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

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 .