Abstract：
Bispecific antibodies are an important tool for the management and treatment of acute leukemias. As a next step toward clinical translation of engineered plasma cells, we describe approaches for secretion of bispecific antibodies by human plasma cells. We show that human plasma cells expressing either fragment crystallizable domain-deficient anti-CD19 × anti-CD3 (blinatumomab) or anti-CD33 × anti-CD3 bispecific antibodies mediate T cell activation and direct T cell killing of B acute lymphoblastic leukemia or acute myeloid leukemia cell lines in vitro. We demonstrate that knockout of the self-expressed antigen, CD19, boosts anti-CD19-bispecific secretion by plasma cells and prevents self-targeting. Plasma cells secreting anti-CD19-bispecific antibodies elicited in vivo control of acute lymphoblastic leukemia patient-derived xenografts in immunodeficient mice co-engrafted with autologous T cells. In these studies, we found that leukemic control elicited by engineered plasma cells was similar to CD19-targeted chimeric antigen receptor-expressing T cells. Finally, the steady-state concentration of anti-CD19 bispecifics in serum 1 month after cell delivery and tumor eradication was comparable with that observed in patients treated with a steady-state infusion of blinatumomab. These findings support further development of ePCs for use as a durable delivery system for the treatment of acute leukemias, and potentially other cancers.
摘要：
双特异性抗体是治疗和治疗急性白血病的重要工具。作为工程浆细胞临床转化的下一步，我们描述了人类浆细胞分泌双特异性抗体的方法。我们表明，表达片段可结晶结构域缺陷型抗CD19×抗CD3（blinatumomab）或抗CD33×抗CD3双特异性抗体的人浆细胞可介导T细胞活化并直接杀死B急性淋巴细胞白血病或急性髓性白血病细胞系。我们证明了自我表达抗原的敲除，CD19促进浆细胞的抗CD19双特异性分泌并防止自我靶向。分泌抗CD19双特异性抗体的浆细胞在与自体T细胞共移植的免疫缺陷小鼠中引起急性淋巴细胞白血病患者来源的异种移植物的体内控制。在这些研究中,我们发现,工程浆细胞引起的白血病控制与CD19靶向嵌合抗原受体表达T细胞相似.最后,在细胞递送和肿瘤根除后1个月,血清中抗CD19双特异性药物的稳态浓度与在接受博纳吐单抗稳态输注治疗的患者中观察到的浓度相当.这些发现支持ePCs作为治疗急性白血病的持久递送系统的进一步发展。和潜在的其他癌症。
