Therapeutic Antibodies
Antibody biotechnology has made considerable progress in recent decades, particularly in the treatment of numerous pathologies, including autoimmune diseases. The antibodies produced can be highly effective, but particular attention must be paid to the risk that the antibody may cause an undesirable immune response (immunogenicity), which can range from reduced therapeutic efficacy to anaphylactic shock.
The Cellular Immunology and Biotechnology Laboratory (LICB, SIMoS, DMTS department) is developing strategies to reduce the immunogenicity of antibodies.
Reduce their immunogenicity
In a recent article published in Frontiers in Immunology, a team from the laboratory, in collaboration with the start-up Deeptope, a CEA spin-off, and the Butantan Institute (Brazil), presents a method for identifying sequence substitutions to make antibodies less immunogenic, by reducing their binding to HLA class II molecules, while preserving their ability to recognise their target.
The method is based on the one hand on the establishment in silico - in the form of heatmaps - of the interactions of substitute peptides with HLA II molecules using prediction software. It also relies on Deep Mutational Scanning to identify experimentally in vitro the amino acid substitutions that are tolerated and the positions that should not be changed to maintain good interaction between the antibody and the antigen.
The team applied its approach to adalimumab, a human anti-TNFa antibody prescribed for the treatment of chronic inflammatory diseases such as rheumatoid arthritis and Crohn's disease, which provokes an immune response in almost a third of patients treated.
Using their method, the researchers identified no fewer than 200 mutants with a lower affinity than adalimumab for HLA II molecules. Three mutants were produced in the form of whole antibodies and showed better affinity and better neutralisation of TNFa than adalimumab.
Contacts for the Frédéric-Joliot Institute for Life sciences: