6 Role of the IgG subclass
Clinical efficacy of allergen-specific immunotherapy or vaccination best correlates with increased levels of IgG4 over IgG1 in human. Hence, it is generally assumed that IgG4 is the key IgG subclass for clinical outcome. However, as pointed out previously, 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 27; 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. IgG4 is not a validated biomarker 28. Negative results may in part be due to suboptimal designs of conventional immunotherapy. However, more recently, it was demonstrated that IgG1 and IgG4 appeared in mucosal fluids after AIT with genetically modified allergens, an active area of ongoing clinical research29.
We compared the ability of 3 different mAbs against Fel d 1 expressed in a IgG1 or IgG4 format (exhibiting identical epitope specificities despite expressed as IgG1 and IgG4) for their ability to block primary human basophil activation via allergen-neutralization or engagement of FcγRIIb 27. 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 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).