IMMUNOGENICITY OF THERAPEUTIC PROTEINS

EDUARDO MUFARREGE; SOFÍA I. GIORGETTI; SONIA RICOTTI; MARINA ECHEVERRIGARAY

Río de Janeiro

Simposio; VIII Simposio Latinoamericano de Tecnología de Cultivos Celulares (SLATCC); 2018

Biologics are drugs widely used to treat several diseases. However, in some cases these products can trigger undesired immune responses that compromise the safety and efficacy of the therapy. Numerous factors may contribute to the overall product immunogenicity: dose, route and frequency of administration, contaminants, formulation, patient-related factors, B and T-cell epitopes.Among the mentioned factors, this talk will deepen in describing current methods for evaluating T-cell mediated immune responses. These strategies usually include an in silico analysis using immune-informatic algorithms to predict potential T-cell epitopes within the protein sequence. Then, in vitro assays are used to validate the predictions. The most used experimental platforms are based on human and mouse cell primary cultures. Even though human Peripheral Blood Mononuclear Cells (PBMC) constitutes a suitable source of immune cells, other specific cells such as macrophages or dendritic cells may also be included in these protocols to provide a better alternative in terms of antigen presentation.In addition, the use of animal models for in vivo studies will be discussed. Regarding this, H-2 KO transgenic mice expressing human MHC molecules (HLA) have shown more reliable immune responses than wild type mice constituting a suitable alternative for evaluating in vivo therapeutic protein immunogenicity.Finally, this presentation will describe how impurities derived from the manufacturing process that escape the purification procedures enhance the product immunogenicity. These entities were defined in the literature as Innate Immune Response Modulating Impurities (IIRMIs) and may lead to the development of neutralizing antibodies (NAbs) against the product and an exacerbated production of pro-inflammatory cytokines and chemokines.In conclusion, monitoring potential intrinsic product immunogenicity and contaminants that alone or in a synergistic manner may breakdown patient immune tolerance is essential during the product quality control process. This pre-clinical study provides valuable product safety information and may also accelerate the process of approval of therapeutic proteins.