美国耶鲁大学Kevan C. Herold研究小组的最新研究发现，一种抗CD3抗体，Teplizumab，可有效延缓高危人群患上1型糖尿病。这一研究成果于2019年8月15日发表在国际顶尖学术期刊《新英格兰医学杂志》上。

1型糖尿病是一种慢性自身免疫性疾病，可破坏生成胰岛素的β细胞，并依赖外源性胰岛素生存。一些干预措施可延缓1型糖尿病患者胰岛素分泌的减少，但在疾病确诊前就进行干预也是有必要的。

该课题组对1型糖尿病患者的亲属进行了一项临床2期、随机、双盲的对照试验，这些亲属没有糖尿病，但患病风险较高。这些参与者被随机分配到teplizumab组（44例）和安慰剂组（32例），治疗14天，并对1型糖尿病的临床进展进行随访，每隔6个月进行一次口服葡萄糖耐量试验。

Teplizumab组中确诊1型糖尿病的中位时间为48.4个月，安慰剂组为24.4个月；teplizumab组中有19例（43%）参与者患上1型糖尿病，而安慰剂组中有23例（72%）患病；teplizumab组与安慰剂组患上1型糖尿病的风险比为0.41。teplizumab组中糖尿病的年诊断率为14.9%，而安慰剂组为35.9%。teplizumab组的预期不良反应包括皮疹和暂时性淋巴减少症。与安慰剂组相比，teplizumab组中KLRG1+TIGIT+CD8+ T细胞更常见。在HLA-DR3阴性、HLA-DR4阳性或锌转运体8抗体阴性的参与者中，teplizumab组患糖尿病的人数显著少于安慰剂组。

综上，teplizumab可有效延缓高危人群患上1型糖尿病。

附：英文原文

Title: An Anti-CD3 Antibody, Teplizumab, in Relatives at Risk for Type 1 Diabetes

Author: Kevan C. Herold, M.D., Brian N. Bundy, Ph.D., S. Alice Long, Ph.D., Jeffrey A. Bluestone, Ph.D., Linda A. DiMeglio, M.D., Matthew J. Dufort, Ph.D., Stephen E. Gitelman, M.D., Peter A. Gottlieb, M.D., Jeffrey P. Krischer, Ph.D., Peter S. Linsley, Ph.D., Jennifer B. Marks, M.D., Wayne Moore, M.D., Ph.D., et al., for the Type 1 Diabetes TrialNet Study Group

Issue&Volume: VOL. 381 NO. 7. 15 August 2019

Abstract: 

BACKGROUND
Type 1 diabetes is a chronic autoimmune disease that leads to destruction of insulin-producing beta cells and dependence on exogenous insulin for survival. Some interventions have delayed the loss of insulin production in patients with type 1 diabetes, but interventions that might affect clinical progression before diagnosis are needed.

METHODS
We conducted a phase 2, randomized, placebo-controlled, double-blind trial of teplizumab (an Fc receptor–nonbinding anti-CD3 monoclonal antibody) involving relatives of patients with type 1 diabetes who did not have diabetes but were at high risk for development of clinical disease. Patients were randomly assigned to a single 14-day course of teplizumab or placebo, and follow-up for progression to clinical type 1 diabetes was performed with the use of oral glucose-tolerance tests at 6-month intervals.

RESULTS
A total of 76 participants (55 [72%] of whom were ≤18 years of age) underwent randomization — 44 to the teplizumab group and 32 to the placebo group. The median time to the diagnosis of type 1 diabetes was 48.4 months in the teplizumab group and 24.4 months in the placebo group; the disease was diagnosed in 19 (43%) of the participants who received teplizumab and in 23 (72%) of those who received placebo. The hazard ratio for the diagnosis of type 1 diabetes (teplizumab vs. placebo) was 0.41 (95% confidence interval, 0.22 to 0.78; P=0.006 by adjusted Cox proportional-hazards model). The annualized rates of diagnosis of diabetes were 14.9% per year in the teplizumab group and 35.9% per year in the placebo group. There were expected adverse events of rash and transient lymphopenia. KLRG1+TIGIT+CD8+ T cells were more common in the teplizumab group than in the placebo group. Among the participants who were HLA-DR3–negative, HLA-DR4–positive, or anti–zinc transporter 8 antibody–negative, fewer participants in the teplizumab group than in the placebo group had diabetes diagnosed.

CONCLUSIONS
Teplizumab delayed progression to clinical type 1 diabetes in high-risk participants. 

DOI: 10.1056/NEJMoa1902226

Source: https://www.nejm.org/doi/full/10.1056/NEJMoa1902226