PDF(Pubmed)
Abstract：
SOT101 is a superagonist fusion protein of interleukin (IL)-15 and the IL-15 receptor α (IL-15Rα) sushi+ domain, representing a promising clinical candidate for the treatment of cancer. SOT101 among other immune cells specifically stimulates natural killer (NK) cells and memory CD8+ T cells with no significant expansion or activation of the regulatory T cell compartment. In this study, we showed that SOT101 induced expression of cytotoxic receptors NKp30, DNAM-1 and NKG2D on human NK cells. SOT101 stimulated dose-dependent proliferation and the relative expansion of both major subsets of human NK cells, CD56brightCD16- and CD56dimCD16+, and these displayed an enhanced cytotoxicity in vitro. Using human PBMCs and isolated NK cells, we showed that SOT101 added concomitantly or used for immune cell pre-stimulation potentiated clinically approved monoclonal antibodies Cetuximab, Daratumumab and Obinutuzumab in killing of tumor cells in vitro. The anti-tumor efficacy of SOT101 in combination with Daratumumab was assessed in a solid multiple myeloma xenograft in CB17 SCID mouse model testing several combination schedules of administration in the early and late therapeutic setting of established tumors in vivo. SOT101 and Daratumumab monotherapies decreased with various efficacy tumor growth in vivo in dependence on the advancement of the tumor development. The combination of both drugs showed the strongest anti-tumor efficacy. Specifically, the sequencing of both drugs did not matter in the early therapeutic setting where a complete tumor regression was observed in all animals. In the late therapeutic treatment of established tumors Daratumumab followed by SOT101 administration or a concomitant administration of both drugs showed a significant anti-tumor efficacy over the respective monotherapies. These results suggest that SOT101 might significantly augment the anti-tumor activity of therapeutic antibodies by increasing NK cell-mediated activity in patients. These results support the evaluation of SOT101 in combination with Daratumumab in clinical studies and present a rationale for an optimal clinical dosing schedule selection.
摘要：
SOT101是白细胞介素（IL）-15和IL-15受体α（IL-15Rα）寿司结构域的超激动剂融合蛋白，代表一个有希望的临床候选治疗癌症。在其他免疫细胞中,SOT101特异性地刺激自然杀伤(NK)细胞和记忆CD8+T细胞,而没有显著的调节性T细胞区室的扩增或活化。在这项研究中,我们显示SOT101诱导人NK细胞上细胞毒性受体NKp30，DNAM-1和NKG2D的表达。SOT101刺激剂量依赖性增殖和人类NK细胞的两个主要亚群的相对扩增，CD56brightCD16-和CD56dimCD16+，这些在体外表现出增强的细胞毒性。使用人类PBMC和分离的NK细胞，我们表明，SOT101同时添加或用于免疫细胞预刺激增强临床批准的单克隆抗体西妥昔单抗，Daratumumab和Obinutuzumab体外杀伤肿瘤细胞。在CB17SCID小鼠模型中的固体多发性骨髓瘤异种移植物中评估了SOT101与Daratumumab的组合的抗肿瘤功效,测试了在体内建立的肿瘤的早期和晚期治疗环境中的几种组合施用方案。SOT101和Daratumumab单一疗法依赖于肿瘤发展的进展而降低了体内肿瘤生长的各种功效。两种药物的组合显示出最强的抗肿瘤功效。具体来说,在所有动物均观察到肿瘤完全消退的早期治疗环境中,两种药物的测序并不重要.在已建立的肿瘤Daratumumab的晚期治疗性治疗中,随后施用SOT101或同时施用两种药物显示出相对于各自的单一疗法的显著抗肿瘤功效。这些结果表明，SOT101可能通过增加患者NK细胞介导的活性来显着增强治疗性抗体的抗肿瘤活性。这些结果支持在临床研究中对SOT101与Daratumumab的组合进行评估，并提出了最佳临床给药方案选择的基本原理。
