IgG subclasses: specificity and affinity for FcγR
Most FcγRs (Table 2) are weak, low‐affinity receptors (affinities in the micromolar range) for IgG‐Fc, irrespective of whether the IgG is uncomplexed, monomeric or when it is complexed with antigen (i.e. an immune complex). The very avid binding of immune complexes to an effector cell surface that displays an array of FcγR molecules is the result of the collective contributions of the low‐affinity interactions of each Fc of the IgGs in the complex with an FcγR. This avidity effect is necessary as the FcγRs operate in vivo in environments of high concentrations of uncomplexed monomeric IgG (normally 3–12 g L–1). Thus, the avid multivalent binding of the complex out competes uncomplexed, monomeric IgG. The notable exception to this is the enigmatic FcγRI. This receptor shows high, nanomolar affinity for uncomplexed monomeric IgG and thus would be expected to be constantly occupied in vivo by the normal circulating monomeric IgG. However, IgG dissociation permits engagement with immune complexes. Furthermore, FcγRI is not expressed or expressed poorly on resting cells, requiring interferon‐γ for induction of its expression, presumably at sites of inflammation.
Although the human IgG heavy‐chain constant domains have greater than 90% identity, key amino acid differences confer each subclass with unique structural and functional properties. IgG1 and IgG3 are “universal” ligands, that is, they bind to all FcγRs. Formal measurement of the weak, micromolar KD interactions of the low‐affinity receptors with monomeric IgG1 also revealed differing affinities between the low‐affinity FcγRs, with inhibitory FcγRIIb generally having the lowest affinity and FcγRIII the higher, sometimes referred to as a “moderate” affinity receptor.7, 61
The strength of IgG1 interaction can also be affected by FcγR polymorphism and in the context of therapeutic mAbs, variation in FcγRIIIa is particularly important. The most common and possibly clinically significant polymorphism is phenylalanine/valine variation at position 158 in the IgG‐binding site, wherein FcγRIIIa‐F158 binds IgG1 less well than the FcγRIIIa‐V158 form.
IgG4 and IgG2 have more restricted FcγR specificity. IgG4 has low affinity (KA = ~2 × 105 m –1) for the inhibitory FcγRIIb, but is also a high‐affinity ligand for FcγRI (KA = ~4 × 108 m –1). IgG2 exhibits a highly restricted specificity, showing functional activity with only one polymorphic form of FcγRIIa (binding affinity KA = ~4.5 × 105 m –1) which is permitted by the presence of histidine at position 131 of its IgG‐binding site. This FcγRIIa–H131 form is expressed in approximately 70% of the population, whereas IgG2 has no functional activity on the other common allelic form, FcγRIIa‐R131, which contains arginine at position 131.11, 61