Generating tolerance to antibody-based drugs

产生对抗体药物的耐受性

• 批准号: 9258339
• 负责人: Steven F Ziegler
• 金额: $ 25.5万
• 依托单位: BENAROYA RESEARCH INST AT VIRGINIA MASON
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-16 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9258339
• 关键词: Antibodies; Antigens; Biological Products; CD4 Positive T Lymphocytes; Caring; Cell Differentiation process; Cell Surface Receptors; Cell physiology; Clinical Trials; Development; Disease; Effectiveness; Exposure to; FOXP3 gene; Flowers; Future; Hormones; Human; Immune; Immune Tolerance; Immune system; Inflammation; Inflammatory; Interferon Type I; Interferon-beta; Interferons; Mediating; Medical; Methods; Mus; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Phenotype; Poly C; Poly I-C; Pre-Clinical Model; Proteins; Regulatory T-Lymphocyte; Safety; T cell differentiation; T-Cell Activation; T-Lymphocyte; Th1 Cells; Time; Work; adalimumab; base; clinical care; clinical practice; cytokine; immunogenicity; immunoreaction; in vivo; multiple sclerosis patient; neutralizing antibody; prevent; time interval; transcriptome

Project Summary The blossoming pharmaceutical field of protein-based “biologic” drugs has been limited by the immunogenicity these agents can provoke from recipients, presenting an unmet medical need for methods to induce tolerance to these agents. We have recently demonstrated in mice that exposure of naïve T cells to interferon beta can favor their differentiation into either pro-inflammatory Th1 cells or tolerogenic FOXP3+ regulatory T cells (Tregs), depending on the time interval between interferon exposure and T cell activation. Thus, we postulate that appropriately-timed interferon beta pretreatment can drive T cells into a tolerogenic phenotype upon subsequent exposure to a foreign antigen, such as a biologic drug. We propose to evaluate in humans the effect of in vivo exposure to interferon beta by evaluating the naïve T cells from multiple sclerosis patients who receive this cytokine as part of their regular medical care. We will evaluate the phenotype such cells differentiate into upon activation, as well as their overall transcriptome, at different time points following interferon exposure, to define the appropriate time interval for interferon pretreatment to induce Tregs in humans. We also propose to treat healthy and colitic mice with interferon beta prior to exposure to exogenous antibodies to demonstrate that interferon pretreatment can reduce the immunogenicity of the latter. This work will serve as a necessary preclinical model to support the application of interferon pretreatment as a mechanism to reduce biologic drug immunogenicity in a future clinical trial.

项目概要 基于蛋白质的“生物”药物蓬勃发展的制药领域受到免疫原性的限制 这些药物可能会引起接受者的反应，从而对诱导耐受性的方法提出了未满足的医疗需求 我们最近在小鼠身上证明，将幼稚 T 细胞暴露于干扰素 β 可以起到作用。 有利于它们分化为促炎性 Th1 细胞或耐受性 FOXP3+ 调节性 T 细胞 （Treg），取决于干扰素暴露和 T 细胞激活之间的时间间隔。因此，我们假设。 适当时机的干扰素β预处理可以驱动T细胞进入耐受表型 随后暴露于外来抗原，例如生物药物，我们建议在人体中进行评估。 通过评估来自多发性硬化症患者的初始 T 细胞来观察体内暴露于干扰素 β 的影响 接受这种细胞因子作为其常规医疗护理的一部分，我们将评估此类细胞的表型。 分化为激活后的不同时间点以及其整体转录组 干扰素暴露，以确定干扰素预处理诱导 Tregs 的适当时间间隔 我们还建议在接触外源性小鼠之前用干扰素β治疗健康小鼠和患有结肠炎的小鼠。 抗体来证明干扰素预处理可以降低后者的免疫原性。 将作为必要的临床前模型来支持干扰素预处理作为 在未来的临床试验中降低生物药物免疫原性的机制。