Section for Immunobiology , Joslin Diabetes Center , Boston , Massachusetts 02215 , United States.
Department of Medicine , Harvard Medical School , Boston , Massachusetts 02215 , United States.
Biochemistry. 2019 Oct 8;58(40):4107-4111. doi: 10.1021/acs.biochem.9b00707. Epub 2019 Sep 24.
Type 1 diabetes (T1D) is an autoimmune disease characterized by an insulin deficiency. Ever since the discovery of insulin almost 100 years ago, patients with T1D have relied on multiple daily insulin injections to survive an otherwise deadly disease. Despite decades of research and clinical trials, no treatment exists yet to prevent or cure T1D. A recent prevention trial using the anti-CD3 antibody teplizumab in individuals at a high risk of developing T1D has provided the first piece of evidence that a safe and transient intervention may be able to delay disease. In this Perspective, we review the 40-year long history of anti-CD3 and discuss how this antibody became a candidate for the treatment of autoimmune diabetes. The path that leads to its use in this latest clinical trial for T1D has been winding and strewn with setbacks. The molecular actions of the anti-CD3 antibody that target T lymphocytes are well-understood, but its systemic effect on immune function has proven more difficult to unravel. Moreover, preclinical data suggested that the utility of anti-CD3 for the prevention of T1D may be limited. However, the latest clinical data are encouraging and exemplify how a basic discovery can, decades later and with much perseverance, become a promising therapeutic candidate.
1 型糖尿病（T1D）是一种自身免疫性疾病，其特征是胰岛素缺乏。自从近 100 年前发现胰岛素以来，T1D 患者一直依赖多次每日胰岛素注射来维持生命，否则这种疾病是致命的。尽管经过几十年的研究和临床试验，仍然没有治疗方法可以预防或治愈 T1D。最近一项使用抗 CD3 抗体 teplizumab 对高风险发展为 T1D 的个体进行的预防试验提供了第一个证据，表明安全且短暂的干预可能能够延缓疾病。在这篇观点文章中，我们回顾了长达 40 年的抗 CD3 历史，并讨论了这种抗体如何成为治疗自身免疫性糖尿病的候选药物。该抗体在 T1D 最新临床试验中的应用之路曲折坎坷，充满挫折。针对 T 淋巴细胞的抗 CD3 抗体的分子作用已得到充分理解，但它对免疫功能的全身影响更难揭示。此外，临床前数据表明，抗 CD3 用于预防 T1D 的效用可能有限。然而，最新的临床数据令人鼓舞，它体现了一个基本发现如何在几十年后，通过不懈努力，成为一个有前途的治疗候选药物。
