Li Yumei, Wu Lingjun, Liu Yueying, Ma Siwen, Huang Biyi, Feng Xianjing, Wang Hui
School of Pharmacy, Guangxi Medical University, Nanning, China.
Department of Hypertension, The First Affiliated Hospital of Guangxi Medical University, Nanning, China.
Transl Oncol. 2022 Jul;21:101424. doi: 10.1016/j.tranon.2022.101424. Epub 2022 Apr 26.
Cancer is the most acute disease and the leading cause of patient death worldwide. Both chemotherapy and molecular-based therapies play an important role in curing cancer. However, the median and overall survival of patients is poor. To date, immune therapies have changed the treatment methods for cancer patients. Programmed death ligand 1 (PD-L1, also known as B-H1, CD274) is a well-studied tumor antigen. PD-L1 is overexpressed in colon cancer, lung cancer, and so on and plays a vital role in cancer development. In this study, anti-PD-L1 single-domain antibodies were identified from recombinant human PD-L1 (rhPD-L1)-immunized llamas. Then, we generated a novel multifunctional anti-PD-L1-CD16a-IL15 antibody targeting PD-L1-positive tumor cells. Anti-PD-L1-CD16a-IL15 was constructed by linking the Interleukin-2 (IL-2) signal peptide, anti-PD-L1 single domain antibody (anti-PD-L1-VHH) and anti-cluster of differentiation 16a single domain antibody (anti-CD16a-VHH), and Interleukin-15/Interleukin-15 receptor alpha (IL15/IL-15Rα). This anti-PD-L1-CD16a-IL15 fusion protein can be expressed and purified from HEK-293F cells. In vitro, our data showed that the anti-PD-L1-CD16a-IL15 fusion protein can recruit T cells and drive natural killer cells (NK) with specific killing of PD-L1-overexpressing tumor cells. Furthermore, in the xenograft model, the anti-PD-L1-CD16a-IL15 fusion protein inhibited tumor growth with human peripheral blood mononuclear cells (PBMCs). These data suggested that the anti-PD-L1-CD16a-IL15 fusion protein has a latent function in antitumour activity, with better guidance for future cancer immunotherapy.
癌症是全球最严重的疾病，也是患者死亡的主要原因。化疗和基于分子的疗法在治疗癌症方面都发挥着重要作用。然而，患者的中位生存期和总生存期都较差。迄今为止，免疫疗法改变了癌症患者的治疗方式。程序性死亡配体1（PD-L1，也称为B-H1、CD274）是一种经过充分研究的肿瘤抗原。PD-L1在结肠癌、肺癌等中过度表达，在癌症发展中起着至关重要的作用。在本研究中，从重组人PD-L1（rhPD-L1）免疫的羊驼中鉴定出抗PD-L1单域抗体。然后，我们构建了一种新型多功能抗PD-L1-CD16a-IL15抗体，靶向PD-L1阳性肿瘤细胞。抗PD-L1-CD16a-IL15是通过连接白细胞介素-2（IL-2）信号肽、抗PD-L1单域抗体（抗PD-L1-VHH）和抗分化簇16a单域抗体（抗CD16a-VHH）以及白细胞介素-15/白细胞介素-15受体α（IL15/IL-15Rα）构建而成。这种抗PD-L1-CD16a-IL15融合蛋白可以从HEK-293F细胞中表达和纯化。在体外，我们的数据表明，抗PD-L1-CD16a-IL15融合蛋白可以募集T细胞，并驱动自然杀伤细胞（NK）特异性杀伤PD-L1过表达的肿瘤细胞。此外，在异种移植模型中，抗PD-L1-CD16a-IL15融合蛋白与人外周血单个核细胞（PBMC）一起抑制了肿瘤生长。这些数据表明，抗PD-L1-CD16a-IL15融合蛋白在抗肿瘤活性方面具有潜在功能，为未来的癌症免疫治疗提供了更好的指导。
