膜近端表位促进抗FcRH5/CD3高效形成T细胞突触，且是杀伤骨髓瘤细胞的必要条件。
Membrane-Proximal Epitope Facilitates Efficient T Cell Synapse Formation by Anti-FcRH5/CD3 and Is a Requirement for Myeloma Cell Killing.
作者信息
Li Ji, Stagg Nicola J, Johnston Jennifer, Harris Michael J, Menzies Sam A, DiCara Danielle, Clark Vanessa, Hristopoulos Maria, Cook Ryan, Slaga Dionysos, Nakamura Rin, McCarty Luke, Sukumaran Siddharth, Luis Elizabeth, Ye Zhengmao, Wu Thomas D, Sumiyoshi Teiko, Danilenko Dimitry, Lee Genee Y, Totpal Klara, Ellerman Diego, Hötzel Isidro, James John R, Junttila Teemu T
机构信息
Genentech, Inc., 1 DNA Way, South San Francisco, San Francisco, CA 94080, USA.
Molecular Immunity Unit, Department of Medicine, University of Cambridge, MRC-LMB, Cambridge, CB2 0QH, UK.
出版信息
Cancer Cell. 2017 Mar 13;31(3):383-395. doi: 10.1016/j.ccell.2017.02.001. Epub 2017 Mar 2.
The anti-FcRH5/CD3 T cell-dependent bispecific antibody (TDB) targets the B cell lineage marker FcRH5 expressed in multiple myeloma (MM) tumor cells. We demonstrate that TDBs trigger T cell receptor activation by inducing target clustering and exclusion of CD45 phosphatase from the synapse. The dimensions of the target molecule play a key role in the efficiency of the synapse formation. The anti-FcRH5/CD3 TDB kills human plasma cells and patient-derived myeloma cells at picomolar concentrations and results in complete depletion of B cells and bone marrow plasma cells in cynomolgus monkeys. These data demonstrate the potential for the anti-FcRH5/CD3 TDB, alone or in combination with inhibition of PD-1/PD-L1 signaling, in the treatment of MM and other B cell malignancies.
抗FcRH5/CD3 T细胞依赖性双特异性抗体（TDB）靶向在多发性骨髓瘤（MM）肿瘤细胞中表达的B细胞谱系标志物FcRH5。我们证明，TDB通过诱导靶点聚集和将CD45磷酸酶排除在突触之外来触发T细胞受体激活。靶点分子的尺寸在突触形成效率中起关键作用。抗FcRH5/CD3 TDB在皮摩尔浓度下可杀死人浆细胞和患者来源的骨髓瘤细胞，并导致食蟹猴的B细胞和骨髓浆细胞完全耗竭。这些数据证明了抗FcRH5/CD3 TDB单独或与抑制PD-1/PD-L1信号传导联合用于治疗MM和其他B细胞恶性肿瘤的潜力。
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