An investigation into the mechanisms which underpin the modulation of immune responses by aggregation of biotherapeutic drugs

生物制药，特别是单克隆抗体（mab），在医学上广泛用于治疗一系列疾病，包括恶性疾病和一系列炎症。尽管单克隆抗体被设计成包含人类序列，但这些药物经常会引起免疫反应，导致抗药物抗体，进而阻断药物作用，或者在某些情况下，给患者带来更严重的医疗并发症。生物制药有能力打破自我耐受性的原因尚不清楚，但一个促成因素是聚集——形成无定形的、不规则的不同大小的蛋白质颗粒（纳米到微米范围）。这一建议建立在我们最近发表的观察结果的基础上，即在小鼠模型中聚集引起th1倾斜的免疫反应（Ratanji等人）。毒理学科学2016)。我们将以两种方式扩展这些观察结果。首先，我们需要扩展我们的研究，以涵盖更广泛的蛋白质，而不是我们迄今为止所研究的蛋白质。这将包括在临床使用中更能代表药物的生物治疗蛋白。其次，我们将研究支撑这种反应的分子机制，重点关注聚集对来自标准细胞系（THP-1）或分化的人外周血单核细胞的抗原呈递细胞（apc）对蛋白质的识别、内化、加工和呈递的影响。

Biopharmaceuticals, particularly monoclonal antibodies (MAbs), are widely used in medicine to treat a range of conditions, including malignant disease and a range of inflammatory conditions. Although MAbs are engineered to contain human sequences, these drugs can frequently elicit immune responses resulting in anti-drug antibodiesthat can, in turn, block drug action or, in some cases, give rise to more serious medical complications for the patient. The reasons why biopharmaceuticals have the ability to break self-tolerance are not well understood, but a contributory factor is aggregation- the formation of amorphous, irregular protein particles of varying sizes (nm to um range). This proposal builds on our recently published observation that aggregation causes a Th1-skewed immune response in a mouse model (Ratanji et al. Toxicological Sciences 2016). We will expand these observations in two ways. First, we need to extend our studies to embrace a wider range of proteins beyond those which we have studied to date. This will include biotherapeutic proteins which are more representative of drugs in clinical use. Second, we will investigate the molecular mechanisms which underpin this response, focusing on the influence of aggregation on the recognition, internalisation, processing and presentation of proteins by antigen presenting cells (APCs), derived from standard cell lines (THP-1), or from differentiated human peripheral blood monocytes .