Comparison of IgG1 and IgG4: A Structural and Molecular Perspective

ABSTRACT IgG1 and IgG4 monoclonal antibodies (mAbs) represent the two most widely used IgG subclasses in therapeutic applications due to their distinct effector functions, structural properties, and developability profiles. This review consolidates current knowledge on the molecular and physicochemical characteristics that differentiate IgG1 and IgG4. Differences in CH2 and CH3 domain composition, hinge region flexibility, and interchain disulfide architecture contribute to the subclasses′ divergent thermal unfolding profiles, charge variant distributions, and susceptibility to chemical degradation. Particular attention is given to site‐specific PTMs—such as deamidation, glycation, oxidation, isomerization and Fab‐arm exchange—that contribute to charge heterogeneity, stability, and functional outcomes. By integrating recent structural, analytical and in silico studies, this review links molecular determinants to therapeutic subclass selection, formulation strategy, viral inactivation resilience, and biosimilar comparability. Collectively, these insights provide a developability‐oriented framework for rational engineering and optimization of IgG1‐ and IgG4‐based therapeutics.