Anti-CD20 Antibody with Multimerized Fc Domains: A Novel Strategy To Deplete B Cells and Augment Treatment of Autoimmune Disease

作者：Zhang, Xiaoyu; Olsen, Henrik S.; Chen, Shaodong; So, Edward; Zhou, Hua; Burch, Erin; Merigeon, Emmanuel Y.; Block, David S.; Strome, Scott E.^*

来源：The Journal of Immunology, 2016, 196(3): 1165-1176.

DOI：10.4049/jimmunol.1501755

• INTRAVENOUS IMMUNE GLOBULIN
• IDIOPATHIC THROMBOCYTOPENIC PURPURA
• PERSISTENT VIRAL-INFECTION
• RHEUMATOID-ARTHRITIS
• MONOCLONAL-ANTIBODIES
• DOUBLE-BLIND
• HUMAN IGG2
• IMMUNOGLOBULIN-G
• GAMMA-RECEPTORS
• IN-VIVO

We developed a fully recombinant anti-CD20 protein derived from cDNA encoding one Fab domain, two IgG1 Fc regions, the IgG2 hinge, and an isoleucine zipper. This protein, called GB4542, contained both the homodimer and higher-order multimers. Binding studies revealed that GB4542 preferentially bound CD20(+) cells yet also recognized CD20(-) Fc gamma R+ PBMC. In contrast, a control mAb containing the identical Fab region, GB4500, failed to bind CD20(-) Fc gamma R+ PBMC. Consistent with these findings, interactions between GB4542 and the canonical Fc gamma Rs had substantially lower K-D values than correlate interfaces between GB4500 and these receptors. At low concentrations, GB4542 showed enhanced Ab-dependent cellular cytotoxicity, Ab-dependent cellular phagocytosis, and complement-dependent cytotoxicity compared with GB4500. However, at higher concentrations, an Fc analog of GB4542 inhibited anti-CD20 mAb mediated B cell clearance through direct blocking of both Fc-Fc gamma R interactions and C1q deposition on target cells. Furthermore, the higher-order multimer fraction of GB4542 demonstrated greater binding avidity with the canonical FcyRs and was associated with inhibitory effects observed in Ab-dependent cellular phagocytosis and complement dependent cytotoxicity assays. These data suggest that GB4542 might have utility in the treatment of autoimmune diseases by combining both mAb-mediated B cell depletion and multimerized Fc-mediated tolerogenic effects.

• 出版日期2016-2-1
• 单位厦门大学