Generating tolerance to antibody-based drugs

项目摘要 基于蛋白质的“生物”药物的蓬勃发展受到免疫原性的限制。 这些药物可能会刺激受体，对诱导耐受性的方法提出了无法满足的医学需求 给这些特工。我们最近在小鼠身上证明，将幼稚的T细胞暴露于β干扰素可以 有利于其分化为促炎Th1细胞或耐受性FOXP3+调节性T细胞 (Tregs)，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预处理可以将T细胞转化为耐受性表型 随后接触外来抗原，如生物药物。我们建议在人体内评估 多发性硬化症患者体内暴露于干扰素β对其幼稚T细胞的影响 接受这种细胞因子作为他们常规医疗护理的一部分。我们将评估这些细胞的表型。 在接下来的不同时间点，分化为激活时，以及它们的整体转录组 干扰素暴露，以确定干扰素预处理的适当时间间隔以在 人类。我们还建议在暴露于外源干扰素之前用β干扰素治疗健康和结肠炎小鼠。 抗体证明，干扰素预处理可降低后者的免疫原性。这部作品 将作为一个必要的临床前模型来支持干扰素预处理作为一种 在未来的临床试验中降低生物药物免疫原性的机制。

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.