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The THP-1 cell line as a model for the assessment of monoclonal antibodies aggregates' immunological effects
Maria Lteif1, Sara Abratanska2, Isabelle Turbica1
1Université Paris Saclay, INSERM, Inflammation, Microbiome, Immunosurveillance, Faculté de Pharmacie, 91400 Orsay, France.
Immunogenicity is a major challenge to the development of biotherapeutics, and it is now well admitted that aggregation of therapeutic antibodies contributes to inducing an immunogenic response. The aim of this work was to investigate the THP-1 cell line as a model to evaluate antibodies (Ab) aggregates' immunological effects, by studying internalization and cell activation. We generated aggregates by submitting infliximab (IFX), an immunogenic anti-TNF-α chimeric Ab, to a heat stress for various time of incubation. Of importance, some IFX aggregates, that were generated in mild conditions, altered THP-1 phenotype. Our results also showed that IFX aggregates are more internalized by THP-1 compared to the native antibody. Larger IFX aggregates, in particular, were able to modify THP-1 cells phenotype through the activation of the FcγRIIa-Syk pathway and to activate Syk in a Src-dependent manner. ERK kinase was also activated. Taken together, our results highlight the possibility of using the THP-1 cell line to assess the biological effects of Abs aggregates by measuring membrane markers and internalization.
Immunogenicity is a major challenge to the development of biotherapeutics, and it is now well admitted that aggregation of therapeutic antibodies contributes to inducing an immunogenic response. The aim of this work was to investigate the THP-1 cell line as a model to evaluate antibodies (Ab) aggregates' immunological effects, by studying internalization and cell activation. We generated aggregates by submitting infliximab (IFX), an immunogenic anti-TNF-α chimeric Ab, to a heat stress for various time of incubation. Of importance, some IFX aggregates, that were generated in mild conditions, altered THP-1 phenotype. Our results also showed that IFX aggregates are more internalized by THP-1 compared to the native antibody. Larger IFX aggregates, in particular, were able to modify THP-1 cells phenotype through the activation of the FcγRIIa-Syk pathway and to activate Syk in a Src-dependent manner. ERK kinase was also activated. Taken together, our results highlight the possibility of using the THP-1 cell line to assess the biological effects of Abs aggregates by measuring membrane markers and internalization.
