靶向人白介素-6蛋白的治疗性单克隆抗体研究进展*

白介素-6(interleukin-6,IL-6)作为一种多效的细胞因子,参与机体内众多生理与病理过程。研究表明,IL-6首先与自身受体(IL-6R、gp130)形成异源六聚体复合物,进而激活下游信号转导通路,最终发挥生物学功能。 IL-6信号通路异常活化及功能失调与多种疾病密切相关,如自身免疫疾病、慢性炎症、恶性肿瘤等。另外IL-6的异常表达在新型冠状病毒肺炎(COVID-19)细胞因子风暴综合征(CSS)中也扮演重要角色。一般而言,阻断IL-6信号通路上的各关键节点,均可用于IL-6相关疾病的治疗。有别于阻断IL-6R或gp130等公共受体分子,阻断IL-6蛋白的治疗性单克隆抗体特异性更高,在临床研究中,部分品种显示出其独有的治疗特点及有益的疗效。现阶段只有1个靶向IL-6蛋白的单克隆抗体药物获美国FDA批准上市,以及超过8个治疗性单克隆抗体在临床研究阶段。重点对国内外靶向人IL-6蛋白的治疗性单克隆抗体及其临床应用进行综述。

Advances of Therapeutic Monoclonal Antibodies Targeting Human Interleukin-6 Protein

Interleukin-6 (IL-6) is a pleiotropic cytokine, which participates in many physiological and pathological functions. Studies have shown that IL-6 first forms a heterohexameric complex with its own receptors (IL-6R, gp130), which further activate downstream signal transduction pathways, and finally exerts biological functions. However, abnormal activation and dysfunction of IL-6 signaling pathway are closely related to a variety of diseases, such as autoimmune diseases, chronic inflammation, and malignant tumors. In addition, the abnormal expression of IL-6 also plays an important role in COVID-19’s cytokine storm syndrome (CSS). In general, treatments that block key molecules in the IL-6 signaling pathway can be used for IL-6-related diseases. Different from blocking shared receptor molecules such as IL-6R or gp130, therapeutic monoclonal antibodies that block IL-6 protein are more specific. In clinical research, some antibodies targeting IL-6 show their unique therapeutic characteristics and beneficial effects. At present, only one monoclonal antibody drug targeting IL-6 protein has been approved by the US FDA for marketing, and more than 8 therapeutic monoclonal antibodies are in the clinical research. This article focuses on a brief review of therapeutic monoclonal antibodies targeting human IL-6 protein around world and their clinical applications.