6 Role of the IgG subclass
Clinical efficacy of allergen-specific immunotherapy (AIT) or vaccination best correlates with increased levels of IgG4 in humans. Hence, it is generally assumed that IgG4 is the key IgG subclass for clinical outcomes. However, as pointed out previously27, the correlation between clinical efficacy and IgG4 may simply be due to the fact that the way we are currently performing immunotherapy is preferentially inducing IgG4 rather than other subclasses; mostly due to the absence of strong toll-like receptor or other innate ligands in the formulations. It should be noted that a correlation between clinical outcome and allergen-specific IgG4 has been reported in some but not all studies. Hence, IgG4 is not a validated biomarker28. Negative results may in part be due to suboptimal designs of conventional immunotherapy. Recently, however, it was demonstrated that IgG1 and IgG4 appeared in mucosal fluids after AIT with genetically modified allergens29. IgG subclass responses after to AIT are not fully understood to date and are therefore an active area of ongoing clinical research.
We compared the ability of 3 different mAbs against Fel d 1 expressed in a IgG1 or IgG4 format (exhibiting identical epitope specificities despite being expressed as IgG1 or IgG4) for their ability to block primary human basophil activation via allergen-neutralization or engagement of FcγRIIb27. Indeed, both antibody subclasses had the same ability to block basophil activation in a quantitative manner. These observations were confirmed when the affinity of the antibodies for recombinant FcγRIIb was assessed by Biolayer Interferometry showing similar affinities for IgG1 and IgG4. Hence, it seems that different IgG subclasses – at least IgG1 and IgG4 – are capable of similar allergen neutralization and FcγRIIb engagement. It is now planned to further assess the diversity and functionality of antibody profiles in response to a vaccine against peanut allergy which is in clinical development (PROTECT trial; ClinicalTrials.gov Identifier: NCT05476497).