Elotuzumab, a potential therapeutic humanized anti-SLAMF7 monoclonal antibody, enhances natural killer cell-mediated killing of primary effusion lymphoma cells
Elotuzumab, a potential therapeutic humanized anti-SLAMF7 monoclonal antibody, enhances natural killer cell-mediated killing of primary effusion lymphoma cells
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Elotuzumab 是一种潜在的治疗性人源化抗 SLAMF7 单克隆抗体，可增强自然杀伤细胞介导的原发性渗出性淋巴瘤细胞杀伤作用
DOI：
10.1007/s00262-022-03177-6
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发表时间：
2022
期刊：
影响因子：
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通讯作者：
Okada Seiji
中科院分区：
文献类型：
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作者：
Panaampon Jutatip;Kariya Ryusho;Okada Seiji
原发性积液性淋巴瘤（PEL）是一种罕见的侵袭性b细胞非霍奇金淋巴瘤，目前尚无最佳治疗方法。信号淋巴细胞激活分子- f7 （SLAMF7, CD319）是一种在多发性骨髓瘤（MM）中高度表达的I型跨膜糖蛋白，是基于单克隆抗体的免疫治疗的一个有希望的靶点。SLAMF7也在包括NK细胞在内的几种造血细胞系上表达。Elotuzumab （Elo）是一种靶向SLAMF7的人源化抗体，已被FDA批准用于MM治疗。在这项研究中，我们分析了SLAMF7在7个PEL细胞系中的表达。所有PEL细胞和NK细胞均高表达SLAMF7。NK细胞通过MACS富集于健康供体pbmc，并在IL-2和IL-15存在下与mhc - I类阴性K562细胞共培养扩增。扩增的NK细胞显示直接杀伤，Elo以效应：靶（E:T）依赖的方式显示对PEL的有效ADCC。在ADCC过程中，NK细胞表面CD107a的表达也有所增加。我们还检测了NK亚群中SLAMF7的表达，发现CD56+CD16+NK亚群中SLAMF7的表达最高。全长elo而非F(ab ')2-Elo直接作用于NK细胞上表达的SLAMF7，促进CD107a的表达，进一步增强NK细胞对PEL的细胞毒性。Elo通过过继性转移人NK细胞提高携带pel的免疫缺陷小鼠的存活率。综上所述，我们的研究结果表明NK细胞在PEL杀伤中发挥作用，Elo引起ADCC/SLAMF7连接增强NK细胞对PEL的毒性，为Elo作为治疗PEL的单克隆抗体提供了有希望的临床前证据。
Primary effusion lymphoma (PEL) is a rare aggressive B-cell non-Hodgkin’s lymphoma with no optimal treatment. Signaling lymphocytic activation molecule-F7 (SLAMF7, CD319), a type I transmembrane glycoprotein highly expressed in multiple myeloma (MM), represents a promising target for mAb-based immunotherapy. SLAMF7 also expresses on several hematopoietic lineages including NK cells. Elotuzumab (Elo), a humanized antibody targeting SLAMF7, is approved by FDA for MM treatment. In this study, we analyzed the expression of SLAMF7 on seven PEL cell lines. All PEL cells and NK cells showed high expression of SLAMF7. NK cells were enriched from PBMCs of healthy donors by MACS and expanded by co-culturing with MHC-class I negative K562 cells in the presence of IL-2 and IL-15. Expanded NK cells showed direct killing, and Elo demonstrated potent ADCC against PEL in an Effector:Target (E:T) dependent manner. Surface expression of CD107a on NK cells also increased in the process of ADCC. We also examined SLAMF7 expression of NK subpopulations and found that the CD56+CD16+NK subpopulation demonstrated the highest SLAMF7 expression. Full-length-Elo but not F(ab’)2-Elo exerts direct engagement to the expressing SLAMF7 on NK cells, promotes CD107a expression, and further augments NK cytotoxicity toward PEL. Elo enhanced survival of PEL-bearing immunodeficient mice with adoptive transfer of human NK cells. Taken together, our results show that NK cells play roles in PEL killing, and Elo causes ADCC/SLAMF7 ligation to boost NK cytotoxicity against PEL, offering promising preclinical evidence of Elo as a therapeutic monoclonal antibody treatment for PEL.