Isotype and glycoform selection for antibody therapeutics.

We live in a hostile environment but are protected by the innate and adaptive immune system. A major component of the latter is mediated by antibody molecules that bind to pathogens, with exquisite specificity, and the immune complex formed activates cellular mechanisms leading to the removal and destruction of the complex. Five classes of antibody are identified; however, the IgG class predominates in serum and a majority of monoclonal antibody (mAb) therapeutics are based on the IgG format. Selection within the antibody repertoire allows the generation of (mAb) having specificity for any selected target, including human antigens. This review focuses on the structure and function of the Fc region of IgG molecules that mediates biologic functions, within immune complexes, by interactions with cellular Fc receptors (FcγR) and/or the C1q component of complement. A property of IgG that is suited to its use as a therapeutic is the long catabolic half life of ~21 days, mediated through the structurally distinct neonatal Fc receptor (FcRn). Our understanding of structure/function relationships is such that we can contemplate engineering the IgG-Fc to enhance or eliminate biologic activities to generate therapeutics considered optimal for a given disease indication. There are four subclasses of human IgG that exhibit high sequence homology but a unique profile of biologic activities. The FcγR and the C1q binding functions are dependent on glycosylation of the IgG-Fc. Normal human serum IgG is comprised of multiple glycoforms and biologic activities, other than catabolism, varies between glycoforms.