Reducing Protein Immunogenicity by Design: Deimmunization and Tolerance Induction

Induction of T cell response is the root cause of the immunogenicity problem associated with protein therapeutics, whether those therapeutics are biosimilars, novel protein scaffolds or replacement therapies. In previous reports, we have described the link between the presence of effector T cell epitopes and clinical immunogenicity, an observation that is now well accepted by most protein therapeutics developers. Pre-clinical efforts are therefore directed towards modulating the presence of T cell epitopes in protein therapeutics by screening for epitopes and deimmunizing (removing T cell epitopes) prior to further development of the protein for clinical use. Of perhaps greater importance to the biotherapeutics field is the discovery of natural regulatory T cell epitopes in the sequence of therapeutic mAbs. These natural Treg epitopes (also known as Tregitopes) are promiscuous MHC Class II T cell epitopes located in the Fc and framework regions of IgG. The discovery of Tregitopes is of great relevance for the development of safer, more effective protein therapeutics, whether these proteins are monoclonal antibodies, novel scaffolds, replacement therapies or biosimilars. The presence or absence of Tregitopes and the number of potential effector epitopes in a protein therapeutic may determine its potential for clinical immunogenicity. These concepts are described in greater detail in this review.