Hörner Sebastian, Moustafa-Oglou Moustafa, Teppert Karin, Hagelstein Ilona, Kauer Joseph, Pflügler Martin, Neumann Kristina, Rammensee Hans-Georg, Metz Thomas, Herrmann Andreas, Salih Helmut R, Jung Gundram, Zekri Latifa
Department of Immunology, Institute for Cell Biology, Eberhard Karls University Tuebingen, German Cancer Consortium (DKTK), Partner Site Tuebingen, 72076 Tuebingen, Germany.
Clinical Collaboration Unit Translational Immunology, German Cancer Consortium (DKTK), Department of Internal Medicine, University Hospital Tuebingen, 72076 Tuebingen, Germany.
Cancers (Basel). 2022 Aug 16;14(16):3941. doi: 10.3390/cancers14163941.
Antibodies against the B cell-specific antigens CD20 and CD19 have markedly improved the treatment of B cell-derived lymphoma and autoimmune diseases by depleting malignant and autoreactive B cells. However, since CD20 and CD19 are also expressed on healthy B cells, such antibodies lack disease specificity. Here, we optimize a previously developed concept that uses bispecific antibodies to induce apoptosis selectively in malignant and autoreactive B cells that express the death receptor CD95. We describe the development and characterization of bispecific antibodies with CD95xCD20 and CD95xCD19 specificity in a new IgG-based format. We could show that especially the CD95xCD20 antibody mediated a strong induction of apoptosis in malignant B cells in vitro. In vivo, the antibody was clearly superior to the previously used Fabsc format with identical specificities. In addition, both IgGsc antibodies depleted activated B cells in vitro, leading to a significant reduction in antibody production and cytokine secretion. The killing of resting B cells and hepatocytes that lack CD95 and CD20/CD19, respectively, was marginal. Thus, our results imply that bispecific anti-CD95 antibodies in the IgGsc format are an attractive tool for a more selective and efficient depletion of malignant as well as autoreactive B cells.
针对B细胞特异性抗原CD20和CD19的抗体，通过清除恶性和自身反应性B细胞，显著改善了B细胞源性淋巴瘤和自身免疫性疾病的治疗效果。然而，由于CD20和CD19也在健康B细胞上表达，此类抗体缺乏疾病特异性。在此，我们优化了先前开发的一种概念，即利用双特异性抗体在表达死亡受体CD95的恶性和自身反应性B细胞中选择性诱导凋亡。我们描述了以新型IgG为基础形式的具有CD95xCD20和CD95xCD19特异性的双特异性抗体的研发及特性。我们能够证明，尤其是CD95xCD20抗体在体外对恶性B细胞凋亡有强烈的诱导作用。在体内，该抗体明显优于先前使用的具有相同特异性的Fabsc形式。此外，两种IgGsc抗体在体外均可清除活化的B细胞，导致抗体产生和细胞因子分泌显著减少。对分别缺乏CD95和CD20/CD19的静止B细胞和肝细胞的杀伤作用微乎其微。因此，我们的结果表明，IgGsc形式的双特异性抗CD95抗体是一种更具选择性和高效性地清除恶性及自身反应性B细胞的有吸引力的工具。
