Aspects of Isotype Selection

The history of isotype selection for therapeutic antibodies clearly demonstrates that solid understanding of the biologic effects mediated by immunoglobulin (Ig) subclasses IgG1, IgG2, IgG3, and IgG4 and their variants is a prerequisite for optimal antibody development. The choices of isotype-constant regions for full-length antibody generation are becoming more complex by the availability of engineered variants and, in some cases, mixed isotypes. This review focuses on important lessons from preclinical studies, and clinical trials, which underscore that careful selection of isotypes is critical given their differential effects on antibody function. The molecular requirements vary for different mechanisms of action of therapeutic antibodies (eg, neutralizing, agonistic, conjugated), and IgG properties beneficial for one mechanism might be detrimental for another. Key isotype selection principles for optimal antibody development are reviewed, and case studies are discussed.