Department of Immunology and Microbiology, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO.
Multiple Sclerosis and Neurorepair Research Unit, Biogen, Cambridge, MA.
J Immunol. 2022 Apr 1;208(7):1566-1584. doi: 10.4049/jimmunol.2101056. Epub 2022 Mar 23.
The BCR comprises a membrane-bound Ig that is noncovalently associated with a heterodimer of CD79A and CD79B. While the BCR Ig component functions to sense extracellular Ag, CD79 subunits contain cytoplasmic ITAMs that mediate intracellular propagation of BCR signals critical for B cell development, survival, and Ag-induced activation. CD79 is therefore an attractive target for Ab and chimeric Ag receptor T cell therapies for autoimmunity and B cell neoplasia. Although the mouse is an attractive model for preclinical testing, due to its well-defined immune system, an obstacle is the lack of cross-reactivity of candidate therapeutic anti-human mAbs with mouse CD79. To overcome this problem, we generated knockin mice in which the extracellular Ig-like domains of CD79A and CD79B were replaced with human equivalents. In this study, we describe the generation and characterization of mice expressing chimeric CD79 and report studies that demonstrate their utility in preclinical analysis of anti-human CD79 therapy. We demonstrate that human and mouse CD79 extracellular domains are functionally interchangeable, and that anti-human CD79 lacking Fc region effector function does not cause significant B cell depletion, but induces 1) decreased expression of plasma membrane-associated IgM and IgD, 2) uncoupling of BCR-induced tyrosine phosphorylation and calcium mobilization, and 3) increased expression of PTEN, consistent with the levels observed in anergic B cells. Finally, anti-human CD79 treatment prevents disease development in two mouse models of autoimmunity. We also present evidence that anti-human CD79 treatment may inhibit Ab secretion by terminally differentiated plasmablasts and plasma cells in vitro.
BCR 由一个膜结合的 Ig 组成，该 Ig 与 CD79A 和 CD79B 的异二聚体非共价结合。虽然 BCR Ig 成分的功能是感知细胞外 Ag，但 CD79 亚基包含细胞质 ITAMs，介导 BCR 信号的细胞内传播，这些信号对于 B 细胞的发育、存活和 Ag 诱导的激活至关重要。因此，CD79 是自身免疫和 B 细胞肿瘤发生的 Ab 和嵌合 Ag 受体 T 细胞治疗的有吸引力的靶标。尽管小鼠是临床前测试的理想模型，因为其免疫系统定义明确，但一个障碍是候选治疗性抗人 mAb 与小鼠 CD79 缺乏交叉反应性。为了克服这个问题，我们生成了 knockin 小鼠，其中 CD79A 和 CD79B 的细胞外 Ig 样结构域被人源等同物取代。在这项研究中，我们描述了表达嵌合 CD79 的小鼠的产生和特征，并报告了证明其在抗人 CD79 治疗的临床前分析中有用的研究。我们证明了人源和小鼠源 CD79 细胞外结构域在功能上是可互换的，并且缺乏 Fc 区域效应功能的抗人 CD79 不会导致显著的 B 细胞耗竭，但会诱导 1）细胞膜相关 IgM 和 IgD 的表达减少，2）BCR 诱导的酪氨酸磷酸化和钙动员脱偶联，和 3）PTEN 的表达增加，与无活性 B 细胞中观察到的水平一致。最后，抗人 CD79 治疗可预防两种自身免疫小鼠模型的疾病发展。我们还提供了证据表明，抗人 CD79 治疗可能会抑制体外终末分化的浆母细胞和浆细胞中 Ab 的分泌。
