Kamalinia Golnaz, Engel Brian J, Srinivasamani Anupallavi, Grindel Brian J, Ong Justin N, Curran Michael A, Takahashi Terry T, Millward Steven W, Roberts Richard W
Department of Chemistry, University of Southern California, Los Angeles, California 90089, United States.
Department of Cancer Systems Imaging, MD Anderson Cancer Center, Houston, Texas 77054, United States.
ACS Chem Biol. 2020 Jun 19;15(6):1630-1641. doi: 10.1021/acschembio.0c00264. Epub 2020 Apr 30.
Programmed death ligand 1 (PD-L1) is a critical immune checkpoint ligand whose overexpression on tumor cells provides a mechanism of escape from immune surveillance. The interaction between PD-L1 and PD-1 on T cell lymphocytes suppresses both T cell activation and effector function and is engaged by cancers to dampen antitumor immunity. Here, we used mRNA display to engineer an 18-residue linear peptide that binds to human PD-L1. This peptide, which we term SPAM (signal peptide-based affinity maturated ligand), is nonhomologous to known PD-L1 binding peptides and mAbs, with dissociation constants () of 119 and 67 nM for unglycosylated and glycosylated human PD-L1, respectively. The SPAM peptide is highly selective for human PD-L1 and shows no significant binding to either mouse PD-L1 or human PD-L2. Competition binding assays indicate that the SPAM peptide binding site overlaps with the binding site of PD-1 as well as therapeutic anti-PD-L1 antibodies. Taken together, these results suggest that the SPAM peptide specifically binds to human PD-L1 and could potentially serve as a PD-L1 affinity agent and PD-L1/PD-1 pathway modulator.
程序性死亡配体1（PD-L1）是一种关键的免疫检查点配体，其在肿瘤细胞上的过表达提供了一种逃避免疫监视的机制。PD-L1与T淋巴细胞上的PD-1之间的相互作用抑制了T细胞的活化和效应功能，癌症利用这种相互作用来削弱抗肿瘤免疫力。在此，我们利用mRNA展示技术设计了一种与人类PD-L1结合的18个氨基酸残基的线性肽。我们将这种肽命名为SPAM（基于信号肽的亲和力成熟配体），它与已知的PD-L1结合肽和单克隆抗体无同源性，对未糖基化和糖基化的人类PD-L1的解离常数（KD）分别为119 nM和67 nM。SPAM肽对人类PD-L1具有高度选择性，对小鼠PD-L1或人类PD-L2均无明显结合。竞争结合试验表明，SPAM肽的结合位点与PD-1以及治疗性抗PD-L1抗体的结合位点重叠。综上所述，这些结果表明SPAM肽能特异性结合人类PD-L1，并有可能作为一种PD-L1亲和剂和PD-L1/PD-1通路调节剂。
