CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
英文原题：Half-Life Extended Nanobody-Based CD38-Specific Bispecific Killercell Engagers Induce Killing of Multiple Myeloma Cells.
Half-Life Extended Nanobody-Based CD38-Specific Bispecific Killercell Engagers Induce Killing of Multiple Myeloma Cells.
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CD38是多发性骨髓瘤免疫治疗的靶点。源自羊驼的CD38特异性纳米抗体易于重新格式化为单特异性、双特异性和多特异性蛋白。为评估纳米抗体用于构建CD38特异性纳米抗体基杀伤细胞衔接器（nano-BiKEs）的实用性，我们将CD38特异性纳米抗体与CD16特异性纳米抗体融合以结合NK细胞上的Fc受体，并进一步与白蛋白特异性纳米抗体融合以延长体内半衰期，从而生成了半衰期延长的nano-BiKEs（HLE-nano-BiKEs）。靶向CD38三个不同表位（E1、E2、E3）的HLE-nano-BiKEs在瞬时转染的HEK-6E细胞中表达。
我们验证了其与骨髓瘤细胞上的CD38、NK细胞上的CD16以及白蛋白的特异性且同时结合。我们以NK92细胞作为效应细胞，在生物发光和流式细胞术检测中测试了这些HLE-nano-BiKEs介导针对表达CD38的多发性骨髓瘤细胞系及来自人骨髓活检的原代骨髓瘤细胞的细胞毒性的能力。
结果显示，对CD38+骨髓瘤细胞系具有特异性的时间和剂量依赖性细胞裂解作用，并能有效清除原代人骨髓样本中表达CD38的多发性骨髓瘤细胞。
我们的结果证明了CD38特异性HLE-nano-BiKEs在体外和离体中的疗效，值得进一步开展体内临床前评估其治疗多发性骨髓瘤的治疗潜力。
CD38 is a target for immunotherapy of multiple myeloma. Llama-derived CD38-specific nanobodies allow easy reformatting into mono-, bi- and multispecific proteins.
To evaluate the utility of nanobodies for constructing CD38-specific nanobody-based killer cell engagers (nano-BiKEs), we generated half-life extended nano-BiKEs (HLE-nano-BiKEs) by fusing a CD38-specific nanobody to a CD16-specific nanobody for binding to the Fc-receptor on NK cells and further to an albumin-specific nanobody to extend the half-life in vivo . HLE-nano-BiKEs targeting three different epitopes (E1, E2, E3) of CD38 were expressed in transiently transfected HEK-6E cells.
We verified specific and simultaneous binding to CD38 on myeloma cells, CD16 on NK cells, and to albumin.
We tested the capacity of these HLE-nano-BiKEs to mediate cytotoxicity against CD38-expressing multiple myeloma cell lines and primary myeloma cells from human bone marrow biopsies in bioluminescence and flowcytometry assays with NK92 cells as effector cells. The results revealed specific time- and dose-dependent cytolysis of CD38+ myeloma cell lines and effective depletion of CD38-expressing multiple myeloma cells from primary human bone marrow samples.
Our results demonstrate the efficacy of CD38-specific HLE-nano-BiKEs in vitro and ex vivo , warranting further preclinical evaluation in vivo of their therapeutic potential for the treatment of multiple myeloma.
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