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Immunogenicity of therapeutic proteins and antibodies

​Head: Bernard Maillere

Published on 12 August 2022

​Therapeutic proteins and antibodies represent an ever-increasing share of drugs. Among the ten best-selling molecules in the world, eight are antibodies. These molecules have the advantage of being very specific to their target and not very toxic. On the other hand, they have the disadvantage of being potentially immunogenic, i.e. of triggering an immune response. The antibodies that patients might produce and that are directed against a therapeutic protein might decrease the pharmacokinetics of the protein, neutralize its therapeutic activity or trigger allergic or autoimmune symptoms. Because of the major role of CD4 T cells in the initiation and regulation of the immune response, the quantification of the repertoire of naive CD4 T cells specific to therapeutic molecules and the identification of the sequences that these cells recognize (T cell epitopes) allows us to better understand the origin of the immunogenicity of therapeutic molecules. By identifying the epitopes of several therapeutic antibodies, we have shown that the T cell epitopes of therapeutic antibodies are present in the mutated parts of the variable sequences (1-3). We have also demonstrated the existence of CD4 T cells specific for lowly expressed proteins in the body such as hormones and growth and replacement factors, explaining immunogenicity of their recombinant form (4-7). Current work focuses on the characterization of the diversity of the specific repertoires of therapeutic proteins, the effector or regulatory phenotype of CD4 T lymphocytes specific to therapeutic proteins as well as on the development of a strategy to create de-immunized molecules, i.e. no longer inducing an immune response.

​Main Publications
  1. Spindeldreher, S., A. Karle, E. Correia, M. Tenon, S. Gottlieb, T. Huber, B. Maillere, and F. Kolbinger. 2020. T cell epitope mapping of secukinumab and ixekizumab in healthy donors. mAbs 12: 1707418.
  2. Meunier, S., M. Hamze, A. Karle, M. de Bourayne, A. Gdoura, S. Spindeldreher, and B. Maillere. 2020. Impact of human sequences in variable domains of therapeutic antibodies on the location of CD4 T-cell epitopes. Cellular & molecular immunology 17: 656-658.
  3. Hamze, M., S. Meunier, A. Karle, A. Gdoura, A. Goudet, N. Szely, M. Pallardy, F. Carbonnel, S. Spindeldreher, X. Mariette, C. Miceli-Richard, and B. Maillere. 2017. Characterization of CD4 T Cell Epitopes of Infliximab and Rituximab Identified from Healthy Donors. Frontiers in immunology 8: 500.
  4. Meunier, S., M. de Bourayne, M. Hamze, A. Azam, E. Correia, C. Menier, and B. Maillere. 2020. Specificity of the T Cell Response to Protein Biopharmaceuticals. Frontiers in immunology 11: 1550.
  5. Azam, A., Y. Gallais, S. Mallart, S. Illiano, O. Duclos, C. Prades, and B. Maillere. 2019. Healthy Donors Exhibit a CD4 T Cell Repertoire Specific to the Immunogenic Human Hormone H2-Relaxin before Injection. J Immunol 202: 3507-3513.
  6. Meunier, S., C. Menier, E. Marcon, S. Lacroix-Desmazes, and B. Maillere. 2017. CD4 T cells specific for factor VIII are present at high frequency in healthy donors and comprise naive and memory cells. Blood advances 1: 1842-1847.
  7. Delluc, S., G. Ravot, and B. Maillere. 2010. Quantification of the preexisting CD4 T-cell repertoire specific for human erythropoietin reveals its immunogenicity potential. Blood 116: 4542-4545.