Plasma-cell depletion therapy for severe Graves' disease

严重格雷夫斯病的浆细胞耗竭疗法

基本信息

批准号：
MR/V005898/1
负责人：
Simon Pearce
金额：
$ 128.2万
依托单位：
Newcastle University
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2021
资助国家：
英国
起止时间：
2021 至无数据
项目状态：
未结题

来源：
https://gtr.ukri.org/projects?ref=MR%2FV005898%2F1
关键词：
Plasma cell depletion therapy severe

项目摘要

Graves' disease (autoimmune thyroid overactivity) affects around 3% of women over their life-time and gives symptoms such as heart palpitations, heat intolerance, unintended weight loss, enlarged thyroid, red and swollen eyelids, protuberant eyeballs and double vision. These symptoms are caused by an abnormal immune response leading to a circulating antibody (known as TRAb) that stimulates the thyroid gland and causes inflammation and growth of the tissues around the eyes. While many patients can be successfully treated with anti-thyroid drugs, these do not improve the eye problems. A sizeable minority of patients have severe Graves' disease, with more intense thyroid overactivity and worse eye inflammation, which is associated with blood TRAb levels that are ten times higher than normal. These people are not cured by medication and frequently have disabling eye disease and occasionally loss of vision. Currently these severe Graves' disease patients have their thyroid gland removed surgically, followed by several eye operations to correct the visual function and appearance of the eyes. These are expensive operations and overall, only 50% of NHS patients feel that the outcomes of such treatment are satisfactory. Better treatments are sorely needed.The TRAb antibodies that drive the thyroid and eye symptoms are produced by a type of white blood cell called a plasma cell, whose sole purpose is to make large quantities of antibodies. This project will find out whether a new treatment called daratumumab that has been developed to treat plasma cell cancer, could also be used to target the benign plasma cells in patients with severe Graves' disease. By removing plasma cells in Graves' disease, we would expect a reduction in the disease-causing TRAb antibody concentration and a rapid improvement in the thyroid overactivity and eye symptoms. This study will perform a 2-stage clinical trial of daratumumab in 30 patients with severe Graves' disease. Because daratumumab has not been used in Graves' disease before, the first part of our study will administer 4 different doses to small groups of participants to see which of the doses works best and has least side-effects. Then we will use these optimal daratumumab doses and a placebo to treat larger groups of patients. The daratumumab is given twice by intravenous infusion to each participant, and the thyroid and eye state of each person will be followed for 6 months afterwards. Our study could change the lives of many people with severe Graves' disease, who in the future might be able to have treatment with infusions of daratumumab, rather than several surgical operations. In addition, our study might open a door whereby daratumumab might be used to treat several other autoimmune conditions where abnormal antibodies also drive the disease process.

格雷夫斯病（自身免疫性甲状腺过度活跃）影响约 3% 的女性一生，并出现心悸、耐热、体重意外减轻、甲状腺肿大、眼睑红肿、眼球突出和复视等症状。这些症状是由异常免疫反应引起的，导致循环抗体（称为 TRAb）刺激甲状腺并导致眼睛周围组织发炎和生长。虽然许多患者可以使用抗甲状腺药物成功治疗，但这些药物并不能改善眼部问题。相当一部分患者患有严重的格雷夫斯病，甲状腺过度活跃和眼部炎症更严重，这与血液 TRAb 水平比正常值高十倍有关。这些人无法通过药物治愈，并且经常患有致残性眼病，有时甚至会丧失视力。目前，这些严重的格雷夫斯病患者通过手术切除了甲状腺，然后进行了多次眼部手术以矫正眼睛的视觉功能和外观。这些手术费用昂贵，总体而言，只有 50% 的 NHS 患者认为此类治疗的效果令人满意。迫切需要更好的治疗方法。引起甲状腺和眼部症状的 TRAb 抗体是由一种称为浆细胞的白细胞产生的，其唯一目的是产生大量抗体。该项目将查明一种名为 daratumumab 的新疗法是否也可以用于治疗严重格雷夫斯病患者的良性浆细胞，该疗法已被开发用于治疗浆细胞癌。通过去除格雷夫斯病中的浆细胞，我们预计会降低引起疾病的 TRAb 抗体浓度，并迅速改善甲状腺过度活跃和眼部症状。该研究将在 30 名患有严重格雷夫斯病的患者中进行 daratumumab 的 2 阶段临床试验。由于达拉妥尤单抗之前尚未用于治疗格雷夫斯病，因此我们研究的第一部分将向一小群参与者施用 4 种不同的剂量，以了解哪种剂量效果最好且副作用最少。然后我们将使用这些最佳达雷妥尤单抗剂量和安慰剂来治疗更大的患者群体。每位参与者通过静脉输注两次达雷妥尤单抗，之后将跟踪每个人的甲状腺和眼睛状态6个月。我们的研究可能会改变许多患有严重格雷夫斯病的人的生活，他们将来可能能够通过注射达雷妥尤单抗（daratumumab）进行治疗，而不是进行多次外科手术。此外，我们的研究可能打开一扇门，达拉妥尤单抗可用于治疗其他几种自身免疫性疾病，在这些疾病中，异常抗体也会驱动疾病进程。