抗 CD3 抗体，特利珠单抗，用于 1 型糖尿病风险亲属。
An Anti-CD3 Antibody, Teplizumab, in Relatives at Risk for Type 1 Diabetes.
机构信息
From the Departments of Immunobiology and Internal Medicine, Yale University, New Haven, CT (K.C.H.); the Departments of Epidemiology and Pediatrics, University of South Florida, Tampa (B.N.B., J.P.K., H.R.), the Department of Medicine, University of Miami, Miami (J.B.M., J.S.S.), and the Department of Pediatrics, University of Florida, Gainesville (D.S.) - all in Florida; Benaroya Research Institute, Seattle (S.A.L., M.J.D., P.S.L., C.J.G.); the Diabetes Center, University of California at San Francisco, San Francisco (J.A.B., S.E.G.); the Department of Pediatrics, Indiana University, Indianapolis (L.A.D.); the Barbara Davis Diabetes Center, University of Colorado, Anschultz (P.A.G.); Children's Mercy Hospital, Kansas City, MO (W.M.); the Department of Pediatrics, University of Minnesota, Minneapolis (A.M.); the Department of Pediatrics and Cell and Developmental Biology, Vanderbilt University, Nashville (W.E.R.); the Department of Pediatrics, University of Iowa, Iowa City (E.T.); the Hospital for Sick Children, University of Toronto, Toronto (D.K.W.); and Forschergruppe Diabetes, Technical University Munich, at Klinikum rechts der Isar, Munich, Germany (A.-G.Z.).
出版信息
N Engl J Med. 2019 Aug 15;381(7):603-613. doi: 10.1056/NEJMoa1902226. Epub 2019 Jun 9.
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. (Funded by the National Institutes of Health and others; ClinicalTrials.gov number, NCT01030861.).
背景
1 型糖尿病是一种慢性自身免疫性疾病，可导致胰岛素产生细胞β的破坏，并依赖外源性胰岛素生存。一些干预措施已经延迟了 1 型糖尿病患者胰岛素分泌的损失，但需要在诊断前就可能影响临床进展的干预措施。
方法
我们进行了一项 2 期、随机、安慰剂对照、双盲试验，研究了 teplizumab（一种 Fc 受体非结合性抗 CD3 单克隆抗体）在 1 型糖尿病患者的亲属中的应用，这些亲属没有糖尿病，但有发生临床疾病的高风险。患者被随机分配接受为期 14 天的 teplizumab 或安慰剂治疗，通过每 6 个月进行口服葡萄糖耐量试验来随访进展为临床 1 型糖尿病。
结果
共有 76 名参与者（55 名[72%]年龄≤18 岁）接受了随机分组 - 44 名接受 teplizumab 治疗，32 名接受安慰剂治疗。teplizumab 组的中位时间为 48.4 个月，安慰剂组为 24.4 个月；接受 teplizumab 治疗的参与者中有 19 人（43%）和接受安慰剂治疗的参与者中有 23 人（72%）被诊断为 1 型糖尿病。1 型糖尿病的诊断（teplizumab 与安慰剂）的风险比为 0.41（95%置信区间，0.22 至 0.78；通过调整后的 Cox 比例风险模型，P=0.006）。teplizumab 组的年诊断率为 14.9%，安慰剂组为 35.9%。有预期的皮疹和短暂性淋巴细胞减少症的不良反应。与安慰剂组相比，teplizumab 组的 KLRG1+TIGIT+CD8+T 细胞更为常见。在 HLA-DR3 阴性、HLA-DR4 阳性或抗锌转运体 8 抗体阴性的参与者中，接受 teplizumab 治疗的参与者中被诊断为糖尿病的人数少于接受安慰剂治疗的参与者。
结论
teplizumab 延迟了高危参与者向临床 1 型糖尿病的进展。（由美国国立卫生研究院等资助；ClinicalTrials.gov 编号，NCT01030861）。
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