Current Considerations for Immunoglobulin Isotype Characterization of Antibody Response against Biotherapeutics

The ability of biotherapeutics to induce immune response in patients has been broadly accepted. Humoral immune response to biotherapeutics is expected to be polyclonal in nature with a high degree of diversity, including treatment-induced anti-drug antibodies (ADA) immunoglobulin isotype composition. Therapeutics with strong potential to induce immunity may produce a T cell-dependent response resulting in a gradual transition from initial IgM based to mature, IgG-based ADAs. Immunoglobulin class switch and transition to high affinity IgG1 and IgG4 antibodies were linked to a reduced drug efficacy, accelerated clearance, development of drug neutralizing antibodies, and modulation of hypersensitivity reaction rates. Examples presented herein demonstrate that understanding of isotype composition of ADA response can be highly important to predict future of disease progression. Isotype characterization of ADA response can be viewed highly useful, particularly for high immunogenicity risk biotherapeutics although may be less relevant or used as a research tool only for medium and low immunogenicity risk level therapeutics. Isotype-specific characteristics, methods of detection, and several case studies are presented herein.