Abatacept for the treatment of Common Variable Immunodeficiency with Interstitial Lung Disease (ABCVILD) IND #152820 9/2/20

阿巴西普用于治疗常见变异性免疫缺陷伴间质性肺病 (ABCVILD) IND

• 批准号: 10281394
• 负责人: Michael Jordan
• 金额: $ 81.53万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-10 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10281394
• 关键词: Abatacept; treatment; Common; Variable; Immunodeficiency

Common variable immunodeficiency (CVID) affects approximately 10,000 people in the USA and is caused by an expanding array of genetic lesions. It is defined by international consensus criteria that may be summarized as loss of B cell function developing after infancy with or without a well-described constellation of autoimmune or lymphoproliferative complications. The development of a distinctive form of interstitial lung dis- ease, termed granulomatous-lymphocytic interstitial lung disease (GLILD), is particularly problematic in CVID because it is relatively common, associated with significant mortality and morbidity, and has an unmet need for adequate treatments. We found that the biologic drug abatacept showed good efficacy for reversal of severe, often refractory GLILD in a small series of patients with CVID. Abatacept is a recombinant fusion protein incor- porating CTLA-4 (cytotoxic T lymphocyte–associated protein 4) that blocks T cell activation by binding to CD80/CD86, thereby preventing CD28 engagement. Our findings suggest that abatacept would be an effec- tive therapy for GLILD in CVID. However, rigorous clinical trials are needed to prospectively define the risks and benefits of abatacept as a therapy for GLILD. To fill this critical gap, we have designed the ABCVILD trial. In this trial, we plan to treat with either pla- cebo or abatacept in a double-blinded fashion. Following a six-month blinded treatment phase, patients will enter a six-month open-label phase in which they will start or continue abatacept. On the basis of our clinical experience to date, we hypothesize that 6 months of abatacept therapy (compared to placebo) will clinically improve GLILD (as assessed by objective and QOL measures) across CVID genotypes and improve sCD25 and other exploratory biomarkers of T cell activation. We will test this hypothesis by pursuing these aims: Aim 1: Determine the response rate of GLILD after six months of abatacept therapy (versus placebo). Our readouts for the ABCVILD trial include quantitative assessment of chest CT scans, pulmonary function tests, quality of life measures, and radiation-free measure 129Xe magnetic resonance image (MRI). Aim 2: Determine whether genotype and/or lung histology predict GLILD responsiveness to abatacept therapy. As CD4+ T cells are often the most prominent infiltrating cells in GLILD and T follicular helper (Tfh) cells have been shown experimentally to be sensitive to CD28/CTLA4 manipulation, we hypothesize that GLILD is largely a disease of Tfh cells and that responsiveness will correlate with these cells in lesions. Aim 3: Define the utility of sCD25, abatacept pharmacokinetics, or exploratory biomarkers of T cell acti- vation for predicting response to therapy. We will serially assess sCD25, various exploratory biomarkers, and abatacept levels to test the predictive value of each, understand the effects of our adaptive dosing regimen on these parameters, and further test our hypothesize that GLILD is a consequence of inappropriate T cell activa- tion in patients with CVID.

普通变量免疫缺陷（CVID）在美国影响了大约10,000个peple，而IS是IS。 由于遗传病变不断扩大。 总结为婴儿期B细胞功能的丧失，有或没有很好的常数 自身免疫性或淋巴增生性汇编。 轻松称为肉芽肿 - 淋巴细胞间质性肺疾病（Glild），在CVID中尤其有问题 因为它相对普遍，与死亡率和病态的显着相关，并且对 充分治疗 在一系列的CVID患者中，经常耐火。 Porating CTLA-4（细胞毒性T淋巴细胞 - 相关蛋白4），该蛋白4）通过结合与T细胞活化。 CD80/CD86，从而防止CD28参与。 但是，需要对CVID的精灵疗法。 Abatacept作为高光的疗法的好处。 为了填补这个关键的空白，我们已经在这条小径上设计了abcvild小径。 在六个月的治疗阶段以双眼的方式，Cebo或Abatacept。 在我们的临床基础上输入六个月的开放标签阶段。 迄今为止的经验，我们假设6个月的Abatacept治疗 改善跨CVID基因型的高光（通过客观和QOL测量评估）并改善SCD25 和其他T细胞激活的探索性生物标志物。 AIM 1：确定六个月的Abatacept疗法（与安慰剂）后的高灵魂反应率。 我们对ABCVILD试验的读数包括对胸部CT扫描的定量评估，肺功能 测试，生活质量度量和无辐射测量的129倍磁共振图像（MRI）。 AIM 2：确定基因型和/或肺组织学是否预测对Abatacepttpt的高光反应 治疗。 已经显示了细胞对CD28/CTLA4操纵敏感的实验性，我们假设 高光在很大程度上是TFH细胞的一种疾病，这种反应能力将与病变中的这些细胞相关。 AIM 3：定义SCD25的效用，Abatacept药代动力学或T细胞活化的探索性生物标志物 预测对治疗的反应。 abatacept水平测试每个的预测价值，了解我们的自适应剂量方案的影响 这些参数，并进一步测试了我们假设的杂质是不适当的T细胞活化的结果 CVID患者的影响。