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).