Membrane-Proximal Epitope Facilitates Efficient T Cell Synapse Formation by Anti-FcRH5/CD3 and Is a Requirement for Myeloma Cell Killing.
Membrane-Proximal Epitope Facilitates Efficient T Cell Synapse Formation by Anti-FcRH5/CD3 and Is a Requirement for Myeloma Cell Killing.
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DOI：
10.1016/j.ccell.2017.02.001
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发表时间：
2017-03-13
期刊：
影响因子：
50.3
通讯作者：
Junttila TT
中科院分区：
文献类型：
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作者：
Li J;Stagg NJ;Johnston J;Harris MJ;Menzies SA;DiCara D;Clark V;Hristopoulos M;Cook R;Slaga D;Nakamura R;McCarty L;Sukumaran S;Luis E;Ye Z;Wu TD;Sumiyoshi T;Danilenko D;Lee GY;Totpal K;Ellerman D;Hötzel I;James JR;Junttila TT
抗 FcRH5/CD3 T 细胞依赖性双特异性抗体 (TDB) 靶向多发性骨髓瘤 (MM) 肿瘤细胞中表达的 B 细胞谱系标记物 FcRH5。我们证明 TDB 通过诱导靶点聚集和从突触中排除 CD45 磷酸酶来触发 T 细胞受体激活。目标分子的尺寸对突触形成的效率起着关键作用。抗 FcRH5/CD3 TDB 在皮摩尔浓度下杀死人浆细胞和患者来源的骨髓瘤细胞，并导致食蟹猴中 B 细胞和骨髓浆细胞完全耗尽。这些数据证明了抗 FcRH5/CD3 TDB 单独或与 PD-1/PD-L1 信号传导抑制联合治疗 MM 和其他 B 细胞恶性肿瘤的潜力。多发性骨髓瘤中 FcRH5 表达的流行率为 100% 抗 FcRH5/CD3 TDB 重定向 T 细胞以杀死骨髓瘤细胞 靶点聚集和 CD45 排除激活 T 细胞 抗 FcRH5/CD3 TDB 是一种针对骨髓瘤的高效免疫疗法 Li 等人。报道称，靶标的大小和表位位置对于 T 细胞依赖性双特异性抗体 (TDB) 诱导的 T 细胞激活效率起着关键作用。他们开发了一种针对所有多发性骨髓瘤肿瘤细胞中表达的 FcRH5 的 TDB，并展示了其治疗这种疾病的潜力。
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. Prevalence of FcRH5 expression in multiple myeloma is 100% Anti-FcRH5/CD3 TDB redirects T cells to kill myeloma cells Target clustering and CD45 exclusion activate T cells Anti-FcRH5/CD3 TDB is a highly efficacious immunotherapy for myeloma Li et al. report that the size and epitope location of the target play a key role in the efficiency of T cell activation induced by T cell-dependent bispecific antibodies (TDBs). They develop a TDB targeting FcRH5 expressed in all multiple myeloma tumor cells and show its potential in treating this disease.