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 这些药剂可从接受者中激发，从而呈现出对诱导耐受性的方法的未满足的医学需求 这些代理商。我们最近在小鼠中证明，将幼稚T细胞暴露于干扰素β可以 有利于它们分化为促炎性Th1细胞或致耐受性FOXP3+调节性T细胞 （T细胞），取决于干扰素暴露和T细胞活化之间的时间间隔。因此，我们假设 适当时间的干扰素β预处理可以驱使T细胞进入致耐受性表型， 随后暴露于外源抗原，如生物药物。我们建议在人类中评估 通过评估多发性硬化症患者的初始T细胞来评估体内暴露于干扰素β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 在激活后的不同时间点， 干扰素暴露，以确定干扰素预处理诱导凝血酶的适当时间间隔 人类我们还建议在暴露于外源性干扰素之前用干扰素β治疗健康和结肠炎小鼠。 抗体，以证明干扰素预处理可以降低后者的免疫原性。这项工作 将作为一个必要的临床前模型，以支持干扰素预处理的应用， 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.