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).