Ex-vivo CS1-OKT3 dual specific bivalent antibody-armed effector T cells mediate cellular immunity against multiple myeloma.
Ex-vivo CS1-OKT3 dual specific bivalent antibody-armed effector T cells mediate cellular immunity against multiple myeloma.
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DOI：
10.1038/s41598-023-47115-7
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发表时间：
2023-11-27
影响因子：
4.6
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中科院分区：
文献类型：
--
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双特异性T细胞接合抗体（bsAb）已经成为用于将T细胞重定向至抗原特异性肿瘤杀伤的新型且强大的治疗剂。细胞表面糖蛋白和SLAM家族成员CS 1在包括多发性骨髓瘤在内的恶性浆细胞上表现出稳定和高水平的表达，这表明bsAb治疗的理想靶点。在这里，我们使用点击化学开发了CS 1 bsAb（CS 1-dbBiTE），以在其各自的铰链区缀合完整的抗CS 1抗体（埃罗妥珠单抗）和抗huOKT 3抗体。使用细胞治疗方法，在检查效应子活性之前，用CS 1-dbBiTE离体武装人T细胞。我们的数据表明，用CS 1-dbBiTE武装T细胞诱导T细胞活化和扩增以及随后对携带CS 1的MM肿瘤的细胞毒性活性，这通过显著的CD 107 a表达以及炎性细胞因子分泌来证明。如预期的，CS 1-dbBiTE武装的T细胞在不存在CS 1表达的情况下显示出显著降低的效应子活性。同样，在MM小鼠异种移植物研究中，与对照组相比，装备的T细胞表现出有效的抗肿瘤疗效，突出表现为MM. 1 S荷瘤小鼠的肿瘤负荷降低。在这些发现的基础上，通过装备有CS 1-dbBiTE的人T细胞靶向CS 1的基本原理提出了靶向MM的潜在有效的治疗方法。
Bispecific T cell engaging antibodies (bsAbs) have emerged as novel and powerful therapeutic agents for redirecting T cells towards antigen-specific tumor killing. The cell surface glycoprotein and SLAM family member, CS1, exhibits stable and high-level expression on malignant plasma cells including multiple myeloma, which is indicative of an ideal target for bsAb therapy. Here, we developed a CS1 bsAb (CS1-dbBiTE) using Click chemistry to conjugate intact anti-CS1 antibody (Elotuzumab) and anti-huOKT3 antibody at their respective hinge regions. Using a cellular therapy approach, human T cells were armed ex-vivo with CS1-dbBiTE prior to examining effector activity. Our data indicates that arming T cells with CS1-dbBiTE induced T cell activation and expansion and subsequent cytotoxic activity against CS1-bearing MM tumors, demonstrated by significant CD107a expression as well as inflammatory cytokine secretion. As expected, CS1-dbBiTE armed T cells showed significantly reduced effector activity in the absence of CS1 expression. Similarly, in MM mouse xenograft studies, armed T cells exhibited effective anti-tumor efficacy highlighted by reduced tumor burden in MM.1S tumor-bearing mice compared to controls. On the basis of these findings, the rationale for CS1 targeting by human T cells armed with CS1-dbBiTE presents a potentially effective therapeutic approach for targeting MM.
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影响因子：
3.8
作者：
Kujawski, Maciej;Li, Lin;Shively, John E.
通讯作者：
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通讯作者：
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