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.