Human Antibody Isotypes, Subclasses, Allotypes and Fc Biology: Clinical Implications in Infectious Diseases, Autoimmunity, and Cancer.

Therapeutic antibodies have transformed the management of infectious diseases, autoimmune disorders, and cancer, yet most approved agents continue to rely on a limited range of IgG-based Fc scaffolds. Consequently, the broader therapeutic potential of antibody isotypes, subclasses, allotypes, and host Fc receptor (FcR) genetics remains incompletely integrated into antibody design and clinical development. Emerging evidence indicates that these determinants profoundly influence effector function, pharmacokinetics, tissue distribution, immunogenicity, and therapeutic efficacy. This review provides a comprehensive, translational perspective on how antibody isotype selection, IgG subclass biology, allotypic variation, Fcγ receptor (FcγR) and neonatal Fc receptor (FcRn) genetics, and Fc engineering collectively shape therapeutic outcomes. Distinct from previous reviews that examine these factors individually, we integrate their roles across infectious diseases, autoimmunity, and cancer to identify common principles governing Fc-dependent immunity and therapeutic response. We further describe the clinical implications of Fc-mediated mechanisms, Fc glycoengineering, FcRn-targeted therapies, systems serology, and emerging non-IgG antibody platforms, highlighting both established applications and unresolved challenges. By unifying structural immunology, Fc pharmacology, host genetics, and disease biology, this review advances the concept of precision Fc pharmacology, in which antibody scaffold selection and Fc optimization are tailored to specific disease contexts and patient immune profiles. This framework provides a roadmap for the rational development of next-generation antibody therapeutics with improved efficacy, safety, and clinical precision.