THE ISSUE OF THERAPEUTIC ANTIBODIES
The introduction of biopharmaceuticals (BPs) or biomedicines [1] is a true therapeutic revolution and has already brought clear clinical benefits to patients suffering from chronic inflammatory diseases such as rheumatoid arthritis, Crohn's disease and certain cancers. However, this type of treatment is confronted with the problem of the immunogenicity of BPs, i.e., their capacity to trigger an immune response that results mainly into the production of antibodies directed against them (anti-drug antibodies), thus diminishing their effectiveness. Monoclonal antibodies [2] are one of the most developed classes of biomedicines for which the problem of immunogenicity remains a major obstacle to their use in the clinic.
A SOLUTION ?
Pegylation [3] of BPs is the most common strategy to increase their half-life in blood and is associated with reduced immunogenicity. In this study, researchers investigated the response of T cells to certolizumab, a monoclonal antibody fragment directed against a protein produced in excess during Crohn's disease, TNFα [4], in its pegylated (certolizumab pegol, CZP) or non-pegylated (CZNP) form. T cells are the lymphocytes involved in the initiation of immune responses and, in particular, the anti-drug antibodies response. These cells are stimulated by the presence of immunogenic molecules and by other cells called dendritic cells. The researchers show that pegylation reduces the uptake of certolizumab pegol by dendritic cells and its ability to stimulate T cells. Pegylation therefore decreases the activation signals that initiate the anti-drug antibodies response.
Demonstrating the mechanisms leading to lower immunogenicity of pegylated certolizumab compared to its non-pegylated form should be useful and promising for the development of new therapeutic antibodies.
Contact : Bernard Maillère (bernard.maillere@cea.fr)
See also : Frédéric Joliot Institute for Life Sciences - Evaluation of the immunogenicity of peptide-drugs containing non-natural modifications (cea.fr)
[1] Biomedicines have the particularity of being produced from a living biological source such as cells or bacteria.
[2] Monoclonal antibodies are produced in vitro by cells selected in culture for their ability to produce an antibody directed against a single antigen (molecule foreign to our body). More than 30 therapeutic monoclonal antibodies are marketed in France (source: Vidal)
[3] Pegylation is the chemical coupling (conjugation) of polyethylene glycol (PEG) chains, a high molecular weight organic molecule, to biologically active molecules.
[4] TNFalpha (Tumor Necrosis Factor) is a molecule involved in inflammatory processes and immune reactions.