Title:Glyco-Engineering of Human IgG-Fc to Modulate Biologic Activities
Volume: 17
Issue: 15
Author(s): Roy Jefferis
Affiliation:
Keywords:
Antibody therapeutics, cost-of-treatment, effector functions, function, glycosylation, human IgG structure, IgG
subclasses, recombinant antibodies, solubility, stability.
Abstract: Advances in genetic and protein engineering and the ability to maintain proliferating mammalian
cells in vitro, has allowed reverse engineering of antibodies, i.e. generation of antibodies having
specificity for self-antigens. Thus, the lethal consequence of horror autotoxicus, anti-self-responses as
envisaged by Paul Ehrlich (1854-1915), has been turned to advantage for treatment of multiple disease
states. In order to reap these benefits, it is essential that, in addition to target specificity, the antibody is
customised to deliver appropriate downstream biologic effector activities. Genetic engineering allows
the development of any chosen isotype; however, The IgG class predominates in human serum and the
majority of monoclonal antibody (mAb) therapeutics are based on the IgG format. This review focuses
on the structure and function of the four human IgG isotypes (subclasses) and the biologic functions that
their immune complexes activate through interactions with cellular Fc receptors (FcγR & FcRn) and/or
the C1q component of complement. The long catabolic half-life (~21 days) of IgG contributes to its efficacy
as a therapeutic. Each human IgG subclass exhibits a unique profile of biologic activities that are
dependent on the glycoform profile of the IgG-Fc. Our current understanding of IgG structure/function
relationships allows protein and glycosylation engineering of the IgG-Fc to enhance or eliminate biologic
activities and the generation of therapeutics optimal for a given disease indication.