Laboratory of Molecular Biology, Center for Cancer Research, NCI, NIH, Bethesda, MD 20892, USA.
Biomolecules. 2020 Sep 29;10(10):1387. doi: 10.3390/biom10101387.
Multiple myeloma (MM) is a B-cell malignancy that is incurable for a majority of patients. B-cell maturation antigen (BCMA) is a lineage-restricted differentiation protein highly expressed in multiple myeloma cells but not in other normal tissues except normal plasma B cells. Due to the restricted expression and being a cell surface membrane protein, BCMA is an ideal target for immunotherapy approaches in MM. Recombinant immunotoxins (RITs) are a novel class of protein therapeutics that are composed of the Fv or Fab portion of an antibody fused to a cytotoxic agent. RITs were produced by expressing plasmids encoding the components of the anti-BCMA RITs in followed by inclusion body preparation, solubilization, renaturation, and purification by column chromatography. The cytotoxic activity of RITs was tested in vitro by WST-8 assays using BCMA expressing cell lines and on cells isolated from MM patients. The in vivo efficacy of RITs was tested in a xenograft mouse model using BCMA expressing multiple myeloma cell lines. Anti-BCMA recombinant immunotoxins are very effective in killing myeloma cell lines and cells isolated from myeloma patients expressing BCMA. Two mouse models of myeloma showed that the anti-BCMA immunotoxins can produce a long-term complete response and warrant further preclinical development.
多发性骨髓瘤（MM）是一种不可治愈的 B 细胞恶性肿瘤，对于大多数患者来说。B 细胞成熟抗原（BCMA）是一种谱系受限的分化蛋白，在多发性骨髓瘤细胞中高度表达，但在其他正常组织中不表达，除了正常的浆细胞。由于表达受限且为细胞表面膜蛋白，BCMA 是 MM 免疫治疗方法的理想靶点。重组免疫毒素（RIT）是一类新型的蛋白质治疗药物，由抗体的 Fv 或 Fab 部分与细胞毒性剂融合而成。通过表达编码抗 BCMA RIT 成分的质粒，随后进行包涵体制备、溶解、复性和柱层析纯化，生产 RIT。通过使用表达 BCMA 的细胞系进行 WST-8 测定和对来自 MM 患者的细胞进行测定，在体外测试 RIT 的细胞毒性活性。在使用表达 BCMA 的多发性骨髓瘤细胞系的异种移植小鼠模型中测试 RIT 的体内疗效。抗 BCMA 重组免疫毒素在杀伤骨髓瘤细胞系和表达 BCMA 的骨髓瘤患者分离的细胞方面非常有效。两种骨髓瘤小鼠模型表明，抗 BCMA 免疫毒素可以产生长期完全缓解，并值得进一步进行临床前开发。
