Tyler F Hill, Parnal Narvekar, Gregory D Asher, Jasmine N Edelstein, Nathan D Camp, Annaiz Grimm, Kerri R Thomas, Michael D Leiken, Katherine M Molloy, Peter J Cook, Sean P Arlauckas, Richard A Morgan, Sarah K Tasian, David J Rawlings, Richard G James
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引用次数: 0
摘要
双特异性抗体是管理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。我们发现,表达片段可结晶结构域缺陷的抗 CD19 × 抗 CD3(blinatumomab)或抗 CD33 × 抗 CD3 双特异性抗体的人浆细胞能在体外介导 T 细胞活化并直接杀伤 B 型急性淋巴细胞白血病或急性髓性白血病细胞系。我们证明,敲除自身表达的抗原 CD19 会促进浆细胞分泌抗 CD19 双特异性抗体,并阻止自身靶向。分泌抗 CD19 双特异性抗体的浆细胞在免疫缺陷小鼠体内控制了与自体 T 细胞共同移植的急性淋巴细胞白血病患者衍生的异种移植物。在这些研究中,我们发现工程浆细胞诱导的白血病控制与 CD19 靶向嵌合抗原受体表达 T 细胞相似。最后,细胞递送和肿瘤根除1个月后,血清中抗CD19双特异性的稳态浓度与稳态输注blinatumomab治疗患者的浓度相当。这些研究结果支持进一步开发ePCs,将其用作治疗急性白血病和其他潜在癌症的持久递送系统。
Human plasma cells engineered to secrete bispecifics drive effective in vivo leukemia killing.
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.
期刊介绍:
Molecular Therapy is the leading journal for research in gene transfer, vector development, stem cell manipulation, and therapeutic interventions. It covers a broad spectrum of topics including genetic and acquired disease correction, vaccine development, pre-clinical validation, safety/efficacy studies, and clinical trials. With a focus on advancing genetics, medicine, and biotechnology, Molecular Therapy publishes peer-reviewed research, reviews, and commentaries to showcase the latest advancements in the field. With an impressive impact factor of 12.4 in 2022, it continues to attract top-tier contributions.