肿瘤细胞治疗研究
英文原题：Targeting BCMA in multiple myeloma with a trifunctional NK cell engager.
这些发现支持SAR'514的进一步开发。
多发性骨髓瘤（MM）是第二常见的血液系统恶性肿瘤，目前仍无法治愈，凸显了对持久疗法的需求。自然杀伤（NK）细胞衔接器（NKCEs）是T细胞疗法的一种有前景的替代方案，具有强效抗肿瘤活性且细胞因子释放有限。SAR445514（SAR'514）是一种三功能NKCE，可同时衔接NKp46和FcγRIIIa以激活NK细胞，同时靶向MM细胞上的B细胞成熟抗原（BCMA）。在探索了多种具有不同BCMA和NKp46价态的分子形式后，我们选择了SAR'514，这是一种具有增强抗体依赖性细胞毒性（ADCC）的单价形式。SAR'514在体外和体内均具有强效且选择性的抗肿瘤活性，优于其他FcγRIIIa免疫细胞衔接器，同时与靶向同一抗原的T细胞衔接器相比，诱导的细胞因子释放极少。在离体实验中，SAR'514能有效激活MM患者的NK细胞，并诱导对自体恶性细胞的细胞毒性，包括对标准疗法耐药的细胞。这些发现支持SAR'514的进一步开发。
Multiple myeloma (MM), the second most common hematologic malignancy, remains incurable, highlighting the need for durable therapies. Natural killer (NK) cell engagers (NKCEs) represent a promising alternative to T cell therapies, offering potent anti-tumor activity with limited cytokine release. SAR445514 (SAR'514) is a trifunctional NKCE that co-engages NKp46 and FcγRIIIa to activate NK cells while targeting B cell maturation antigen (BCMA) on MM cells. After exploring several molecular formats with varied BCMA and NKp46 valency, we selected SAR'514, a monovalent format with enhanced antibody-dependent cellular cytotoxicity (ADCC). SAR'514 has potent and selective anti-tumor activity in vitro and in vivo, outperforming other FcγRIIIa-immune cell engagers, while inducing minimal cytokine release compared to T cell engagers targeting the same antigen. Ex vivo, SAR'514 efficiently activates NK cells from MM patients and induces cytotoxicity against autologous malignant cells, including those resistant to standard therapies. These findings support further development of SAR'514.
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