CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
英文原题：Affibody-based hBCMA x CD16 dual engagers for NK cell-mediated killing of multiple myeloma cells.
Affibody-based hBCMA x CD16 dual engagers for NK cell-mediated killing of multiple myeloma cells.
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本文介绍了迄今最小的自然杀伤（NK）细胞重定向双特异性衔接器——人 B 细胞成熟抗原（hBCMA）×CD16 双靶衔接器的开发和表征。该衔接器基于小型、58 个氨基酸、非免疫球蛋白类 affibody 亲和蛋白组合，有望用于治疗多发性骨髓瘤。研究人员通过噬菌体展示，从组合文库中筛选人 CD16a 结合 affibody，鉴定出 3 种独特结合分子，其与 CD16a 的亲和力（KD）约为 100 nM 至 3 μM。亲和力最高的 affibody 对 CD16a 158F/V 同种异型不敏感，也不会干扰 IgG（Fc）与 CD16a 结合。为构建 hBCMA×CD16 双靶衔接器，研究人员将不同的 CD16a 结合臂（包括双位点 affibody 组合）与高亲和力 hBCMA 特异性 affibody 进行基因融合。所得 15–23 kDa 双靶衔接器可同时结合 hBCMA 和 CD16a，有效活化静息状态的人原代 NK 细胞，并触发其对一组 hBCMA 阳性多发性骨髓瘤细胞系的特异性裂解。
因此，本研究报告了一类新型、体积独特小巧的 NK 细胞衔接器，具有特异性结合特性和强效功能表现。
We describe the development and characterization of the (to date) smallest Natural Killer (NK) cell re-directing human B Cell Maturation Antigen (hBCMA) x CD16 dual engagers for potential treatment of multiple myeloma, based on combinations of small 58 amino acid, non-immunoglobulin, affibody affinity proteins. Affibody molecules to human CD16a were selected from a combinatorial library by phage display resulting in the identification of three unique binders with affinities (K D ) for CD16a in the range of 100 nM-3 M. The affibody exhibiting the highest affinity demonstrated insensitivity towards the CD16a allotype (158F/V) and did not interfere with IgG (Fc) binding to CD16a.
For the construction of hBCMA x CD16 dual engagers, different CD16a binding arms, including bi-paratopic affibody combinations, were genetically fused to a high-affinity hBCMA-specific affibody. Such 15-23 kDa dual engager constructs showed simultaneous hBCMA and CD16a binding ability and could efficiently activate resting primary NK cells and trigger specific lysis of a panel of hBCMA-positive multiple myeloma cell lines. Hence, we report a novel class of uniquely small NK cell engagers with specific binding properties and potent functional profiles.
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