Anti-TNF biologics have achieved great success in the treatment of autoimmune diseases and have been the most selling biologics on market. However, the anti-TNF biologics have shown some disadvantages such as poor efficacy to some patients and high risk of infection and malignancies during clinical application. Current anti-TNF biologics are antibodies or antibody fragments that bind to TNF-α and subsequently block both TNF-TNFR1 and TNF-TNFR2 signaling. Transgenic animal studies indicate that TNFR1 signaling is responsible for chronic inflammation and cell apoptosis whereas TNFR2 signaling regulates tissue regeneration and inflammation. Recent studies propose to selectively inhibit TNFR1 to enhance efficacy and avoid side effects. In this review, we introduce the biology of TNF-TNFR1 and TNF-TNFR2 signaling, the advantages of selective inhibition of TNF-TNFR1 signaling and research updates on the development of selective inhibitors for TNF-TNFR1 signaling. Antibodies, small molecules and aptamers that selectively inhibit TNFR1 have showed therapeutic potential and less side effects in preclinical studies. Development of selective inhibitors for TNFR1 is a good strategy to enhance the efficacy and reduce the side effects of anti-TNF inhibitors and will be a trend for next-generation of anti-TNF inhibitors.

抗 TNF 生物制剂在治疗自身免疫性疾病方面取得了巨大成功，一直是市场上最畅销的生物制剂。然而，抗TNF生物制剂在临床应用中存在对部分患者疗效差、感染和恶性肿瘤风险高等缺点。目前的抗 TNF 生物制剂是与 TNF-α 结合并随后阻断 TNF-TNFR1 和 TNF-TNFR2 信号传导的抗体或抗体片段。转基因动物研究表明，TNFR1 信号负责慢性炎症和细胞凋亡，而 TNFR2 信号调节组织再生和炎症。最近的研究提出选择性抑制 TNFR1 以提高疗效并避免副作用。在这篇综述中，我们介绍了 TNF-TNFR1 和 TNF-TNFR2 信号传导的生物学，TNF-TNFR1 信号选择性抑制的优势以及 TNF-TNFR1 信号选择性抑制剂开发的研究进展。在临床前研究中，选择性抑制 TNFR1 的抗体、小分子和适体已显示出治疗潜力和较少的副作用。开发TNFR1选择性抑制剂是提高抗TNF抑制剂疗效和降低副作用的良好策略，将成为下一代抗TNF抑制剂的发展趋势。