Internalization of therapeutic antibodies into dendritic cells as a risk factor for immunogenicity.

Autor:	Siegel M; Roche Pharma Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Basel, Basel, Switzerland., Bolender AL; Roche Pharma Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Munich, Penzberg, Germany., Ducret A; Roche Pharma Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Basel, Basel, Switzerland., Fraidling J; Roche Pharma Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Munich, Penzberg, Germany., Hartman K; Roche Pharma Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Basel, Basel, Switzerland., Looney CM; Roche Pharma Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Basel, Basel, Switzerland., Rohr O; Unité Propre de Recherche CNRS 9002 RNA, Université de Strasbourg, Strasbourg, France.; Institut Universitaire de Technologie Louis Pasteur, Université de Strasbourg, Schiltigheim, France., Hickling TP; Roche Pharma Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Basel, Basel, Switzerland., Kettenberger H; Roche Pharma Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Munich, Penzberg, Germany., Lechmann M; Roche Pharma Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Munich, Penzberg, Germany., Marban-Doran C; Roche Pharma Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Basel, Basel, Switzerland., Kraft TE; Roche Pharma Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Munich, Penzberg, Germany.
Jazyk:	angličtina
Zdroj:	Frontiers in immunology [Front Immunol] 2024 Aug 28; Vol. 15, pp. 1406643. Date of Electronic Publication: 2024 Aug 28 (Print Publication: 2024).
DOI:	10.3389/fimmu.2024.1406643
Abstrakt:	Introduction: Immunogenicity, the unwanted immune response triggered by therapeutic antibodies, poses significant challenges in biotherapeutic development. This response can lead to the production of anti-drug antibodies, potentially compromising the efficacy and safety of treatments. The internalization of therapeutic antibodies into dendritic cells (DCs) is a critical factor influencing immunogenicity. Using monoclonal antibodies, with differences in non-specific cellular uptake, as tools to explore the impact on the overall risk of immunogenicity, this study explores how internalization influences peptide presentation and subsequently T cell activation. Materials and Methods: To investigate the impact of antibody internalization on immunogenicity, untargeted toolantibodies with engineered positive or negative charge patches were utilized. Immature monocyte-derived DCs (moDCs), known for their physiologically relevant high endocytic activity, were employed for internalization assays, while mature moDCs were used for MHC-II associated peptide proteomics (MAPPs) assays. In addition to the lysosomal accumulation and peptide presentation, subsequent CD4+ T cell activation has been assessed. Consequently, a known CD4+ T cell epitope from ovalbumin was inserted into the tool antibodies to evaluate T cell activation on a single, shared epitope. Results: Antibodies with positive charge patches exhibited higher rates of lysosomal accumulation and epitope presentation compared to those with negative charge patches or neutral surface charge. Furthermore, a direct correlation between internalization rate and presentation on MHC-II molecules could be established. To explore the link between internalization, peptide presentation and CD4+ T cell activation, tool antibodies containing the same OVA epitope were used. Previous observations were not altered by the insertion of the OVA epitope and ultimately, an enhanced CD4+ T cell response correlated with increased internalization in DCs and peptide presentation. Discussion: These findings demonstrate that the biophysical properties of therapeutic antibodies, particularly surface charge, play a crucial role in their internalization into DCs. Antibodies internalized faster and processed by DCs, are also more prone to be presented on their surface leading to a higher risk of triggering an immune response. These insights underscore the importance of considering antibody surface charge and other properties that enhance cellular accumulation during the preclinical development of biotherapeutics to mitigate immunogenicity risks. Competing Interests: MS, A-LB, AD, JF, KH, CL, TH, HK, ML, CM-D and TEK were employed by Roche. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be constructed as a potential conflict of interest. The authors declared that they were an editorial board member of Frontiers, at the time of submission. (Copyright © 2024 Siegel, Bolender, Ducret, Fraidling, Hartman, Looney, Rohr, Hickling, Kettenberger, Lechmann, Marban-Doran and Kraft.)
Databáze:	MEDLINE
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