Immunogenicity of protein therapeutics and the interplay between tolerance and antibody responses

Patients can mount sustained immune responses to protein therapeutics with the production of neutralizing antibodies (NAbs) that can compromise efficacy or safety of these drugs. Dendritic cells (DCs) are required for immunoglobulin (Ig) isotype switching and the production of IgG, a process involving presentation of MHC class 11 binding epitopes to helper T cells (CD4+ T cells) and subsequent B cell activation. DCs, CD4+ T cells and MHC class 11 binding epitopes are also involved in self-tolerance. While many assay formats are available for reliable antibody detection, the complex in vivo interplay between immunogenicity and tolerance hinders accurate pre-clinical predictions of protein drug immunogenicity to humans.