Optimising IgG effector function
IgG Fc-effector functions are mediated via complement and FcγRs which are either activating (FcγRI, FcγRIIa/IIc, FcγRIIIa, FcγRIIIb10) or inhibitory (FcγRIIb)11. Since most effector cells co-express both activating and inhibitory FcγRs, the outcome of IgG binding is a result of the relative binding affinity, receptor availability and signalling capacity. The relative receptor affinity is defined as the activating-to-inhibitory (A/I) ratio12(fig.3 ) and differs across IgG subclasses. Thus, depending on their A/I ratio, IgG subclasses can be defined as highly activating with strong Fc-effector function (IgG1, IgG3) or poorly activating with limited Fc-effector function (IgG2, IgG4)13. Although less relevant for effector functions, an additional IgG receptor is the neonatal Fc receptor (FcRn) which mediates IgG transport through the placenta as well as IgG cellular recycling, providing IgG with a relatively long serum half-life and thus favourable pharmacokinetic properties14. FcRn also binds albumin with similar effects14.
Currently, most of the clinically approved tumour-targeting mAbs are of IgG1 isotype which was shown to be superior to other isotypes and subclasses in inducing ADCC by mononuclear cells as well as CDC in vitro 15. IgG1 achieves most of its Fc-effector functions via FcγRIIIa present on macrophages and NK cells (ADCC, ADCP), as well as via complement activation16. Furthermore, IgG1 shows favourable biopharmaceutical characteristics with regard to production and purification. However, independent of their specificity all tumour-targeting IgG used hitherto in the clinic displayed a therapeutic effect only in a subset of patient. Therefore, over the years different strategies have been explored to further optimise tumour-targeting mAbs, many of which focused on improving Fc-mediated functions.