Title: Immunogenicity of therapeutic antibodies: Role of aggregation in T lymphocyte response
Abstract:
Immunogenicity has been described as a major concern to the clinical use of therapeutic antibodies, as treated patients frequently develop anti-drug antibodies (ADA) with potential neutralizing capacities leading to loss of clinical response. Among other factors, it is now well accepted that protein aggregation is associated with an enhanced potential for immunogenicity. Moreover, the presence of ADA suggests a CD4 T-cell dependent adaptive immune response and therefore a pivotal role for antigen presenting cells, such as dendritic cells.
This talk will focus on the optimization of in vitro methods to evaluate the potential of aggregated therapeutic antibodies to induce early adaptive immune responses that could drive ADA development.
We first developed a model of nano-sized, well-characterized infliximab (IFX) aggregates by exposing the native antibody to ultraviolet light. Then, using an original autologous co-culture model with monocyte-derived dendritic cells (moDC) and CD4 T cells, we identified a higher frequency of CD4 T cells specific of IFX aggregates compared to the native antibody. Even though IFX aggregates did not induce moDC maturation, they tend to be more internalized by healthy donors’ moDC compared to native IFX, with endocytosis being the main pathway. The implicated receptors and mechanisms are currently under investigation. Our results indicate that nano-sized aggregates have a significant role in immune system activation, emphasizing the importance of assessing the implicated cellular mechanisms that drive the immune response to aggregated proteins. In conclusion, cell-based assays are valuable tools to anticipate and prevent immunogenicity of therapeutic antibodies.
Audience Take Away Notes:
- Immunogenicity due to aggregation of therapeutic antibodies represent a significant challenge and our study highlights the importance of evaluating the immune effect of small aggregates as they could increase the probability of recruiting aggregate-recognizing CD4 T cells.
- Audience will learn information regarding the impact of therapeutic antibodies aggregates on innate and specific immune responses, and also some keys about the potential mechanisms that could give rise to immunogenicity.
- The presented data allow to gain insight the internalization and processing mechanisms of monoclonal antibodies by dendritic cells.
- In vitro cell-based models are non-clinical valuable tools for the assessment of therapeutic antibodies immunogenicity, and therefore can help for screening of therapeutic antibodies under development
