Abstract：
The development of immune cell engagers (ICEs) can be limited by logistical and functional restrictions associated with fusion protein designs, thus limiting immune cell recruitment to solid tumors. Herein, a high affinity superantigen-based multivalent ICE is developed for simultaneous activation and recruitment of NK and T cells for tumor treatment. Yeast library-based directed evolution is adopted to identify superantigen variants possessing enhanced binding affinity to immunoreceptors expressed on human T cells and NK cells. High-affinity superantigens exhibiting improved immune-stimulatory activities are then incorporated into a superantigen-based tri-functional yeast-display-enhanced multivalent immune cell engager (STYMIE), which is functionalized with a nanobody, a Neo-2/15 cytokine, and an Fc domain for tumor targeting, immune stimulation, and prolonged circulation, respectively. Intravenous administration of STYMIE enhances NK and T cell recruitment into solid tumors, leading to enhanced inhibition in multiple tumor models. The study offers design principles for multifunctional ICEs.
摘要：
免疫细胞衔接剂（ICE）的发展可能受到与融合蛋白设计相关的后勤和功能限制的限制。从而限制了实体瘤的免疫细胞募集。在这里，开发了一种高亲和力的基于超抗原的多价ICE，用于同时激活和募集NK和T细胞以治疗肿瘤。采用基于酵母文库的定向进化来鉴定对在人T细胞和NK细胞上表达的免疫受体具有增强的结合亲和力的超抗原变体。然后将表现出改善的免疫刺激活性的高亲和力超抗原掺入基于超抗原的三功能酵母展示增强的多价免疫细胞接合器（STYMIE）中，用纳米体功能化，Neo-2/15细胞因子，和用于肿瘤靶向的Fc结构域，免疫刺激，和延长的循环，分别。STYMIE静脉给药可增强NK和T细胞募集至实体瘤，在多种肿瘤模型中导致抑制增强。该研究提供了多功能ICE的设计原则。
