Ulitzka Michael, Harwardt Julia, Lipinski Britta, Tran Hue, Hock Björn, Kolmar Harald
Institute for Organic Chemistry and Biochemistry, Technical University of Darmstadt, Peter-Grünberg-Str. 4, 64287 Darmstadt, Germany.
Centre of Synthetic Biology, Technical University of Darmstadt, 64283 Darmstadt, Germany.
Molecules. 2024 Mar 4;29(5):1140. doi: 10.3390/molecules29051140.
Valued for their ability to rapidly kill multiple tumor cells in succession as well as their favorable safety profile, NK cells are of increasing interest in the field of immunotherapy. As their cytotoxic activity is controlled by a complex network of activating and inhibiting receptors, they offer a wide range of possible antigens to modulate their function by antibodies. In this work, we utilized our established common light chain (cLC)-based yeast surface display (YSD) screening procedure to isolate novel B7-H3 and TIGIT binding monoclonal antibodies. The chicken-derived antibodies showed single- to low-double-digit nanomolar affinities and were combined with a previously published CD16-binding Fab in a 2+1 format to generate a potent NK engaging molecule. In a straightforward, easily adjustable apoptosis assay, the construct B7-H3xCD16xTIGIT showed potent apoptosis induction in cancer cells. These results showcase the potential of the TIGIT NK checkpoint in combination with activating receptors to achieve increased cytotoxic activity.
自然杀伤（NK）细胞因其能够连续快速杀死多个肿瘤细胞以及良好的安全性而受到重视，在免疫治疗领域越来越受到关注。由于其细胞毒性活性受激活和抑制受体的复杂网络控制，它们提供了广泛的可能抗原，可通过抗体调节其功能。在这项工作中，我们利用已建立的基于共同轻链（cLC）的酵母表面展示（YSD）筛选程序，分离新型B7-H3和TIGIT结合单克隆抗体。鸡源抗体显示出单位数到低双位数纳摩尔的亲和力，并与先前发表的以2+1形式结合CD16的Fab片段组合，以产生一种有效的NK细胞接合分子。在一个简单、易于调整的凋亡试验中，构建体B7-H3xCD16xTIGIT在癌细胞中显示出强大的凋亡诱导作用。这些结果展示了TIGIT NK细胞检查点与激活受体结合以实现增强细胞毒性活性的潜力。
