，但识别鼠CD19而非人CD19，可抑制来自B6.hRIIb和NZM.hRIIb小鼠的BCR触发的B细胞活化。给B6.hRIIb或NZM.hRIIb小鼠注射XENP8206后，脾脏和淋巴结中的B细胞数量保持稳定，但对BCR触发的活化反应减弱，至少持续14天。这些发现证明了原理，即BCR与人FcγRIIb的药理学共同参与可抑制非自身免疫和易患系统性红斑狼疮宿主中的B细胞活化，同时保留B细胞数量。这些观察结果为使用共同参与BCR和FcγRIIb的药物进行人类系统性红斑狼疮的临床试验奠定了坚实的基础。此外，B6.hRIIb和NZM.hRIIb应作为强大的模型，用于阐明BCR/FcγRIIb共同参与诱导的变化的细胞和分子基础。
